TY - CONF TI - Characterization of a prototype transmit 2 MHz receive 21 MHz array for superharmonic imaging AU - Newsome, Isabel G. AU - Lindsey, Brooks D. AU - Shelton, Sarah E. AU - Cherin, Emmanuel AU - Yin, Jianhua AU - Foster, F. Stuart AU - Dayton, Paul A. T2 - 2017 IEEE International Ultrasonics Symposium (IUS) AB - The role of angiogenesis in cancer has spurred the development of new methods for imaging vasculature. One such method is acoustic angiography, a dual-frequency superharmonic contrast imaging technique. Custom transducers are necessary for the ultra-wide bandwidth required for this technique, but the current single-element designs present several limitations for translation to clinical use, such as a fixed focus and limited frame rates. In this work, we present initial tests of a dual-frequency array for superharmonic contrast-enhanced microvascular imaging. The array was characterized by in vitro measurements, including imaging of microcellulose tubes in water and phantom material. C2 - 2017/9// C3 - 2017 IEEE International Ultrasonics Symposium (IUS) DA - 2017/9// DO - 10.1109/ultsym.2017.8092707 PB - IEEE UR - http://dx.doi.org/10.1109/ultsym.2017.8092707 ER - TY - CONF TI - Which properties of the vascular architecture are reflected by dynamic contrast-enhanced ultrasound imaging of dispersion and wash-in rate? A comparison with acoustic angiography AU - Panfilova, Anastasiia AU - Shelton, Sarah AU - van Sloun, Ruud J G AU - Caresio, Cristina AU - Wijkstra, Hessel AU - Dayton, Paul AU - Mischi, Massimo T2 - 2017 IEEE International Ultrasonics Symposium (IUS) AB - Tumor growth requires formation of new angiogenic vessels, which differ in their morphology from those of healthy tissue. These vascular abnormalities result in altered blood flow dynamics, which can be assessed by dynamic contrast-enhanced ultrasound (DCE-US). Two distinct approaches are typically employed in DCE-US following an intravenous injection of ultrasound contrast agent: assessment of perfusion or dispersion parameters from the measured time intensity curves [1]. In this paper, we compare maps of dispersion and perfusion with those of acoustic angiography (AA), a 3D high-resolution technique capable of capturing the vascular morphology [2]. We aim at determining those properties of the vascular architecture that are reflected by perfusion and dispersion parameters, as well as their evolution over time as tumor grows. To this end, a longitudinal study has been performed with tumor models in 3 rats. C2 - 2017/9// C3 - 2017 IEEE International Ultrasonics Symposium (IUS) DA - 2017/9// DO - 10.1109/ultsym.2017.8092873 PB - IEEE UR - http://dx.doi.org/10.1109/ultsym.2017.8092873 ER - TY - JOUR TI - Metaplastic Cells in the Stomach Arise, Independently of Stem Cells, via Dedifferentiation or Transdifferentiation of Chief Cells. T2 - Gastroenterology AB - Spasmolytic polypeptide-expressing metaplasia (SPEM) develops in patients with chronic atrophic gastritis due to infection with Helicobacter pylori; it might be a precursor to intestinal metaplasia and gastric adenocarcinoma. Lineage tracing experiments of the gastric corpus in mice have not established whether SPEM derives from proliferating stem cells or differentiated, post-mitotic zymogenic chief cells in the gland base. We investigated whether differentiated cells can give rise to SPEM using a nongenetic approach in mice. Mice were given intraperitoneal injections of 5-fluorouracil, which blocked gastric cell proliferation, plus tamoxifen to induce SPEM. Based on analyses of molecular and histologic markers, we found SPEM developed even in the absence of cell proliferation. SPEM therefore did not arise from stem cells. In histologic analyses of gastric resection specimens from 10 patients with adenocarcinoma, we found normal zymogenic chief cells that were transitioning into SPEM cells only in gland bases, rather than the proliferative stem cell zone. Our findings indicate that SPEM can arise by direct reprogramming of existing cells-mainly of chief cells. DA - 2017/12/14/ PY - 2017/12/14/ DO - 10.1053/j.gastro.2017.11.278 UR - http://europepmc.org/articles/PMC5847468 ER - TY - JOUR TI - Unintended targeting of Dmp1-Cre reveals a critical role for Bmpr1a signaling in the gastrointestinal mesenchyme of adult mice AU - Lim, J. AU - Burclaff, J. AU - He, G. AU - Mills, J.C. AU - Long, F. T2 - Bone Research AB - Cre/loxP technology has been widely used to study cell type-specific functions of genes. Proper interpretation of such data critically depends on a clear understanding of the tissue specificity of Cre expression. The Dmp1-Cre mouse, expressing Cre from a 14-kb DNA fragment of the mouse Dmp1 gene, has become a common tool for studying gene function in osteocytes, but the presumed cell specificity is yet to be fully established. By using the Ai9 reporter line that expresses a red fluorescent protein upon Cre recombination, we find that in 2-month-old mice, Dmp1-Cre targets not only osteocytes within the bone matrix but also osteoblasts on the bone surface and preosteoblasts at the metaphyseal chondro-osseous junction. In the bone marrow, Cre activity is evident in certain stromal cells adjacent to the blood vessels, but not in adipocytes. Outside the skeleton, Dmp1-Cre marks not only the skeletal muscle fibers, certain cells in the cerebellum and the hindbrain but also gastric and intestinal mesenchymal cells that express Pdgfra. Confirming the utility of Dmp1-Cre in the gastrointestinal mesenchyme, deletion of Bmpr1a with Dmp1-Cre causes numerous large polyps along the gastrointestinal tract, consistent with prior work involving inhibition of BMP signaling. Thus, caution needs to be exercised when using Dmp1-Cre because it targets not only the osteoblast lineage at an earlier stage than previously appreciated, but also a number of non-skeletal cell types. DA - 2017/// PY - 2017/// DO - 10.1038/boneres.2016.49 VL - 5 UR - http://www.scopus.com/inward/record.url?eid=2-s2.0-85011306014&partnerID=MN8TOARS ER - TY - JOUR TI - Targeted Apoptosis of Parietal Cells Is Insufficient to Induce Metaplasia in Stomach AU - Burclaff, J. AU - Osaki, L.H. AU - Liu, D. AU - Goldenring, J.R. AU - Mills, J.C. T2 - Gastroenterology AB - Parietal cell atrophy is considered to cause metaplasia in the stomach. We developed mice that express the diphtheria toxin receptor specifically in parietal cells to induce their death, and found this to increase proliferation in the normal stem cell zone and neck but not to cause metaplastic reprogramming of chief cells. Furthermore, the metaplasia-inducing agents tamoxifen or DMP-777 still induced metaplasia even after previous destruction of parietal cells by diphtheria toxin. Atrophy of parietal cells alone therefore is not sufficient to induce metaplasia: completion of metaplastic reprogramming of chief cells requires mechanisms beyond parietal cell injury or death. Parietal cell atrophy is considered to cause metaplasia in the stomach. We developed mice that express the diphtheria toxin receptor specifically in parietal cells to induce their death, and found this to increase proliferation in the normal stem cell zone and neck but not to cause metaplastic reprogramming of chief cells. Furthermore, the metaplasia-inducing agents tamoxifen or DMP-777 still induced metaplasia even after previous destruction of parietal cells by diphtheria toxin. Atrophy of parietal cells alone therefore is not sufficient to induce metaplasia: completion of metaplastic reprogramming of chief cells requires mechanisms beyond parietal cell injury or death. Gastric metaplasia consistently occurs after parietal cell atrophy in autoimmune gastritis patients,1Adams J.F. et al.Lancet. 1964; 1: 401-403Abstract PubMed Scopus (27) Google Scholar in Helicobacter pylori–induced atrophic gastritis,2Lennerz J.K. et al.Am J Pathol. 2010; 177: 1514-1533Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar and in animal models of acute injury.3Huh W.J. Khurana S.S. et al.Gastroenterology. 2012; 142: 21-24.e27Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar, 4Nomura S. Yamaguchi H. et al.Am J Physiol Gastrointest Liver Physiol. 2005; 288: G362-G375Crossref PubMed Scopus (120) Google Scholar Thus, it has been proposed that parietal cell death causes metaplasia, perhaps because parietal cells elaborate gastric-differentiation–promoting factors whose loss elicits aberrant (metaplastic) differentiation of remaining cells. Alternatively, parietal cell death could cause a metaplasia-promoting immune response, or injured parietal cells might release metaplasia-promoting factors before dying. Here, to test the role of parietal cells in metaplasia, we developed a method to precisely kill parietal cells in adults. We bred parietal cell–specific, Cre-inducible simian diphtheria toxin receptor (Atp4b-Cre;LSL-DTR) mice (DTR mice) (Supplementary Figure 1), in which parietal cells alone respond to apoptosis-inducing diphtheria toxin. As a positive control for parietal cell atrophy and spasmolytic polypeptide-expressing metaplasia (SPEM), the metaplasia seen in direct temporal and spatial correlation with human and mouse parietal cell atrophy,2Lennerz J.K. et al.Am J Pathol. 2010; 177: 1514-1533Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar we used a previously described system3Huh W.J. Khurana S.S. et al.Gastroenterology. 2012; 142: 21-24.e27Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar, 5Saenz J.B. et al.Methods Mol Biol. 2016; 1422: 329-339Crossref PubMed Google Scholar, 6Matsuo J. et al.Gastroenterology. 2017; 152: 218-231.e14Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar involving 3 daily injections of high-dose (5 mg/20 g body mass) tamoxifen (TAM). Consistent with previous results, TAM caused more than 90% parietal cell atrophy and increased proliferation throughout the gastric unit. The pathognomonic pattern for SPEM was identified in more than 75% of units: gastric intrinsic factor (GIF+) chief cells at the unit base co-expressing the epitope for the Griffonia simplicifolia lectin II (GSII). Many SPEM cells were proliferative (Figure 1A and B, yellow arrowheads). Three daily injections with 225 ng DT also killed more than 90% of parietal cells and increased proliferation from the isthmus through the neck (Figure 1A–C). Both atrophy and proliferation were maintained for up to 14 days, whereas complete recovery occurred at that time point if injections were ceased at day 3 (Figure 1C). To confirm that DT directly targeted parietal cells, we grew gastroids from DTR × Rosa26/loxP-membrane tdTomato-loxP-membrane green fluorescent protein (mTmG) reporter mice in which DTR-expressing parietal cells also express membrane-associated enhanced green fluorescent protein (eGFP) (Supplementary Figure 1). Control gastroids showed negligible death (Supplementary Figure 2), whereas DT caused specific extrusion of enhanced GFP+ cells without change in gastroid size or number. Thus, DT specifically kills parietal cells. In contrast to TAM, DT never caused substantial SPEM at any time point (N > 40 total mice examined). Proliferation occurred in the isthmus and neck, but not in the base (Figure 1A and B). SPEM is thought to arise in part from re-entry of chief cells into the cell cycle.7Mills J.C. Sansom O.J. Sci Signal. 2015; 8: re8Crossref PubMed Scopus (95) Google Scholar, 8Nam K.T. et al.Gastroenterology. 2010; 139: 2028-2037 e2029Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar We observed that chief cells after TAM had the expected simple columnar morphology, with scant GIF observed in SPEM cells, whereas chief cells after DT maintained largely normal morphology with apical GIF granules still apparent, even through day 14 (Figure 1D and Supplementary Figure 3A). We quantified neck cells (GSII+), chief cells (GIF+), and GSII+/GIF+ cells, and their proliferative activity (Figure 1E and F). DT did not significantly change GIF+ or GSII+/GIF+ cell census vs control; however, TAM caused loss of chief cells and increased co-staining cells. DT and TAM both increased proliferation in unlabeled isthmal and neck cells, whereas TAM also increased proliferating, GSII+/GIF+ SPEM cells. We next analyzed additional markers of SPEM. The mouse ortholog of CD44 variant 9,9Wada T. et al.Cancer Sci. 2013; 104: 1323-1329Crossref PubMed Scopus (64) Google Scholar neck cell marker trefoil factor 2 (TFF2), and secreted SPEM marker Clusterin10Weis V.G. et al.Gut. 2013; 62: 1270-1279Crossref PubMed Scopus (75) Google Scholar all were increased only in the proliferative neck of DT-treated mice, whereas TAM increased expression in both the neck and base (Supplementary Figure 3B–D). Thus, by all markers, parietal cell apoptosis alone was insufficient to cause metaplasia. We next performed quantitative analyses of normal and metaplastic differentiation markers. GIF and the critical chief cell differentiation factor MIST1 (BHLHA15) decreased across the gastric corpus in DT mice; however, both were substantially lower in TAM mice (Supplementary Figure 4). SPEM markers Clusterin and HE4 (Wfdc2)11Nozaki K. et al.Gastroenterology. 2008; 134: 511-522Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar also were increased significantly only after TAM (Supplementary Figure 4). TAM alone caused significantly increased expression of 6 other genes involved in metaplasia and the immune response (Cd14, Ceacam10, Cftr, Ctss, Dmbt1, and Vil1), with both treatments increasing proliferation-related transcripts (Ccnb2 and Chek2) (Supplementary Figure 4). These results argued against the model wherein parietal cells constitutively elaborate differentiation-promoting factors because chief cells were maintained after parietal cell death. However, it still was possible that parietal cell atrophy caused metaplasia: perhaps parietal cells dying via H pylori infection or TAM, but not DT, release metaplasia-inducing signals when injured. If true, metaplasia should not occur in mice with parietal cells already killed. Thus, we injected DTR mice with DT to kill parietal cells first and then co-injected DT and TAM for 3 days (DT+TAM). Five days of DT injection caused increased isthmal/neck proliferation without SPEM; however, TAM after DT caused proliferative SPEM similar to TAM alone (Figure 2A–C). Similar results were obtained with another atrophy/SPEM-inducing agent: DMP-777 ([S-(R∗,S∗)]-N-[1-(1,3-benzodioxol-5-yl)butyl]-3,3-diethyl-2- [4-[(4-methyl-1-piperazinyl)carbonyl]phenoxy]-4-oxo-1-azetidine carboxamide).4Nomura S. Yamaguchi H. et al.Am J Physiol Gastrointest Liver Physiol. 2005; 288: G362-G375Crossref PubMed Scopus (120) Google Scholar DMP-777 treatment caused SPEM equally effectively even with parietal cells already killed (Figure 2D–F and Supplementary Figure 5). Therefore, SPEM can occur without substances released from injured parietal cells. Overall, our results show that parietal cell atrophy alone is insufficient to induce metaplasia, and signals from injured/dying parietal cells are not necessary for metaplasia induction. In addition, DTR mice increased proliferation only in the isthmal progenitor zone and neck, whereas TAM/DMP777 treatment showed these plus proliferative basal metaplastic cells. The number of metaplastic (GIF+/GSII+) cells arising in the base was approximately equivalent to the decrease in differentiated GIF+ GSII− only chief cells (Figure 1E and F). Thus, parietal cell atrophy alone can cause isthmal stem cell and mucous neck cell proliferation; however, the rapid emergence of basal metaplastic cells likely involves an additional basal cellular source. Our results, therefore, favor a model (supported by Matsuo et al6Matsuo J. et al.Gastroenterology. 2017; 152: 218-231.e14Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar) identifying 2 distinct zones of proliferation that can expand during injury: the isthmus/neck,12Hayakawa Y. Ariyama H. et al.Cancer Cell. 2015; 28: 800-814Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar, 13Khurana S.S. et al.J Biol Chem. 2013; 288: 16085-16097Crossref PubMed Scopus (85) Google Scholar and a more mature cell of the chief cell lineage that reprograms to co-label with neck cell markers and re-enter the cell cycle.6Matsuo J. et al.Gastroenterology. 2017; 152: 218-231.e14Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, 7Mills J.C. Sansom O.J. Sci Signal. 2015; 8: re8Crossref PubMed Scopus (95) Google Scholar, 8Nam K.T. et al.Gastroenterology. 2010; 139: 2028-2037 e2029Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar The re-entry of differentiated secretory cells to serve as progenitors resonates with emerging work on pancreatic acinar cell plasticity and quiescent intestinal stem cells.7Mills J.C. Sansom O.J. Sci Signal. 2015; 8: re8Crossref PubMed Scopus (95) Google Scholar Earlier work showed that, with constitutive absence of parietal cells throughout development, mature chief cells never emerge, and gastric units show abundant isthmal, pre-neck, neck, and neck/chief co-labeled cells.14Li Q. et al.J Biol Chem. 1996; 271: 3671-3676Crossref PubMed Scopus (184) Google Scholar It is unclear whether that signifies SPEM or simply a failure of units without parietal cells to ever adopt the adult pattern with distinct neck and chief cell zones (juvenile gastric units are SPEM-like15Keeley T.M. Samuelson L.C. Am J Physiol Gastrointest Liver Physiol. 2010; 299: G1241-G1251Crossref PubMed Scopus (41) Google Scholar). The usefulness of those mice as a model for adult-onset atrophy/metaplasia thus may be limited. Future progress in understanding the process of chief cell reprogramming will require a system allowing perpetual induced parietal cell atrophy to determine if long-term parietal cell absence is sufficient to induce SPEM. In any case, our current results suggest that parietal cell loss alone is insufficient to directly induce SPEM and that metaplasia induction may require additional unidentified factors (eg, cytokines or specific immune cell activation) that recruit chief cells back into the cell cycle. Joseph Burclaff was responsible for the study concept and design, data acquisition, analysis, and interpretation of all mouse work, and drafting the manuscript; Luciana H. Osaki and Dengqun Liu were responsible for data collection and analysis; James R. Goldenring performed data interpretation, supplied a reagent, and edited the manuscript; and Jason C. Mills was responsible for the study concept and design, analysis and interpretation of data, statistical analysis, funding, supervision, and editing. All experiments involving animals were performed according to protocols approved by the Washington University School of Medicine Animal Studies Committee. Mice were maintained in a specified pathogen-free barrier facility under a 12-hour light cycle. Wild-type C57BL/6, Gt(ROSA)26Sortm1(HBEGF)Awai (inducible DTR),1Buch T. et al.Nat Methods. 2005; 2: 419-426Crossref PubMed Scopus (600) Google Scholar and B6.129(Cg)-Gt(ROSA)26Sortm4(ACTB-tdTomato,-EGFP)Luo/J (mT/mG)2Muzumdar M.D. et al.Genesis. 2007; 45: 593-605Crossref PubMed Scopus (2258) Google Scholar mice all were purchased from Jackson Laboratories (Bar Harbor, ME). ATP4b-Cre mice3Syder A.J. et al.Proc Natl Acad Sci U S A. 2004; 101: 4471-4476Crossref PubMed Scopus (87) Google Scholar were crossed with inducible DTR mice, which express the inducible simian diphtheria toxin receptor under the control of the Rosa26 promoter. Littermate controls were housed together when possible to minimize differences in gastric microflora. To selectively kill parietal cells, diphtheria toxin (225 ng/mouse; Sigma, St Louis, MO) was injected intraperitoneally 1 or 3 times per day. Because parietal cells die at a comparable rate with those previously published with D3 TAM, most analysis was performed at day 3 of DT. Diphtheria toxin was dissolved in sterile 0.9% sodium chloride saline. To induce SPEM, tamoxifen (5 mg/20 g body weight; Toronto Research Chemicals, Inc, Toronto, Canada) was injected intraperitoneally daily for 3 days4Saenz J.B. et al.Methods Mol Biol. 2016; 1422: 329-339Crossref PubMed Scopus (35) Google Scholar or DMP-777 (7 mg/20 g body weight, a gift from DuPont-Merck Corporation, Rahway, NJ) was gavaged daily for 14 days. Tamoxifen was dissolved in a vehicle of 10% ethanol and 90% sunflower oil (Sigma), and DMP-777 was suspended in 1% methylcellulose (Sigma) in distilled H2O. Mice were given an intraperitoneal injection containing 5-bromo-2’-deoxyuridine (120 mg/kg) and 5-fluoro-2’-deoxyuridine (12 mg/kg) in sterile water 90 minutes before death. After death, stomachs immediately were excised and flushed with phosphate-buffered saline, then pinned out and fixed in freshly prepared methacarn (60% methanol, 30% chloroform, and 10% glacial acetic acid) for 20 minutes, and stored overnight in 70% ethanol. Tissues were arranged in 3% agar in a tissue cassette, underwent routine paraffin processing, and 5-μm sections were cut and mounted on glass slides. Sections underwent a standard deparaffinization and rehydration protocol, were blocked in 1% bovine serum albumin and 0.3% Triton X-100 in phosphate-buffered saline, left overnight with primary antibodies, washed in phosphate-buffered saline, and incubated for 1 hour with secondary antibodies, washed, incubated for 5 minutes in 1 g/mL bisbenzimide (Molecular Probes, Eugene, OR), washed, and then mounted using glycerol:phosphate-buffered saline. Primary antibodies used in this study were as follows: rabbit anti-human gastric intrinsic factor (1:10,000; a gift from Dr David Alpers, Washington University, St Louis, MO), goat anti–5-bromo-2’-deoxyuridine (1:20,000; a gift from Dr Jeff Gordon, Washington University, St Louis, MO), goat anti–vascular endothelial factor B (1:100; Santa Cruz Biotechnology, Santa Cruz, CA), goat anti-clusterin (1:100; Santa Cruz Biotechnology), mouse anti–E-cadherin (1:200; BD Biosciences, Franklin Lanes, NJ), rabbit anti-GFP (1:100; Santa Cruz Biotechnology), mouse anti–trefoil factor 2 (1:500; Abcam, Cambridge, MA), rat anti-CD44 v10-e16, ortholog of human v9 (1:200; Cosmo Bio, Tokyo, Japan), or 1 g/mL fluorescently labeled GSII lectin (Alexa Fluor 488 and 594; Molecular Probes). Secondary antibodies included AlexaFluor (488, 594, or 647) conjugated donkey anti-goat, anti-rabbit, or anti-mouse (1:500; Molecular Probes). All time points were quantified with at least 3 mice, with representatives from both sexes. Stomachs were stained fluorescently with bisbenzimide and either anti–5-bromo-2’-deoxyuridine or anti–vascular endothelial growth factor B markers along with the neck cell marker GSII lectin and zymogenic cell marker anti-GIF. Images were captured as TIFF files from a Zeiss Axiovert 200 microscope with an Axiocam MRM camera with an Apotome optical sectioning filter (Carl Zeiss, Jena, Germany). Each stomach had at least 5 images taken containing 10 or more well-oriented gastric units each. Units were counted using the neck staining, and total quantifications of proliferating cells (5-bromo-2’-deoxyuridine+) or parietal cells (vascular endothelial growth factor B+)5Mills J.C. et al.J Biol Chem. 2003; 278: 46138-46145Crossref PubMed Scopus (32) Google Scholar were averaged over the total unit numbers per mouse. For quantifying units showing SPEM, SPEM was defined exclusively in corpus gastric units as either 5 or more cells per unit co-expressing GSII and GIF or GSII-expressing cells extending to the base of the unit. Tissue was lysed with Direct polymerase chain reaction reagent (Viagen Biotech, Inc, Los Angeles, CA) with added Proteinase K (New England BioLabs, Ipswich, MA) at 55°C for 11 hours, then at 85°C for 15 minutes. Genotyping polymerase chain reaction was run with Redtaq (Sigma). The primers used were as follows: H+/K+ATPase-Cre forward: AGGGATCGCCAGGCGTTTTC, reverse: GTTTTCTTTTCGGATCCGCC. Gastric glands from the corpus of the stomach were isolated from Atp4b-Cre;LSL-DTR; ROSAmT/mG mice2Muzumdar M.D. et al.Genesis. 2007; 45: 593-605Crossref PubMed Scopus (2258) Google Scholar according to Barker et al6Barker N. et al.Cell Stem Cell. 2010; 6: 25-36Abstract Full Text Full Text PDF PubMed Scopus (1115) Google Scholar and Stange et al.7Stange D.E. et al.Cell. 2013; 155: 357-368Abstract Full Text Full Text PDF PubMed Scopus (362) Google Scholar Whole gastric glands were mixed with Matrigel (BD Biosciences, Franklin Lanes, NJ), distributed in 48-well plates, and grown in Advanced Dulbecco's modified Eagle medium/F12 medium (Invitrogen, Carlsbad, CA), 50% Wnt3a conditioned medium, 10% R-Spondin1, and Noggin conditioned medium supplemented with 10 mmol/L HEPES, 1× N-2, 1× B27, 1× glutaMAX (Invitrogen), 2.5 mmol/L N-Acetylcysteine (Sigma-Aldrich, St Louis, MO), 50 ng/mL epidermal growth factor, 100 ng/mL fibroblast growth factor 10 (Peprotech, Rocky Hill, NJ), and 10 nmol/L gastrin (Sigma-Aldrich). A total of 10 μmol/L Rho-associated, coiled-coil containing protein kinase (ROCK) inhibitor (Y-27632; Sigma-Aldrich) was provided for the first 3 days. Three days after initial culturing, gastroids were treated with 10 ng/mL diphtheria toxin in the absence of Wnt3a, R-Spondin 1, and Noggin. Fresh medium containing DT was added the following day. By using Cytation 3 (Biotek, Winooski, VT), all wells were scanned microscopically every 24 hours throughout the whole experiment, and the number of dead gastroids was scored. Total RNA was extracted from corpus stomach tissue using the RNeasy Mini Kit (Qiagen, Valencia, CA). RNA was treated with DNAse I, and then complementary DNA was synthesized with Superscript III (Invitrogen) and random primers. Quantitative reverse-transcription polymerase chain reaction was performed using PowerUp SYBR Green Master Mix (ThermoFisher, Waltham, MA) and gene-specific primers (Supplementary Table 1) on a QuantStudio 3 polymerase chain reaction system (ThermoFisher), and data were analyzed using QuantStudio Design and Analysis Software. Every run was standardized to TATA box binding protein primers. All primers were exon-spanning when possible (ie, for genes having multiple exons of sufficient length). For a full list of primers, see Supplementary Table 1. All graphs and statistics were completed in GraphPad Prism (La Jolla, CA), using 1-way analysis of variance with either the Dunnett or the Tukey post hoc multiple comparison tests to determine significance.Supplementary Figure 2DT specifically kills parietal cells in gastroids. (A) Gastroids from DTR mice with the Atp4b+ parietal cell lineage fluorescing green (Atp4b-Cre;LSL-DTR;ROSAmTmG mice) and all other lineages in red. The same gastroids were monitored over 3 days of control or DT treatment. Note that DT treatment does not affect gastroid survival, but parietal cells specifically are extruded into lumen of gastroids by day 1 (inset: arrowheads), and then are largely gone by day 3. Parietal cells extrusion, which is consistent with cell death in these cultures, does not occur in controls. (B) Immunofluorescence co-staining with anti-GFP (green) and anti–parietal cell marker H+/K+ATPase (red) antibodies. ATPase, adenosine triphosphatase.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Supplementary Figure 3Changes in protein localization for markers of SPEM and chief cell differentiation after TAM and DT. (A) Base of day 14 DT-treated unit with anti–E-cadherin (green) and anti-GIF (red). (B–D) Immunofluorescence of stomachs after 3 days of vehicle, DT, or TAM injections. (B) Red, CD44v; green, GSII; magenta, 5-bromo-2’-deoxyuridine. (C) Red, GIF; green, trefoil factor 2. (D) Red, GIF; green, clusterin.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Supplementary Figure 4Quantitative real-time polymerase chain reaction of selected transcripts implicated in SPEM. Transcripts were analyzed from RNA isolated from the whole gastric corpus of mice treated with vehicle, DT, or TAM for 3 days. Twelve transcripts with significant changes in experimental groups compared with control. *P ≤ .05 and **P ≤ .01.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Supplementary Figure 5DMP-777 control showing deletion of parietal cells. Immunofluorescence of stomachs after 16 days control, DT, or DT then DMP-777 for the parietal cells marker vascular endothelial growth factor B (VEGFB) (red).View Large Image Figure ViewerDownload Hi-res image Download (PPT)Supplementary Table 1Quantitative RT-PCR Primer SequencesGeneForward primer 5′→3′Reverse primer 3′→5′TBPCAAACCCAGAATTGTTCTCCTTATGTGGTCTTCCTGAATCCCTGIFGAAAAGTGGATCTGTGCTACTTGCTAGACAATAAGGCCCCAGGATGMist1GAGCGAGAGAGGCAGCGGATGAGTAAGTATGGTGGCGGTCAGTFF2TGCTTTGATCTTGGATGCTGGGAAAAGCAGCAGTTTCGACClusterinCCAGCCTTTCTTTGAGATGACTCCTGGCACTTTTCACACTWfdc2/HE4TGCCTGCCTGTCGCCTCTGTGTCCGCACAGTCCTTGTCCAMal2GCTTTCGTCTGTCTGGAGATTGACACAAACATGACCCATCCTTGArhgap9TGCTGCCTGACTTTCGTGATGGCGGTCATTCGGTTCTTATCCCasp1GAAAGACAAGCCCAAGGTGATGGTGTTGAAGAGCAGAAAGCACcnb2TGAAGTCCTGGAAGTCATGCGAGGCCAGGTCTTTGATGATCD14CTCTGTCCTTAAAGCGGCTTACGTTGCGGAGGTTCAAGATGTTCeacam1CCTCAGCACATCTCCACAAAGTATAGCCGTAGTGTTTCCCTTGCeacam10CTCCGATTTCTGTGCGATTTCGTCCGTGGCAGATTGTGAACCenpkAATACTGGACACTCTTAACGGGATCTTAGTTGTCAGTTCATCFTRCTGGACCACACCAATTTTGAGGGCGTGGATAAGCTGGGGATChek2TCGGCTATGGGCTCTTCACGTCCTTCTCAACAGTGGTCCtssTCTATGACGACCCCTCCTGTTGCCATCCGAATGTATCCTTCxcl17AGGTGGCTCTTGGAAGGTGCTCTGGAGGGTCTTTGCGADmbt1ACCTCCTCACGGTGCTACAGGCTTCTTCACATCCTCCACTGETV5GCTCTTGGTGCTAAGTAGGATCTGATGGGTGGGTGACAFignl1TTATATTCCCCTCCCAGAAGCGCCAGAAAACCCATCAGACTGlipr1CCAGCTTCGGTCAAAAGTGAGTGGGTGTATCCGTGAATGCAGGpx2CAGGGCTGTGCTGATTGAGCGGACATACTTGAGGCTGTTCLy6aGACTTCTTGCCCATCAATTACCTTAGTACCCAGGATCTCCATACLyz2GCCAGAACTCTGAAAAGGAATGCTTTGGTCTCCACGGTTGTAGMad2l1TGCTTACAACTACTGACCCCGACTGCCATCTTTCAAGGACTTCMmp12CATGAAGCGTGAGGATGTAGACCTAGTGTACCACCTTTGCCAMs4a6bTCCCTCCAATCTACACTTTACCGACTTTGTCTCCGTGACGATGMs4a6cAAAAGACGAGTCCCAGCCTACATGGGACAGGAGGAACAGATGMuc4GCTGCCTGTATTCTTGCCTATGTTCTGGTGCTGCTGGAPigrGATTTGGGAGGCAATGACAACGCTTTCTTGGATTCTTCTGGCProm1TGGATAACACAGGAAGGAAGAGCAGGGTAGAGGCAAATGTCAGSlfn9TCCTTAGTGGTGAAACGGTCTTCAGGTTGCTCACTCTGGTTGTmem48GCTGCTACAAATGGGAGGATCACGGAAGGCGTCTGACTATop2aCGAAATGGCTATGGAGCTAATATCTTTGTCCAGGCTTTGCTraf4CAGGTGTTAGGCTTGGCTATCCGATTAGGGCAGGGGACTATyrobpGGTGTTGACTCTGCTGATTGCAAGCTCCTGATAAGGCGACTCUbe2cCAACATCTGCCTGGACATCCCTGCTTTGAATAGGTTTCTTGCVil1TCAAAGGCTCTCTCAACATCACGGTGCTGGAAGGAACAGG Open table in a new tab DA - 2017/// PY - 2017/// DO - 10.1053/j.gastro.2016.12.001 VL - 152 IS - 4 SP - 762-766 UR - http://www.scopus.com/inward/record.url?eid=2-s2.0-85014316912&partnerID=MN8TOARS ER - TY - JOUR TI - Cell biology: Healthy skin rejects cancer AU - Burclaff, J. AU - Mills, J.C. T2 - Nature DA - 2017/// PY - 2017/// DO - 10.1038/nature23534 VL - 548 IS - 7667 SP - 289-290 UR - http://www.scopus.com/inward/record.url?eid=2-s2.0-85027870170&partnerID=MN8TOARS ER - TY - MGZN TI - The how and why of sweetener synergies AU - Schiffman, S.S. T2 - The World of Food Ingredients DA - 2017/9// PY - 2017/9// SP - 40, 42-44 PB - September ER - TY - ER - TY - CONF TI - Cognitive workload in conventional direct control vs. pattern recognition control of an upper-limb prosthesis AU - Zhang, W. AU - White, M. AU - Zahabi, M. AU - Winslow, A.T. AU - Zhang, F. AU - Huang, H. AU - Kaber, D. AB - The purpose of this study was to compare the cognitive workload of able-bodied individuals when using a myoelectric prosthetic under direct control (DC) or electromyography pattern recognition (PR) control. Different from existing clinical evaluations involving dual-task performance, pupillography measured with an eye-tracking system was used to quantitatively assess user cognitive workload in using a 2 degree-of-freedom prosthesis for a clothespin task. Test results revealed the PR control to produce superior task performance and to require lower cognitive load than demanded of participants under the DC condition. This study provided evidence of both performance and workload advantages of PR control over DC control. PR control was more intuitive to the prosthesis user and, therefore, required less cognitive effort. Furthermore, the study identified a new effective measure of cognitive workload in upper limb prosthesis use via pupillography. C2 - 2017/// C3 - 2016 IEEE International Conference on Systems, Man, and Cybernetics, SMC 2016 - Conference Proceedings DA - 2017/// DO - 10.1109/SMC.2016.7844587 SP - 2335-2340 UR - http://www.scopus.com/inward/record.url?eid=2-s2.0-85015802131&partnerID=MN8TOARS ER - TY - JOUR TI - A New Powered Lower Limb Prosthesis Control Framework Based on Adaptive Dynamic Programming AU - Wen, Y. AU - Si, J. AU - Gao, X. AU - Huang, S. AU - Huang, H.H. T2 - IEEE Transactions on Neural Networks and Learning Systems AB - This brief presents a novel application of adaptive dynamic programming (ADP) for optimal adaptive control of powered lower limb prostheses, a type of wearable robots to assist the motor function of the limb amputees. Current control of these robotic devices typically relies on finite state impedance control (FS-IC), which lacks adaptability to the user's physical condition. As a result, joint impedance settings are often customized manually and heuristically in clinics, which greatly hinder the wide use of these advanced medical devices. This simulation study aimed at demonstrating the feasibility of ADP for automatic tuning of the twelve knee joint impedance parameters during a complete gait cycle to achieve balanced walking. Given that the accurate models of human walking dynamics are difficult to obtain, the model-free ADP control algorithms were considered. First, direct heuristic dynamic programming (dHDP) was applied to the control problem, and its performance was evaluated on OpenSim, an often-used dynamic walking simulator. For the comparison purposes, we selected another established ADP algorithm, the neural fitted Q with continuous action (NFQCA). In both cases, the ADP controllers learned to control the right knee joint and achieved balanced walking, but dHDP outperformed NFQCA in this application during a 200 gait cycle-based testing. DA - 2017/// PY - 2017/// DO - 10.1109/TNNLS.2016.2584559 VL - 28 IS - 9 SP - 2215-2220 UR - http://www.scopus.com/inward/record.url?eid=2-s2.0-84978229791&partnerID=MN8TOARS ER - TY - BOOK TI - Design and modeling of a compact rotary series elastic actuator for an elbow rehabilitation robot AU - Zhang, Q. AU - Xu, B. AU - Guo, Z. AU - Xiao, X. AB - Rehabilitation robot has direct physical interaction with human body, in which the adaptability to interaction, safety and robustness is of great significance. In this paper, a compact rotary series elastic actuator (SEA) is proposed to develop an elbow rehabilitation robot for assisting stroke victims with upper limb impairments perform activities of daily living (ADLs). The compliant SEA ensures inherent safety and improves torque control at the elbow joint of this rehabilitation robot. After modeling of the rotary stiffness and dynamics of the SEA, a PD feedback plus feedforward control architecture is introduced. A test bench has been designed to experimentally characterize the performance of the proposed compliant actuator with controller. It shows an excellent torque tracking performance at low motion frequency, which can satisfy the elbow rehabilitation training requirement. These preliminary results can be readily extended to a full upper limb exoskeleton-type rehabilitation robot actuated by SEA without much difficulty. DA - 2017/// PY - 2017/// DO - 10.1007/978-3-319-65298-6_5 VL - 10464 LNAI SE - 44-56 UR - http://www.scopus.com/inward/record.url?eid=2-s2.0-85028355256&partnerID=MN8TOARS KW - Series elastic actuator (SEA) KW - PD feedback control KW - Torque control KW - Elbow rehabilitation robot ER - TY - CONF TI - Synthesis and Characterization of Modular PEG-Peptide Bioinks C2 - 2017/10/11/ C3 - Biomedical Engineering Society Annual Meeting DA - 2017/10/11/ ER - TY - CONF TI - A direct-write, near-field electrospinning system for creating 3D printed scaffolds with nanoscale structure C2 - 2017/4// C3 - NC State University Spring Undergraduate Research Symposium DA - 2017/4// ER - TY - JOUR TI - Demonstration of extended field-of-view ultrasound’s potential to increase the pool of muscles for which in vivo fascicle length is measurable AU - Adkins, A.N. AU - Franks, P.W. AU - Murray, W.M. T2 - Journal of Biomechanics AB - Static, B-mode ultrasound is the most common method of measuring fascicle length in vivo. However, most forearm muscles have fascicles that are longer than the field-of-view of traditional ultrasound (T-US). As such, little work has been done to quantify in vivo forearm muscle architecture. The extended field-of-view ultrasound (EFOV-US) method, which fits together a sequence of B-mode images taken from a continuous ultrasound scan, facilitates direct measurements of longer, curved fascicles. Here, we test the validity and reliability of the EFOV-US method for obtaining fascicle lengths in the extensor carpi ulnaris (ECU). Fascicle lengths from images of the ECU captured in vivo with EFOV-US were compared to lengths from a well-established method, T-US. Images were collected in a joint posture that shortens the ECU such that entire fascicle lengths were captured within a single T-US image. Resulting measurements were not significantly different (p=0.18); a Bland-Altman test demonstrated their agreement. A novice sonographer implemented EFOV-US in a phantom and in vivo on the ECU. The novice sonographer's measurements from the ultrasound phantom indicate that the combined imaging and analysis method is valid (average error=2.2±1.3mm) and the in vivo fascicle length measurements demonstrate excellent reliability (ICC=0.97). To our knowledge, this is the first study to quantify in vivo fascicle lengths of the ECU using any method. The ability to define a muscle's architecture in vivo using EFOV-US could lead to improvements in diagnosis, model development, surgery guidance, and rehabilitation techniques. DA - 2017/10/3/ PY - 2017/10/3/ DO - 10.1016/j.jbiomech.2017.08.012 VL - 63 SP - 179– 185 KW - Skeletal muscle KW - Muscle architecture KW - Fascicle length KW - Ultrasonography KW - Forearm ER - TY - JOUR TI - Effects of Cinching Force on the Tricuspid Annulus: a Species Comparison AU - Aleman, J. AU - Adkins, A.N. AU - Boies, L. AU - Al-Quiati, F. AU - Sako, E. AU - Bhattacharya, S. T2 - Journal of Cardiovascular Disease and Diagnosis AB - Tricuspid annuloplasty rings are commonly used to cinch an enlarged tricuspid annulus back to its original shape and size in patients with severe functional tricuspid regurgitation. However, the invasive operation is contraindicated for patients at risk for reoperation. Fortunately, transcatheter repair procedures, currently in the development process, are minimally invasive alternatives to current repair techniques. This study aims to determine the species-dependence of cinching force with the potential of informing transcatheter repair design by quantifying the minimum required cinching force necessary to reduce tricuspid regurgitation.The cinching force necessary to reduce the septal-lateral diameter of a dilated annuls was quantified and compared in ten ovine hearts and nine porcine hearts. Additionally, a deparaffinization protocol and Verhoeff-Van Gieson stain were used to compare the microscopic structure of tissue samples at different stages of the experimental procedure in the two species.The maximum annulus dilation observed for the porcine was 11.2%, and the maximum cinching force was 0.40 ± 0.12 N. As previously demonstrated, ovine hearts yielded a maximum annulus dilation and cinching force of 8.82% and 0.38 ± 0.09 N respectively. Histological stains revealed no gross tissue differences between ovine and porcine septal or free wall tissues.The cinching force was not species dependent between ovine and porcine models. This study is an essential first step for determining which animal model should be utilized for the development of transcatheter devices. DA - 2017/// PY - 2017/// DO - 10.4172/2329-9517.1000283 VL - 5 IS - 283 ER - TY - CONF TI - Extended Field-of-View Ultrasound Does Not Yield Greater Error than Traditional Ultrasound AU - Adkins, A.N. AU - Murray, W.M. T2 - Biomedical Engineering Society (BMES) Annual Conference C2 - 2017/10// CY - Phoenix, Arizona DA - 2017/10// PY - 2017/10// ER - TY - CONF TI - Extended Field-of-View Ultrasound in the Extensor Carpi Ulnaris AU - Adkins, A.N. AU - Franks, P. AU - Murray, W.M. T2 - American Society of Biomechanics (ASB) Annual Conference. Colorado School of Mines C2 - 2017/8// CY - Boulder, Colorado DA - 2017/8// PY - 2017/8// ER - TY - CONF TI - Smart Heparin Transcutaneous Patch AU - Zhang, Yuqi AU - Yu, Jicheng AU - Wang, Jinqiang AU - Hanne, Nicholas J AU - Cui, Zheng AU - Qian, Chenggen AU - Wang, Chao AU - Xin, Hongliang AU - Cole, Jacqueline H AU - Gallippi, Caterina M AU - others C2 - 2017/// C3 - Society for Biomaterials Annual Meeting DA - 2017/// ER - TY - CONF TI - Diet-induced obesity deteriorates cancellous bone structure despite increased blood perfusion AU - Hanne, NJ AU - Steward, AJ AU - Easter, ED AU - Pinnamaraju, SV AU - Cole, JH T2 - http://www.ors.org/Transactions/63/1699.pdf C2 - 2017/// C3 - Orthopaedic Research Society Annual Meeting, San Diego, CA, March 19-22 DA - 2017/// ER - TY - SOUND TI - Shared control of functional electrical stimulation and an electric motor in a hybrid neuroprosthesis AU - Sharma, S. DA - 2017/3/8/ PY - 2017/3/8/ ER - TY - CONF TI - A Tube-based Model Predictive Control Method for Sharing Control Inputs in a Hybrid Neuroprosthesis AU - Bao, X. AU - Sheng, Z. AU - Sharma, N. T2 - IROS workshop on Assistance and Service Robotics in a Human Environment C2 - 2017/10/24/ CY - Vancouver, British Columbia, Canada DA - 2017/10/24/ PY - 2017/10/24/ ER - TY - CONF TI - Shared control of functional electrical stimulation and an electric motor in a hybrid neuroprosthesis AU - Sharma, N. T2 - 2017 IEEE International Conference on Robotics and Automation (ICRA) : Innovation, Entrepreneurship, and Real-world Sollutions C2 - 2017/5/29/ CY - Marina Bay Sands, Singapore DA - 2017/5/29/ PY - 2017/5/29/ ER - TY - CONF TI - Human Motor Control Inspired Controller to Compensate for Actuator Redundancy in a Hybrid Neuroprosthesis AU - Sharma, N. T2 - 2017 IEEE/RSJ International Conference on Intelligent Robots and Systems C2 - 2017/9/28/ C3 - Workshop on Assistance and Service Robotics in a Human Environment CY - Vancouver, British Columbia, Canada DA - 2017/9/28/ PY - 2017/9/24/ ER - TY - CHAP TI - Modeling and Dynamic Optimization of a Hybrid Neuroprosthesis for Gait Restoration AU - Sharma, N. AU - Kirsch, N. T2 - Human Modelling for Bio-Inspired Robotics A2 - Ueda, J. A2 - Kurita, Y. AB - A hybrid neuroprosthesis that combines functional electrical stimulation (FES) with an orthosis can be used to restore lower limb function in persons with paraplegia. This artificial intervention can substantially improve the walking duration vis-à-vis a sole FES walking system. However, it is unknown how to achieve optimal limb trajectories and their corresponding optimal control inputs for their use in the hybrid walking system. Optimization of limb angle trajectories and control inputs can minimize muscle fatigue due to FES and the metabolic fatigue in arms, which is caused by a user’s supported weight on a walker. Thus, reduction in total fatigue, due to optimization, can further enhance the benefits of the hybrid neuroprosthesis. We show that dynamic optimization can be used to compute stimulation/torque profiles and their corresponding joint angle trajectories which minimize electrical stimulation and walker push or pull forces. Importantly, the computation of these optimal stimulation or torque profiles did not require a predefined or a nominal gait trajectory (ie, a tracking control problem was not solved). Rather the trajectories were computed based only on predefined endpoints. Different optimal actuation strategies for FES and orthosis aided gait under various scenarios (eg, use of a powered or an unpowered orthosis combined with stimulation of all or a few selected lower-limb muscles) were calculated. The qualitative comparison of these results depict the advantages and disadvantages of each actuation strategy. PY - 2017/// DO - 10.1016/b978-0-12-803137-7.00008-2 SP - 139–159 PB - Academic Press/Elsevier SN - 9780128031377 UR - http://dx.doi.org/10.1016/b978-0-12-803137-7.00008-2 ER - TY - JOUR TI - An adaptive low-dimensional control to compensate for actuator redundancy and FES-induced muscle fatigue in a hybrid neuroprosthesis AU - Alibeji, Naji AU - Kirsch, Nicholas AU - Sharma, Nitin T2 - Control Engineering Practice AB - To restore walking and standing function in persons with paraplegia, a hybrid walking neuroprosthesis that combines a powered exoskeleton and functional electrical stimulation (FES) can be more advantageous than sole FES or powered exoskeleton technologies. However, the hybrid actuation structure introduces certain control challenges: actuator redundancy, cascaded muscle activation dynamics, FES-induced muscle fatigue, and unmeasurable states. In this paper, a human motor control inspired control scheme is combined with a dynamic surface control method to overcome these challenges. The new controller has an adaptive muscle synergy-based feedforward component which requires a fewer number of control signals to actuate multiple effectors in a hybrid neuroprosthesis. In addition, the feedforward component has an inverse fatigue signal to counteract the effects of the muscle fatigue. A dynamic surface control (DSC) method is used to deal with the cascaded actuation dynamics without the need for acceleration signals. The DSC structure was modified with a delay compensation term to deal with the electromechanical delays due to FES. A model based estimator is used to estimate the unmeasurable fatigue and actuator activation signals. The development of the controller and a Lyapunov stability analysis, which yielded semi-global uniformly ultimately boundedness, are presented in the paper. Computer simulations were performed to test the new controller on a 2 degrees of freedom fixed hip model after which preliminary experiments were conducted on one able-bodied male subject in the fixed hip configuration. DA - 2017/2// PY - 2017/2// DO - 10.1016/j.conengprac.2016.07.015 VL - 59 SP - 204-219 J2 - Control Engineering Practice LA - en OP - SN - 0967-0661 UR - http://dx.doi.org/10.1016/j.conengprac.2016.07.015 DB - Crossref KW - Functional electrical stimulation KW - Muscle fatigue KW - Dynamic surface control KW - Synergies KW - Human inspired control KW - Adaptive control KW - State estimator KW - Input delays KW - Electromechanical delays ER - TY - CHAP TI - Dynamic Optimization of a Hybrid Gait Neuroprosthesis to Improve Efficiency and Walking Duration: A Simulation Study AU - Kirsch, Nicholas A. AU - Alibeji, Naji A. AU - Redfern, Mark AU - Sharma, Nitin T2 - Converging Clinical and Engineering Research on Neurorehabilitation II A2 - Ibáñez, J. A2 - González-Vargas, J. A2 - Azorín, J. A2 - Akay, M. A2 - Pons, J. T3 - Biosystems & Biorobotics AB - The walking duration of gait restoration systems that use functional electrical stimulation (FES) is severely limited by the rapid onset of muscle fatigue. Alternatively, fully actuated orthoses can also be employed to restore walking in paraplegia. However, due to the high power consumption of electric motors the walking duration of such devices are limited by the charge of the batteries. This paper proposes that a hybrid system, which uses FES and an actuated orthosis, is capable of achieving greater walking durations than an FES only system and more energetically efficient than a lower-limb exoskeleton. This is illustrated through results of optimizations of a musculoskeletal gait model for three actuation cases: FES only, electric motors only, and a hybrid system. The presented results illustrate that a hybrid system may be capable of greater walking durations than FES-based systems while using half the energy of a lower-limb exoskeleton. PY - 2017/// DO - 10.1007/978-3-319-46669-9_113 VL - 15 SP - 687–691 PB - Springer International Publishing SN - 9783319466682 9783319466699 SV - 15 UR - http://dx.doi.org/10.1007/978-3-319-46669-9_113 ER - TY - CHAP TI - Preliminary Experiments of an Adaptive Low-Dimensional Control for a Hybrid Neuroprosthesis AU - Alibeji, Naji A. AU - Kirsch, Nicholas A. AU - Sharma, Nitin T2 - Converging Clinical and Engineering Research on Neurorehabilitation II A2 - Ibáñez, J. A2 - González-Vargas, J. A2 - Azorín, J. A2 - Akay, M. A2 - Pons, J. T3 - Biosystems & Biorobotics AB - Hybrid neuroprostheses that use both electric motor drives and functional electrical stimulation for the restoration of walking in persons with paraplegia have a promising potential. However, the hybrid actuation structure introduces effector redundancy, making the system complex and difficult to control. In this paper, preliminary experimental results of a recently developed low-dimensional controller, which is inspired from the muscle synergy principle, are presented. The experiments were performed on an able-bodied subject in a configuration where only one leg is actuated in a cycling manner while the contralateral leg was fixed. PY - 2017/// DO - 10.1007/978-3-319-46669-9_114 VL - 15 SP - 693–697 PB - Springer International Publishing SN - 9783319466682 9783319466699 SV - 15 UR - http://dx.doi.org/10.1007/978-3-319-46669-9_114 ER - TY - CONF TI - Experimental demonstration of a delay compensating controller in a hybrid walking neuroprosthesis AU - Dodson, Albert AU - Alibeji, Naji AU - Sharma, Nitin T2 - 2017 8th International IEEE/EMBS Conference on Neural Engineering (NER) AB - A hybrid neuroprosthesis is a device that uses a combination of electric motors and functional electrical stimulation (FES) to provide gait assistance. Its closed-loop control performance can be potentially affected by the presence of electromechanical delay (EMD) during FES. In this paper, a tracking control scheme for a hybrid walking neuroprosthesis that combines electric motor actuation at the hip and FES actuation at the knee is presented. The knee joint controller uses a delay compensation technique to compensate for EMD during FES. This neuroprosthesis controller is combined within a finite state machine that also features gait detection, wherein force sensors in the foot can detect gait phases and create a fully automated and functional assisted gait cycle. Experiments were performed on an able bodied subject to demonstrate the efficacy of the tracking control scheme. Results from the experiments show a maximum error at the hip of less than 1 degree and a maximum error at the knee of 13.66 degrees. The maximum error at the knee is attributed to overshoot caused by the unidirectional actuation of the FES. C2 - 2017/5// C3 - 2017 8th International IEEE/EMBS Conference on Neural Engineering (NER) DA - 2017/5// DO - 10.1109/ner.2017.8008390 SP - 465-468 PB - IEEE SN - 9781509046034 UR - http://dx.doi.org/10.1109/ner.2017.8008390 DB - Crossref ER - TY - CONF TI - A recurrent neural network based MPC for a hybrid neuroprosthesis system AU - Bao, Xuefeng AU - Sun, Ziyue AU - Sharma, Nitin T2 - 2017 IEEE 56th Annual Conference on Decision and Control (CDC) AB - Control input sequence in a hybrid neuroprosthesis that combines functional electrical stimulation (FES) and an electric motor can be optimized by a model based optimization method, like model predictive control (MPC). However, because the human muscle model is highly nonlinear, time-varying, and contains unmeasurable state variables, it is often difficult to identify the model. Therefore, a three-layer recurrence neural network (RNN) is developed in this paper, in which backpropagation through time (BPTT) is used as training technique and the internal states are used to represent the unmeasurable states. This structure shows the potential to approximate the model of the hybrid neuroprosthesis system. After the NN model is obtained, an adaptive model predictive control is used to simulate regulation and tracking tasks to test the performance of the NN training and the MPC method. C2 - 2017/12// C3 - 2017 IEEE 56th Annual Conference on Decision and Control (CDC) DA - 2017/12// DO - 10.1109/cdc.2017.8264356 PB - IEEE SN - 9781509028733 UR - http://dx.doi.org/10.1109/cdc.2017.8264356 DB - Crossref ER - TY - JOUR TI - Nonlinear model predictive control of functional electrical stimulation AU - Kirsch, Nicholas AU - Alibeji, Naji AU - Sharma, Nitin T2 - Control Engineering Practice AB - Minimizing the amount of electrical stimulation can potentially mitigate the adverse effects of muscle fatigue during functional electrical stimulation (FES) induced limb movements. A gradient projection-based model predictive controller is presented for optimal control of a knee extension elicited via FES. A control Lyapunov function was used as a terminal cost to ensure stability of the model predictive control. The controller validation results show that the algorithm can be implemented in real-time with a steady-state RMS error of less than 2°. The experiments also show that the controller follows step changes in desired angles and is robust to external disturbances. DA - 2017/1// PY - 2017/1// DO - 10.1016/j.conengprac.2016.03.005 VL - 58 SP - 319-331 J2 - Control Engineering Practice LA - en OP - SN - 0967-0661 UR - http://dx.doi.org/10.1016/j.conengprac.2016.03.005 DB - Crossref KW - Functional electrical stimulation KW - Nonlinear model predictive control KW - Muscle parameter identification KW - Rehabilitation engineering KW - Gradient projection algorithm ER - TY - JOUR TI - A Non-Linear Control Method to Compensate for Muscle Fatigue during Neuromuscular Electrical Stimulation AU - Sharma, Nitin AU - Kirsch, Nicholas Andrew AU - Alibeji, Naji A. AU - Dixon, Warren E. T2 - Frontiers in Robotics and AI AB - Neuromuscular electrical stimulation (NMES) is a promising technique to artificially activate muscles as a means to potentially restore the capability to perform functional tasks in persons with neurological disorders. A pervasive problem with NMES is that overstimulation of the muscle (among other factors) leads to rapid muscle fatigue, which limits the use of clinical and commercial NMES systems. The objective of this paper is to develop an NMES controller that incorporates the effects of muscle fatigue during NMES-induced non-isometric contraction of the human quadriceps femoris muscle. Our previous work that used the RISE class of nonlinear controllers cannot accommodate fatigue and muscle activation dynamics. A totally new control design approach and associated stability proof is required to derive a new class of NMES control design that accounts for muscle fatigue dynamics and a first order activation dynamics, in addition to the second order musculoskeletal dynamics. Motivated from a control method for robotic systems in a strict-feedback form, a backstepping based nonlinear NMES controller was designed to accommodate for the additional muscle activation dynamics. Further, experimentally identified estimates of the fatigue and activation dynamics were incorporated in the control design. The developed controller uses a neural network-based estimate of the musculoskeletal dynamics and error due to fatigue estimation. A globally uniformly ultimately bounded stability is proven the new controller that accounts for an uncertain nonlinear muscle model and bounded nonlinear disturbances (e.g., spasticity, changing load dynamics). The developed controller was validated through experiments on the left and right legs of 3 able-bodied subjects and was compared with a proportional-derivative (PD) controller and a PD augmented with a neural network. The statistical analysis showed improved control performance compared to the PD controller. DA - 2017/12/22/ PY - 2017/12/22/ DO - 10.3389/frobt.2017.00068 VL - 4 IS - DEC J2 - Front. Robot. AI OP - SN - 2296-9144 UR - http://dx.doi.org/10.3389/frobt.2017.00068 DB - Crossref KW - integrator backstepping KW - neural networks KW - muscle fatigue KW - Lyapunov stability KW - neuromuscular electrical stimulation ER - TY - JOUR TI - Bilateral control of functional electrical stimulation and robotics-based telerehabilitation AU - Alibeji, Naji AU - Dicianno, Brad E. AU - Sharma, Nitin T2 - International Journal of Intelligent Robotics and Applications AB - Currently, a telerehabilitation system includes a therapist and a patient where the therapist interacts with the patient, typically via a verbal and visual communication, for assessment and supervision of rehabilitation interventions. This mechanism often fails to provide physical assistance, which is a modus operandi during physical therapy or occupational therapy. Incorporating an actuation modality such as functional electrical stimulation (FES) or a robot at the patient’s end that can be controlled by a therapist remotely to provide therapy or to assess and measure rehabilitation outcomes can significantly transform current telerehabilitation technology. In this paper, a position-synchronization controller is derived for FES-based telerehabilitation to provide physical assistance that can be controlled remotely. The newly derived controller synchronizes an FES-driven human limb with a remote physical therapist’s robotic manipulator despite constant bilateral communication delays. The control design overcomes a major stability analysis challenge: the unknown and unstructured nonlinearities in the FES-driven musculoskeletal dynamics. To address this challenge, the nonlinear muscle model was estimated through two neural network functions that approximated unstructured nonlinearities and an adaptive control law for structured nonlinearities with online update laws. A Lyapunov-based stability analysis was used to prove the globally uniformly ultimately bounded tracking performance. The performance of the state synchronization controller was validated through experiments on an able-bodied subject. Specifically, we demonstrated bilateral control of FES-elicited leg extension and a human-operated robotic manipulator. The controller was shown to effectively synchronize the system despite unknown and different delays in the forward and backward channels. DA - 2017/2// PY - 2017/2// DO - 10.1007/s41315-016-0003-5 VL - 1 IS - 1 SP - 6-18 UR - https://doi.org/10.1007/s41315-016-0003-5 ER - TY - JOUR TI - A Modified Dynamic Surface Controller for Delayed Neuromuscular Electrical Stimulation AU - Alibeji, Naji AU - Kirsch, Nicholas AU - Dicianno, Brad E. AU - Sharma, Nitin T2 - IEEE/ASME Transactions on Mechatronics AB - A widely accepted model of muscle force generation during neuromuscular electrical stimulation (NMES) is a second-order nonlinear musculoskeletal dynamics cascaded to a delayed first-order muscle activation dynamics. However, most nonlinear NMES control methods have either neglected the muscle activation dynamics or used an ad hoc strategies to tackle the muscle activation dynamics, which may not guarantee control stability. We hypothesized that a nonlinear control design that includes muscle activation dynamics can improve the control performance. In this paper, a dynamic surface control (DSC) approach was used to design a PID-based NMES controller that compensates for EMD in the activation dynamics. Because the muscle activation is unmeasurable, a model based estimator was used to estimate the muscle activation in realtime. The Lyapunov stability analysis confirmed that the newly developed controller achieves semi-global uniformly ultimately bounded (SGUUB) tracking for the musculoskeletal system. Experiments were performed on two able-bodied subjects and one spinal cord injury subject using a modified leg extension machine. These experiments illustrate the performance of the new controller and compare it to a previous PID-DC controller that did not consider muscle activation dynamics in the control design. These experiments support our hypothesis that a control design that includes muscle activation improves the NMES control performance. DA - 2017/8// PY - 2017/8// DO - 10.1109/TMECH.2017.2704915 VL - 22 IS - 4 SP - 1755-1764 UR - https://doi.org/10.1109/TMECH.2017.2704915 KW - Activation dynamics KW - delay systems KW - dynamic surface control KW - feedback KW - input delays KW - Lyapunov methods KW - nonlinear controls KW - nonlinear control systems KW - neuromuscular electrical stimulation ER - TY - JOUR TI - A Nonlinear Dynamics-Based Estimator for Functional Electrical Stimulation: Preliminary Results From Lower-Leg Extension Experiments AU - Allen, Marcus AU - Zhong, Qiang AU - Kirsch, Nicholas AU - Dani, Ashwin AU - Clark, William W. AU - Sharma, Nitin T2 - IEEE Transactions on Neural Systems and Rehabilitation Engineering AB - Miniature inertial measurement units (IMUs) are wearable sensors that measure limb segment or joint angles during dynamic movements. However, IMUs are generally prone to drift, external magnetic interference, and measurement noise. This paper presents a new class of nonlinear state estimation technique called state-dependent coefficient (SDC) estimation to accurately predict joint angles from IMU measurements. The SDC estimation method uses limb dynamics, instead of limb kinematics, to estimate the limb state. Importantly, the nonlinear limb dynamic model is formulated into state-dependent matrices that facilitate the estimator design without performing a Jacobian linearization. The estimation method is experimentally demonstrated to predict knee joint angle measurements during functional electrical stimulation of the quadriceps muscle. The nonlinear knee musculoskeletal model was identified through a series of experiments. The SDC estimator was then compared with an extended kalman filter (EKF), which uses a Jacobian linearization and a rotation matrix method, which uses a kinematic model instead of the dynamic model. Each estimator's performance was evaluated against the true value of the joint angle, which was measured through a rotary encoder. The experimental results showed that the SDC estimator, the rotation matrix method, and EKF had root mean square errors of 2.70°, 2.86°, and 4.42°, respectively. Our preliminary experimental results show the new estimator's advantage over the EKF method but a slight advantage over the rotation matrix method. However, the information from the dynamic model allows the SDC method to use only one IMU to measure the knee angle compared with the rotation matrix method that uses two IMUs to estimate the angle. DA - 2017/12// PY - 2017/12// DO - 10.1109/TNSRE.2017.2748420 VL - 25 IS - 12 SP - 2365-2374 J2 - IEEE Trans. Neural Syst. Rehabil. Eng. OP - SN - 1534-4320 1558-0210 UR - http://dx.doi.org/10.1109/tnsre.2017.2748420 DB - Crossref KW - State-dependent coefficient KW - extended kalman filter KW - rotation matrix KW - functional electrical stimulation KW - nonlinear state estimator ER - TY - JOUR TI - A PID-Type Robust Input Delay Compensation Method for Uncertain Euler–Lagrange Systems AU - Alibeji, Naji AU - Sharma, Nitin T2 - IEEE Transactions on Control Systems Technology AB - Robust delay compensation techniques for uncertain nonlinear systems with unknown input delays are, in general, lacking. The result in this brief extends a modified proportional-integral derivative (PID)-type controller that contains a distributed delay term to Euler-Lagrange systems with an unknown constant input delay. Additive disturbances and uncertainties in the nonlinear system were considered in the control development and stability analysis. The stability analysis also hinges upon Lyapunov-Krasovskii functionals that were designed to prove semiglobal uniformly ultimately bounded tracking. Experiments on a 3-degree of freedom robot were performed to depict the performance of the new controller. DA - 2017/11// PY - 2017/11// DO - 10.1109/TCST.2016.2634503 VL - 25 IS - 6 SP - 2235-2242 UR - https://doi.org/10.1109/TCST.2016.2634503 KW - Delay compensation KW - Euler-Lagrange systems KW - robust control KW - unknown input delay. ER - TY - JOUR TI - Liquid-Phase Laser Induced Forward Transfer for Complex Organic Inks and Tissue Engineering AU - Nguyen, Alexander K. AU - Narayan, Roger J. T2 - Annals of Biomedical Engineering DA - 2017/1// PY - 2017/1// DO - 10.1007/S10439-016-1617-3 VL - 45 IS - 1 SP - 84–99 SN - 0090-6964 1573-9686 UR - http://dx.doi.org/10.1007/S10439-016-1617-3 KW - Laser induced forward transfer KW - Cell printing KW - Regenerative medicine KW - Tissue engineering ER - TY - CHAP TI - Introduction of an EMG-Controlled Game to Facilitate Hand Rehabilitation After Stroke AU - Ghassemi, Mohammad AU - Ranganathan, Rajiv AU - Barry, Alex AU - Triandafilou, K. AU - Kamper, Derek T2 - Converging Clinical and Engineering Research on Neurorehabilitation II AB - Stroke survivors often have difficulty creating the proper muscle activation patterns to perform functional tasks. We have developed an electromyographically (EMG)-controlled game to assist stroke survivors in rehabilitating activation patterns. Players must produce specific EMG patterns in order to move a cursor throughout a computer screen. We ran a pilot study with neurologically intact subjects playing the game on three separate days. Significant carryover in improvement of activation was seen from one day to the next. PY - 2017/// DO - 10.1007/978-3-319-46669-9_75 SP - 451–455 PB - Springer International Publishing SN - 9783319466682 9783319466699 UR - http://dx.doi.org/10.1007/978-3-319-46669-9_75 ER - TY - JOUR TI - Inflammation-Triggered Cancer Immunotherapy by Programmed Delivery of CpG and Anti-PD1 Antibody AU - Wang, Chao AU - Sun, Wujin AU - Wright, Grace AU - Wang, Andrew Z. AU - Gu, Zhen T2 - Advanced Materials AB - Adv. Mater. 2016, 40, 8912–8920 The digital bioluminescent intensity scales of images for Figure 3A,B and Figure 4A,B were inadvertently omitted in the published article. Meanwhile, several of the mice (bright field) in Figure 3A and 4A were not displayed correctly: the bioluminensence signals were not merged correspondingly with the bright-field images of those mice. The corrected figures are presented here. The quantitative analysis and overall conclusions of the article are unaffected. DA - 2017/4// PY - 2017/4// DO - 10.1002/ADMA.201700761 VL - 29 IS - 15 J2 - Adv. Mater. LA - en OP - SN - 0935-9648 UR - http://dx.doi.org/10.1002/ADMA.201700761 DB - Crossref ER - TY - JOUR TI - In situ activation of platelets with checkpoint inhibitors for post-surgical cancer immunotherapy AU - Wang, Chao AU - Sun, Wujin AU - Ye, Yanqi AU - Hu, Quanyin AU - Bomba, Hunter N. AU - Gu, Zhen T2 - Nature Biomedical Engineering DA - 2017/1/23/ PY - 2017/1/23/ DO - 10.1038/S41551-016-0011 VL - 1 IS - 2 J2 - Nat Biomed Eng LA - en OP - SN - 2157-846X UR - http://dx.doi.org/10.1038/S41551-016-0011 DB - Crossref ER - TY - JOUR TI - Injectable Thermosensitive Polypeptide-Based CDDP-Complexed Hydrogel for Improving Localized Antitumor Efficacy AU - Yu, Shuangjiang AU - Zhang, Dianliang AU - He, Chaoliang AU - Sun, Wujin AU - Cao, Rangjuan AU - Cui, Shusen AU - Deng, Mingxiao AU - Gu, Zhen AU - Chen, Xuesi T2 - Biomacromolecules AB - In this study, a type of novel thermosensitive polypeptide-based hydrogel with tunable gelation behavior through changing the content of carboxyl groups was developed for the purpose of improving the cisplatin (CDDP) release behavior and enhancing the localized antitumor efficiency. The introduction of carboxyl groups in methoxy-poly(ethylene glycol)-b-(poly(γ-ethyl-l-glutamate-co-l-glutamic acid) (mPEG-b-P(ELG-co-LG)) not only led to adjustable mechanical properties of the hydrogel but also significantly reduced the burst release of the drug through the complexation between the carboxyl groups of polypeptide and CDDP. Furthermore, both the good biocompatibility and the biodegradable properties of mPEG-b-P(ELG-co-LG) hydrogel were observed in vivo. Interestingly, the CDDP-complexed mPEG-b-P(ELG-co-LG) hydrogel exhibited significantly enhanced antitumor efficacy in vivo compared to the mPEG-b-PELG hydrogel loaded with CDDP without complexation, although a lower cytotoxicity and IC50 of the CDDP-complexed hydrogel was observed in vitro. Overall, the new type of injectable CDDP-complexed hydrogel may serve as an efficient platform for sustained CDDP delivery in localized tumor therapy. DA - 2017/11/27/ PY - 2017/11/27/ DO - 10.1021/ACS.BIOMAC.7B01374 VL - 18 IS - 12 SP - 4341-4348 J2 - Biomacromolecules LA - en OP - SN - 1525-7797 1526-4602 UR - http://dx.doi.org/10.1021/ACS.BIOMAC.7B01374 DB - Crossref ER - TY - JOUR TI - Red Blood Cells for Drug Delivery AU - Yan, Junjie AU - Yu, Jicheng AU - Wang, Chao AU - Gu, Zhen T2 - Small Methods AB - Abstract Red blood cells (RBCs), or erythrocytes, have been promising endogenous candidates for drug delivery for more than four decades. Armed with a better understanding of the diverse mechanisms and paths for drug delivery, researchers have achieved great progress in manufacturing RBC‐based carriers, from both the scientific and clinical viewpoints. Here, the loading methods and loading therapeutics by RBC carriers are surveyed, and recent advances in the design of stimuli‐triggered RBC carriers highlighted. Key developing trends and challenges, are also discussed, and an outlook is presented. DA - 2017/11/14/ PY - 2017/11/14/ DO - 10.1002/SMTD.201700270 VL - 1 IS - 12 SP - 1700270 J2 - Small Methods LA - en OP - SN - 2366-9608 UR - http://dx.doi.org/10.1002/SMTD.201700270 DB - Crossref KW - interface engineering KW - layer-by-layer assembly KW - multilayer thin films KW - optoelectronic devices ER - TY - JOUR TI - Insulin-Responsive Glucagon Delivery for Prevention of Hypoglycemia AU - Yu, Jicheng AU - Zhang, Yuqi AU - Sun, Wujin AU - Kahkoska, Anna R. AU - Wang, Jinqiang AU - Buse, John B. AU - Gu, Zhen T2 - Small AB - Hypoglycemia, the state of abnormally low blood glucose level, is an acute complication of insulin and sulfonylurea therapy in diabetes management. Frequent insulin dosing and boluses during daily diabetes care leads to an increased risk of dangerously low glucose levels, which can cause behavioral and cognitive disturbance, seizure, coma, and even death. This study reports an insulin-responsive glucagon delivery method based on a microneedle (MN)-array patch for the prevention of hypoglycemia. The controlled release of glucagon is achieved in response to elevated insulin concentration by taking advantage of the specific interaction between insulin aptamer and target insulin. Integrating a painless MN-array patch, it is demonstrated that this insulin-triggered glucagon delivery device is able to prevent hypoglycemia following a high-dose insulin injection in a chemically induced type 1 diabetic mouse model. DA - 2017/3/20/ PY - 2017/3/20/ DO - 10.1002/SMLL.201603028 VL - 13 IS - 19 SP - 1603028 J2 - Small LA - en OP - SN - 1613-6810 UR - http://dx.doi.org/10.1002/SMLL.201603028 DB - Crossref ER - TY - JOUR TI - Inside Cover: Anaerobe-Inspired Anticancer Nanovesicles (Angew. Chem. Int. Ed. 10/2017) AU - Qian, Chenggen AU - Feng, Peijian AU - Yu, Jicheng AU - Chen, Yulei AU - Hu, Quanyin AU - Sun, Wujin AU - Xiao, Xuanzhong AU - Hu, Xiuli AU - Bellotti, Adriano AU - Shen, Qun-Dong AU - Gu, Zhen T2 - Angewandte Chemie International Edition AB - An anaerobe-inspired drug delivery vehicle is described by Q. D. Shen, Z. Gu, and co-workers in their Communication on page 2588 ff. The biomimetic nanovesicles are stable in cells with normal physiological redox and oxygen balance. Upon disruption by external light stimuli, they show dual synergistic anticancer actions with enhanced therapeutic efficacy. DA - 2017/2/15/ PY - 2017/2/15/ DO - 10.1002/ANIE.201701131 VL - 56 IS - 10 SP - 2516-2516 J2 - Angew. Chem. Int. Ed. LA - en OP - SN - 1433-7851 UR - http://dx.doi.org/10.1002/ANIE.201701131 DB - Crossref ER - TY - JOUR TI - Nanosilver-PMMA composite coating optimized to provide robust antibacterial efficacy while minimizing human bone marrow stromal cell toxicity AU - Petrochenko, Peter E. AU - Zheng, Jiwen AU - Casey, Brendan J. AU - Bayati, M. Reza AU - Narayan, Roger J. AU - Goering, Peter L. T2 - Toxicology in Vitro AB - Porous PMMA is a versatile biomaterial with good biocompatibility but high susceptibility to bacterial colonization, which we mitigated by utilizing immobilized antimicrobial silver nanoparticles (AgNPs). A uniform porous thin film was deposited onto silicon wafers by simultaneously ablating PMMA and silver (Ag) using pulsed laser deposition (PLD) optimized for minimal human cell toxicity and antibacterial efficacy. PMMA without Ag became heavily colonized by E. coli in simulated dynamic conditions, while Ag-containing samples prevented all colonization. ICP-MS analysis demonstrated that the amount of leached Ag after 24h under simulated in vivo conditions (with serum media at 37°C and 5% CO2) increased in proportion to film thickness (and total silver content). 10,000, 14,000, and 20,000 laser pulse-deposited films released 0.76, 1.05, and 1.67μg/mL Ag, respectively, after 24h. Human bone marrow stromal cells (hBMSCs) grown directly on 10,000-pulse films (0.76μg/mL Ag released) for 24-h exhibited no cytotoxicity. Exposure to the remaining films produced cytotoxicity, necrosis, and apoptosis detected using flow cytometry. Examining both leachates and direct cell contact allowed us to develop an in vitro cytotoxicity test method and optimize a novel device material and coating to be nontoxic and bactericidal during both potential initial implantation and external use. DA - 2017/10// PY - 2017/10// DO - 10.1016/J.TIV.2017.07.014 VL - 44 SP - 248-255 J2 - Toxicology in Vitro LA - en OP - SN - 0887-2333 UR - http://dx.doi.org/10.1016/J.TIV.2017.07.014 DB - Crossref KW - PMMA KW - Silver nanoparticles KW - Antibacterial KW - Pulsed laser deposition (PLD) KW - Metal leaching ER - TY - JOUR TI - Additive manufacturing for regenerative medicine: Where do we go from here? AU - Bouten, Carlijn V.C. AU - Ramakrishna, Seeram AU - Narayan, Roger T2 - Current Opinion in Biomedical Engineering DA - 2017/6// PY - 2017/6// DO - 10.1016/J.COBME.2017.07.002 VL - 2 SP - iii-v J2 - Current Opinion in Biomedical Engineering LA - en OP - SN - 2468-4511 UR - http://dx.doi.org/10.1016/J.COBME.2017.07.002 DB - Crossref ER - TY - JOUR TI - Thrombin-Responsive Transcutaneous Patch for Auto-Anticoagulant Regulation AU - Zhang, Yuqi AU - Yu, Jicheng AU - Wang, Jinqiang AU - Hanne, Nicholas J. AU - Cui, Zheng AU - Qian, Chenggen AU - Wang, Chao AU - Xin, Hongliang AU - Cole, Jacqueline H. AU - Gallippi, Caterina M. AU - Zhu, Yong AU - Gu, Zhen T2 - Advanced Materials AB - A thrombin-responsive closed-loop patch is developed for prolonged heparin delivery in a feedback-controlled manner. This microneedle-based patch can sense activated thrombin and subsequently releases heparin to prevent coagulation in the blood flow. This “smart” heparin patch can be transcutaneously inserted into skin without drug leakage and can sustainably regulate blood coagulation in response to thrombin. DA - 2017/1// PY - 2017/1// DO - 10.1002/ADMA.201604043 VL - 29 IS - 4 SP - 1604043 SN - 0935-9648 UR - http://dx.doi.org/10.1002/ADMA.201604043 ER - TY - JOUR TI - Leveraging H2O2Levels for Biomedical Applications AU - Wang, Jinqiang AU - Zhang, Yuqi AU - Archibong, Edikan AU - Ligler, Frances S. AU - Gu, Zhen T2 - Advanced Biosystems AB - Hydrogen peroxide (H 2 O 2 )‐responsive materials have been employed as drug delivery or diagnostic systems to treat or detect diseases with abnormal oxidative stress. A number of H 2 O 2 ‐responsive systems have been developed, and they have achieved great progress in controlled drug delivery for disease treatment. However, pathological sites with elevated H 2 O 2 level, such as cancer and inflammation, have their own characteristics; therefore the material structures and the subsequent formulations should be reasonably designed to acquire maximized therapeutic effects. In this progress report, we overview the development of H 2 O 2 ‐responsive functional groups for constructing H 2 O 2 ‐responsive formulations, as well as the guidance for designing suitable formulations to treat each specific pathological condition. The challenges and perspectives in this field are also discussed. DA - 2017/7/17/ PY - 2017/7/17/ DO - 10.1002/ADBI.201700084 VL - 1 IS - 9 SP - 1700084 J2 - Adv. Biosys. LA - en OP - SN - 2366-7478 UR - http://dx.doi.org/10.1002/ADBI.201700084 DB - Crossref KW - diagnosis KW - drug delivery KW - H2O2-responsive KW - oxidation-responsive KW - polymers ER - TY - CHAP TI - Minimally invasive microneedle array electrodes employing direct electron transfer type glucose dehydrogenase for the development of continuous glucose monitoring sensors AU - Sharma, Sanjiv AU - Takagi, Eri AU - Cass, Tony AU - Tsugawa, Wakako AU - Sode, Koji T2 - Biosensors 2016 AB - Closed loop systems hinge on the accuracy and precision of the continuous glucose monitoring sensors. Most of the commercially available continuous glucose monitoring sensors is implanted subcutaneously for a period of 7-14 days. The subsequent biofouling effects have implications on the performance of the sensors over time especially at low glucose concentrations. In addition, the commercially available sensors are sensitive to the presence of interfering species such as acetaminophen in the skin compartment. We report here on the marriage of minimally invasive, continuous glucose sensors and a direct electron transfer type glucose dehydrogenase enzymatic system. Whilst the microneedles here are designed to sit in the dermal interstitial fluid over a 24-48 hour period to minimize the biofouling effect, the direct electron transfer enzyme allows operation of the electrochemical sensor at lower potentials to minimize the effect of interference. The microneedle structure design also enables the use of compensation electrodes for background subtraction to further nullify the effects of interference. PY - 2017/// DO - 10.1016/j.protcy.2017.04.087 VL - 27 SP - 208-209 PB - SE - UR - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=ORCID&SrcApp=OrcidOrg&DestLinkType=FullRecord&DestApp=WOS_CPL&KeyUT=WOS:000419272600089&KeyUID=WOS:000419272600089 KW - continuous glucose monitoring KW - minimally invasive sensors KW - direct electron transfer KW - microneedles ER - TY - JOUR TI - Mediator Preference of Two Different FAD-Dependent Glucose Dehydrogenases Employed in Disposable Enzyme Glucose Sensors AU - Loew, Noya AU - Tsugawa, Wakako AU - Nagae, Daichi AU - Kojima, Katsuhiro AU - Sode, Koji T2 - Sensors AB - Most commercially available electrochemical enzyme sensor strips for the measurement of blood glucose use an artificial electron mediator to transfer electrons from the active side of the enzyme to the electrode. One mediator recently gaining attention for commercial sensor strips is hexaammineruthenium(III) chloride. In this study, we investigate and compare the preference of enzyme electrodes with two different FAD-dependent glucose dehydrogenases (FADGDHs) for the mediators hexaammineruthenium(III) chloride, potassium ferricyanide (the most common mediator in commercial sensor strips), and methoxy phenazine methosulfate (mPMS). One FADGDH is a monomeric fungal enzyme, and the other a hetero-trimeric bacterial enzyme. With the latter, which contains a heme-subunit facilitating the electron transfer, similar response currents are obtained with hexaammineruthenium(III), ferricyanide, and mPMS (6.8 µA, 7.5 µA, and 6.4 µA, respectively, for 10 mM glucose). With the fungal FADGDH, similar response currents are obtained with the negatively charged ferricyanide and the uncharged mPMS (5.9 µA and 6.7 µA, respectively, for 10 mM glucose), however, no response current is obtained with hexaammineruthenium(III), which has a strong positive charge. These results show that access of even very small mediators with strong charges to a buried active center can be almost completely blocked by the protein. DA - 2017/// PY - 2017/// DO - 10.3390/s17112636 VL - 17 IS - 11 UR - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=ORCID&SrcApp=OrcidOrg&DestLinkType=FullRecord&DestApp=WOS_CPL&KeyUT=WOS:000416790500198&KeyUID=WOS:000416790500198 KW - glucose dehydrogenase KW - flavin adenine dinucleotide KW - Aspergillus flavus KW - Burkholderia cepacia KW - enzyme sensor strip KW - mediated electron transfer KW - potassium ferricyanide KW - methoxy phenazine methosulfate KW - hexaammineruthenium chloride ER - TY - JOUR TI - X-ray structures of fructosyl peptide oxidases revealing residues responsible for gating oxygen access in the oxidative half reaction AU - Shimasaki, Tomohisa AU - Yoshida, Hiromi AU - Kamitori, Shigehiro AU - Sode, Koji T2 - Scientific Reports AB - Abstract Current enzymatic systems for quantifying glycated hemoglobin are based on the FAD-containing enzyme fructosyl peptide oxidase (FPOX). FPOX has substrate specificity for fructosyl- α N -valyl-histidine derived from proteolytic digestion of the N-terminus of the HbA1c β-chain. This study reports the X-ray structures of the wild-type and Asn56Ala (N56A) mutant of Phaeosphaeria nodorum fructosyl peptide oxidase (PnFPOX) to elucidate the residues responsible for the oxidative half-reaction. N56A showed decreased oxidase activity compared to the wild -type, while its dye-mediated dehydrogenase activity was higher than that of wild type. In wild-type PnFPOX, Asn56 forms a hydrogen bond with Lys274, thereby preventing it from forming a salt bridge with Asp54. By contrast, Lys274 of PnFPOX N56A moves toward Asp54, and they approach each other to form a salt bridge at a distance of 2.92–3.35 Å. Site-directed mutagenesis studies and protein channel analysis suggest that Asp54 assists in accepting oxygen properly at the position of the bound water molecule in the main oxygen channel. These results reveal that Asn56 in PnFPOX is essential for maintaining an effective oxygen accession path, and support the role of Asp54 as a gate keeper that cooperates with Lys274 to enable oxygen to reach the active site properly. DA - 2017/// PY - 2017/// DO - 10.1038/s41598-017-02657-5 VL - 7 IS - 1 UR - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=ORCID&SrcApp=OrcidOrg&DestLinkType=FullRecord&DestApp=WOS_CPL&KeyUT=WOS:000402690200006&KeyUID=WOS:000402690200006 ER - TY - JOUR TI - Novel fungal FAD glucose dehydrogenase derived from Aspergillus niger for glucose enzyme sensor strips AU - Sode, Koji AU - Loew, Noya AU - Ohnishi, Yosuke AU - Tsuruta, Hayato AU - Mori, Kazushige AU - Kojima, Katsuhiro AU - Tsugawa, Wakako AU - LaBelle, Jeffrey T. AU - Klonoff, David C. T2 - Biosensors & Bioelectronics AB - In this study, a novel fungus FAD dependent glucose dehydrogenase, derived from Aspergillus niger (AnGDH), was characterized. This enzyme's potential for the use as the enzyme for blood glucose monitor enzyme sensor strips was evaluated, especially by investigating the effect of the presence of xylose during glucose measurements. The substrate specificity of AnGDH towards glucose was investigated, and only xylose was found as a competing substrate. The specific catalytic efficiency for xylose compared to glucose was 1.8%. The specific activity of AnGDH for xylose at 5mM concentration compared to glucose was 3.5%. No other sugars were used as substrate by this enzyme. The superior substrate specificity of AnGDH was also demonstrated in the performance of enzyme sensor strips. The impact of spiking xylose in a sample with physiological glucose concentrations on the sensor signals was investigated, and it was found that enzyme sensor strips using AnGDH were not affected at all by 5mM (75mg/dL) xylose. This is the first report of an enzyme sensor strip using a fungus derived FADGDH, which did not show any positive bias at a therapeutic level xylose concentration on the signal for a glucose sample. This clearly indicates the superiority of AnGDH over other conventionally used fungi derived FADGDHs in the application for SMBG sensor strips. The negligible activity of AnGDH towards xylose was also explained on the basis of a 3D structural model, which was compared to the 3D structures of A. flavus derived FADGDH and of two glucose oxidases. DA - 2017/// PY - 2017/// DO - 10.1016/j.bios.2016.08.053 VL - 87 SP - 305-311 UR - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=ORCID&SrcApp=OrcidOrg&DestLinkType=FullRecord&DestApp=WOS_CPL&KeyUT=WOS:000390499600044&KeyUID=WOS:000390499600044 KW - FAD-dependent glucose dehydrogenase KW - Aspergillus niger KW - Aspergillus flavus KW - Glucose specificity KW - Xylose KW - BG Monitor ER - TY - JOUR TI - Development of an electrochemical detection system for measuring DNA methylation levels using methyl CpG-binding protein and glucose dehydrogenase-fused zinc finger protein AU - Lee, Jinhee AU - Yoshida, Wataru AU - Abe, Koichi AU - Nakabayashi, Kazuhiko AU - Wakeda, Hironobu AU - Hata, Kenichiro AU - Marquette, Christophe A. AU - Blum, Loic J. AU - Sode, Koji AU - Ikebukuro, Kazunori T2 - Biosensors & Bioelectronics AB - DNA methylation level at a certain gene region is considered as a new type of biomarker for diagnosis and its miniaturized and rapid detection system is required for diagnosis. Here we have developed a simple electrochemical detection system for DNA methylation using methyl CpG-binding domain (MBD) and a glucose dehydrogenase (GDH)-fused zinc finger protein. This analytical system consists of three steps: (1) methylated DNA collection by MBD, (2) PCR amplification of a target genomic region among collected methylated DNA, and (3) electrochemical detection of the PCR products using a GDH-fused zinc finger protein. With this system, we have successfully measured the methylation levels at the promoter region of the androgen receptor gene in 106 copies of genomic DNA extracted from PC3 and TSU-PR1 cancer cell lines. Since no sequence analysis or enzymatic digestion is required for this detection system, DNA methylation levels can be measured within 3 h with a simple procedure. DA - 2017/// PY - 2017/// DO - 10.1016/j.bios.2016.09.060 VL - 93 SP - 118-123 UR - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=ORCID&SrcApp=OrcidOrg&DestLinkType=FullRecord&DestApp=WOS_CPL&KeyUT=WOS:000399259000017&KeyUID=WOS:000399259000017 KW - DNA methylation KW - Electrochemical detection KW - Diagnosis KW - Zinc finger protein KW - Glucose dehydrogenase KW - Methyl-CpG binding domain ER - TY - JOUR TI - Characterization of Electron Mediator Preference of Aerococcus viridans-Derived Lactate Oxidase for Use in Disposable Enzyme Sensor Strips AU - Loew, Noya AU - Fitriana, Maya AU - Hiraka, Kentaro AU - Sode, Koji AU - Tsugawa, Wakako T2 - Sensors and Materials DA - 2017/// PY - 2017/// DO - 10.18494/SAM.2017.1731 VL - 29 IS - 12 SP - 1703-1711 UR - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=ORCID&SrcApp=OrcidOrg&DestLinkType=FullRecord&DestApp=WOS_CPL&KeyUT=WOS:000424184400005&KeyUID=WOS:000424184400005 KW - lactate oxidase KW - screen-printed carbon electrode KW - electron mediator KW - 1-methoxy-5-methyl phenazinium methyl sulfate KW - potassium ferricyanide KW - hexaammineruthenium(III) chloride KW - biomedical engineering ER - TY - JOUR TI - Applying a riboregulator as a new chromosomal gene regulation tool for higher glycogen production in Synechocystis sp PCC 6803 AU - Ueno, Kinuko AU - Sakai, Yuta AU - Shono, Chika AU - Sakamoto, Ippei AU - Tsukakoshi, Kaori AU - Hihara, Yukako AU - Sode, Koji AU - Ikebukuro, Kazunori T2 - Applied Microbiology and Biotechnology DA - 2017/// PY - 2017/// DO - 10.1007/s00253-017-8570-4 VL - 101 IS - 23-24 SP - 8465-8474 UR - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=ORCID&SrcApp=OrcidOrg&DestLinkType=FullRecord&DestApp=WOS_CPL&KeyUT=WOS:000415906900015&KeyUID=WOS:000415906900015 KW - Riboregulator KW - Synechocystis sp PCC 6803 KW - Cyanobacteria KW - cyabrB2 KW - Gene regulation KW - Glycogen production ER - TY - JOUR TI - Development of a screen-printed carbon electrode based disposable enzyme sensor strip for the measurement of glycated albumin AU - Hatada, Mika AU - Tsugawa, Wakako AU - Kamio, Eri AU - Loew, Noya AU - Klonoff, David C. AU - Sode, Koji T2 - Biosensors & Bioelectronics AB - Glycated proteins, such as glycated hemoglobin (HbA1c) or glycated albumin (GA) in the blood, are essential indicators of glycemic control for diabetes mellitus. Since GA, compared to HbA1c, is more sensitive to short term changes in glycemic levels, GA is expected to be used as an alternative or together with HbA1c as a surrogate marker indicator for glycemic control. In this paper we report the development of a sensing system for measuring GA by combining an enzyme analysis method, which is already used in clinical practice, with electrochemical principles. We used fructosyl amino acid oxidase, hexaammineruthenium(III) chloride as the electron mediator, and an inexpensive and economically attractive screen-printed carbon electrode. We used chronoamperometry to measure protease-digested GA samples. The developed sensor strips were able to measure protease-digested samples containing GA in very small sample volumes (1.3μL) within about 1min. We also prepared enzyme sensor strips suitable for clinical use in which the enzyme and the mediator were deposited and dried on. This sensor system showed a clear correlation between the GA concentration and the resulting current. The strips were stable following 3 months of storage at 37°C. We conclude that this disposable enzyme sensor strip system for measuring GA is suitable for point-of-care test (POCT) applications. DA - 2017/// PY - 2017/// DO - 10.1016/j.bios.2016.08.005 VL - 88 SP - 167-173 UR - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=ORCID&SrcApp=OrcidOrg&DestLinkType=FullRecord&DestApp=WOS_CPL&KeyUT=WOS:000389112700023&KeyUID=WOS:000389112700023 KW - Diabetes mellitus KW - Glycated albumin KW - Fructosyl amino acid oxidase KW - Hemoglobin A1c KW - Point-of-care testing KW - Screen-printed carbon electrode ER - TY - JOUR TI - Continuous operation of an ultra-low-power microcontroller using glucose as the sole energy source AU - Lee, Inyoung AU - Sode, Takashi AU - Loew, Noya AU - Tsugawa, Wakako AU - Lowe, Christopher Robin AU - Sode, Koji T2 - Biosensors & Bioelectronics AB - An ultimate goal for those engaged in research to develop implantable medical devices is to develop mechatronic implantable artificial organs such as artificial pancreas. Such devices would comprise at least a sensor module, an actuator module, and a controller module. For the development of optimal mechatronic implantable artificial organs, these modules should be self-powered and autonomously operated. In this study, we aimed to develop a microcontroller using the BioCapacitor principle. A direct electron transfer type glucose dehydrogenase was immobilized onto mesoporous carbon, and then deposited on the surface of a miniaturized Au electrode (7mm2) to prepare a miniaturized enzyme anode. The enzyme fuel cell was connected with a 100 μF capacitor and a power boost converter as a charge pump. The voltage of the enzyme fuel cell was increased in a stepwise manner by the charge pump from 330mV to 3.1V, and the generated electricity was charged into a 100μF capacitor. The charge pump circuit was connected to an ultra-low-power microcontroller. Thus prepared BioCapacitor based circuit was able to operate an ultra-low-power microcontroller continuously, by running a program for 17h that turned on an LED every 60s. Our success in operating a microcontroller using glucose as the sole energy source indicated the probability of realizing implantable self-powered autonomously operated artificial organs, such as artificial pancreas. DA - 2017/// PY - 2017/// DO - 10.1016/j.bios.2016.09.095 VL - 93 SP - 335-339 UR - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=ORCID&SrcApp=OrcidOrg&DestLinkType=FullRecord&DestApp=WOS_CPL&KeyUT=WOS:000399259000047&KeyUID=WOS:000399259000047 KW - Microcontroller KW - BioCapacitor KW - Enzyme fuel cell KW - Direct electron transfer KW - Implantable artificial organs KW - Self-powered KW - Glucose sensor ER - TY - JOUR TI - Irreversible electroporation for the ablation of pancreatic malignancies: A patient‐specific methodology AU - Latouche, Eduardo L. AU - Sano, Michael B. AU - Lorenzo, Melvin F. AU - Davalos, Rafael V. AU - Martin, Robert C. G., II T2 - Journal of Surgical Oncology AB - Background and Objectives Irreversible Electroporation (IRE) is a focal ablation technique highly attractive to surgical oncologists due to its non‐thermal nature that allows for eradication of unresectable tumors in a minimally invasive procedure. In this study, our group sought to address the challenge of predicting the ablation volume with IRE for pancreatic procedures. Methods In compliance with HIPAA and hospital IRB approval, we established a pre‐treatment planning methodology for IRE procedures in pancreas, which optimized treatment protocols for individual cases of locally advanced pancreatic cancer (LAPC). A new method for confirming treatment plans through intraoperative monitoring of tissue resistance was also proved feasible in three patients. Results Results from computational models showed good correlation with experimental data available in the literature. By implementing the proposed resistance measurement system 210 ± 26.1 (mean ± standard deviation) fewer pulses were delivered per electrode‐pair. Conclusion The proposed physics‐based pre‐treatment plan through finite element analysis and system for actively monitoring resistance changes can be paired to significantly reduce ablation times and risk of thermal effects during IRE procedures for LAPC. DA - 2017/2/10/ PY - 2017/2/10/ DO - 10.1002/JSO.24566 VL - 115 IS - 6 SP - 711-717 J2 - J Surg Oncol LA - en OP - SN - 0022-4790 1096-9098 UR - http://dx.doi.org/10.1002/JSO.24566 DB - Crossref KW - finite element analysis KW - impedance KW - IRE KW - pancreatic adenocarcinoma KW - real-time feedback KW - treatment planning ER - TY - JOUR TI - “Data characterizing microfabricated human blood vessels created via hydrodynamic focusing” AU - DiVito, Kyle A. AU - Daniele, Michael A. AU - Roberts, Steven A. AU - Ligler, Frances S. AU - Adams, André A. T2 - Data in Brief AB - This data article provides further detailed information related to our research article titled "Microfabricated Blood Vessels Undergo Neovascularization" (DiVito et al., 2017) [1], in which we report fabrication of human blood vessels using hydrodynamic focusing (HDF). Hydrodynamic focusing with advection inducing chevrons were used in concert to encase one fluid stream within another, shaping the inner core fluid into 'bullseye-like" cross-sections that were preserved through click photochemistry producing streams of cellularized hollow 3-dimensional assemblies, such as human blood vessels (Daniele et al., 2015a, 2015b, 2014, 2016; Roberts et al., 2016) [2], [3], [4], [5], [6]. Applications for fabricated blood vessels span general tissue engineering to organ-on-chip technologies, with specific utility in in vitro drug delivery and pharmacodynamics studies. Here, we report data regarding the construction of blood vessels including cellular composition and cell positioning within the engineered vascular construct as well as functional aspects of the tissues. DA - 2017/10// PY - 2017/10// DO - 10.1016/J.DIB.2017.07.011 VL - 14 SP - 156-162 J2 - Data in Brief LA - en OP - SN - 2352-3409 UR - http://dx.doi.org/10.1016/J.DIB.2017.07.011 DB - Crossref KW - Microfluidics KW - Ge1MA KW - Endothelial cell KW - Blood vessel KW - Microvessel KW - Organ-on-chip ER - TY - JOUR TI - Asymmetric Waveforms Decrease Lethal Thresholds in High Frequency Irreversible Electroporation Therapies AU - Sano, Michael B. AU - Fan, Richard E. AU - Xing, Lei T2 - Scientific Reports AB - Abstract Irreversible electroporation (IRE) is a promising non-thermal treatment for inoperable tumors which uses short (50–100 μs) high voltage monopolar pulses to disrupt the membranes of cells within a well-defined volume. Challenges with IRE include complex treatment planning and the induction of intense muscle contractions. High frequency IRE (H-FIRE) uses bursts of ultrashort (0.25–5 μs) alternating polarity pulses to produce more predictable ablations and alleviate muscle contractions associated with IRE. However, H-FIRE generally ablates smaller volumes of tissue than IRE. This study shows that asymmetric H-FIRE waveforms can be used to create ablation volumes equivalent to standard IRE treatments. Lethal thresholds (LT) of 505 V/cm and 1316 V/cm were found for brain cancer cells when 100 μs IRE and 2 μs symmetric H-FIRE waveforms were used. In contrast, LT as low as 536 V/cm were found for 2 μs asymmetric H-FIRE waveforms. Reversible electroporation thresholds were 54% lower than LTs for symmetric waveforms and 33% lower for asymmetric waveforms indicating that waveform symmetry can be used to tune the relative sizes of reversible and irreversible ablation zones. Numerical simulations predicted that asymmetric H-FIRE waveforms are capable of producing ablation volumes which were 5.8–6.3x larger than symmetric H-FIRE waveforms indicating that in vivo investigation of asymmetric waveforms is warranted. DA - 2017/1/20/ PY - 2017/1/20/ DO - 10.1038/SREP40747 VL - 7 IS - 1 J2 - Sci Rep LA - en OP - SN - 2045-2322 UR - http://dx.doi.org/10.1038/SREP40747 DB - Crossref ER - TY - JOUR TI - A Comprehensive Characterization of Parameters Affecting High-Frequency Irreversible Electroporation Lesions AU - Miklovic, Tyler AU - Latouche, Eduardo L. AU - DeWitt, Matthew R. AU - Davalos, Rafael V. AU - Sano, Michael B. T2 - Annals of Biomedical Engineering DA - 2017/7/18/ PY - 2017/7/18/ DO - 10.1007/S10439-017-1889-2 VL - 45 IS - 11 SP - 2524-2534 J2 - Ann Biomed Eng LA - en OP - SN - 0090-6964 1573-9686 UR - http://dx.doi.org/10.1007/S10439-017-1889-2 DB - Crossref KW - Focal ablation KW - Non-thermal therapy KW - H-FIRE KW - Tissue phantom ER - TY - JOUR TI - Analysis of muscle fiber conduction velocity during finger flexion and extension after stroke AU - Conrad, Megan O. AU - Qiu, Dan AU - Hoffmann, Gilles AU - Zhou, Ping AU - Kamper, Derek G. T2 - Topics in Stroke Rehabilitation AB - Background: Stroke survivors experience greater strength deficits during finger extension than finger flexion. Prior research indicates relatively little observed weakness is directly attributable to muscle atrophy. Changes in other muscle properties, however, may contribute to strength deficits.Objectives: This study measured muscle fiber conduction velocity (MFCV) in a finger flexor and extensor muscle to infer changes in muscle fiber-type after stroke.Methods: Conduction velocity was measured using a linear EMG surface electrode array for both extensor digitorum communis and flexor digitorum superficialis in 12 stroke survivors with chronic hand hemiparesis and five control subjects. Measurements were made in both hands for all subjects. Stroke survivors had either severe (n = 5) or moderate (n = 7) hand impairment.Results: Absolute MFCV was significantly lower in the paretic hand of severely impaired stroke patients compared to moderately impaired patients and healthy control subjects. The relative MFCV between the two hands, however, was quite similar for flexor muscles across all subjects and for extensor muscles for the neurologically intact control subjects. However, MFCV for finger extensors was smaller in the paretic as compared to the nonparetic hand for both groups of stroke survivors.Conclusions: One explanation for reduced MFCV may be a type-II to type-I muscle fiber, especially in extrinsic extensors. Clinically, therapists may use this information to develop therapeutic exercises targeting loss of type-II fiber in extensor muscles. DA - 2017/1/5/ PY - 2017/1/5/ DO - 10.1080/10749357.2016.1277482 VL - 24 IS - 4 SP - 262-268 J2 - Topics in Stroke Rehabilitation LA - en OP - SN - 1074-9357 1945-5119 UR - http://dx.doi.org/10.1080/10749357.2016.1277482 DB - Crossref KW - Stroke KW - muscle KW - conduction velocity KW - finger KW - EMG KW - fiber ER - TY - JOUR TI - Intersegmental kinetics significantly impact mapping from finger musculotendon forces to fingertip forces AU - Qiu, Dan AU - Lee, Sang Wook AU - Amine, Mukarram AU - Kamper, Derek G. T2 - Journal of Biomechanics AB - Predicting the fingertip force vector resulting from excitation of a given muscle remains a challenging but essential task in finger biomechanical modeling. While the conversion of musculotendon force to fingertip force can significantly be affected by finger posture, current techniques utilizing geometric moment arms may not capture such complex postural effects. Here, we attempted to elucidate the postural effects on the mapping between musculotendon force and fingertip force through in vitro experiments. Computer-controlled tendon loading was implemented on the 7 index finger musculotendons of 5 fresh-frozen cadaveric hands across different postures. The resulting fingertip forces/moments were used to compute the effective static moment arm (ESMA), relating tendon force to joint torque, at each joint. The ESMAs were subsequently modeled in three different manners: independent of joint angle; dependent only upon the corresponding joint angle; or dependent upon all joint angles. We found that, for the reconstruction of the fingertip force vector, the multi-joint ESMA model yielded the best outcome, both in terms of direction and magnitude of the vector (mean reconstruction error <4° in direction and <2% in the magnitude), which indicates that intersegmental force transmission through a joint is affected by the posture of neighboring joints. Interestingly, the ESMA model that considers geometric changes of individual joints, the standard model used in biomechanical stimulations, often yielded worse reconstruction results than the simple constant-value ESMA model. Our results emphasize the importance of accurate description of the multi-joint dependency of the conversion of tendon force to joint moment for proper prediction of fingertip force direction. DA - 2017/12// PY - 2017/12// DO - 10.1016/J.JBIOMECH.2017.10.004 VL - 65 SP - 82-88 J2 - Journal of Biomechanics LA - en OP - SN - 0021-9290 UR - http://dx.doi.org/10.1016/J.JBIOMECH.2017.10.004 DB - Crossref KW - Index finger KW - Finger posture KW - Musculotendon KW - Fingertip force KW - Moment arm KW - Extensor mechanism KW - Force distribution ER - TY - JOUR TI - Synthetic beta cells for fusion-mediated dynamic insulin secretion AU - Chen, Zhaowei AU - Wang, Jinqiang AU - Sun, Wujin AU - Archibong, Edikan AU - Kahkoska, Anna R AU - Zhang, Xudong AU - Lu, Yue AU - Ligler, Frances S AU - Buse, John B AU - Gu, Zhen T2 - Nature Chemical Biology AB - Generating artificial pancreatic beta cells by using synthetic materials to mimic glucose-responsive insulin secretion in a robust manner holds promise for improving clinical outcomes in people with diabetes. Here, we describe the construction of artificial beta cells (AβCs) with a multicompartmental 'vesicles-in-vesicle' superstructure equipped with a glucose-metabolism system and membrane-fusion machinery. Through a sequential cascade of glucose uptake, enzymatic oxidation and proton efflux, the AβCs can effectively distinguish between high and normal glucose levels. Under hyperglycemic conditions, high glucose uptake and oxidation generate a low pH (<5.6), which then induces steric deshielding of peptides tethered to the insulin-loaded inner small liposomal vesicles. The peptides on the small vesicles then form coiled coils with the complementary peptides anchored on the inner surfaces of large vesicles, thus bringing the membranes of the inner and outer vesicles together and triggering their fusion and insulin 'exocytosis'. DA - 2017/10/30/ PY - 2017/10/30/ DO - 10.1038/NCHEMBIO.2511 VL - 14 IS - 1 SP - 86-93 J2 - Nat Chem Biol LA - en OP - SN - 1552-4450 1552-4469 UR - http://dx.doi.org/10.1038/NCHEMBIO.2511 DB - Crossref ER - TY - JOUR TI - An Adaptive Classification Strategy for Reliable Locomotion Mode Recognition AU - Liu, M. AU - Zhang, F. AU - Huang, H. T2 - Sensors AB - Algorithms for locomotion mode recognition (LMR) based on surface electromyography and mechanical sensors have recently been developed and could be used for the neural control of powered prosthetic legs. However, the variations in input signals, caused by physical changes at the sensor interface and human physiological changes, may threaten the reliability of these algorithms. This study aimed to investigate the effectiveness of applying adaptive pattern classifiers for LMR. Three adaptive classifiers, i.e., entropy-based adaptation (EBA), LearnIng From Testing data (LIFT), and Transductive Support Vector Machine (TSVM), were compared and offline evaluated using data collected from two able-bodied subjects and one transfemoral amputee. The offline analysis indicated that the adaptive classifier could effectively maintain or restore the performance of the LMR algorithm when gradual signal variations occurred. EBA and LIFT were recommended because of their better performance and higher computational efficiency. Finally, the EBA was implemented for real-time human-in-the-loop prosthesis control. The online evaluation showed that the applied EBA effectively adapted to changes in input signals across sessions and yielded more reliable prosthesis control over time, compared with the LMR without adaptation. The developed novel adaptive strategy may further enhance the reliability of neurally-controlled prosthetic legs. DA - 2017/9/4/ PY - 2017/9/4/ DO - 10.3390/s17092020 VL - 17 IS - 9 SP - 2020 SN - 1424-8220 UR - http://dx.doi.org/10.3390/s17092020 KW - locomotion mode recognition KW - powered prosthesis leg KW - adaptive pattern classifier KW - surface electromyography KW - and human-in-the-loop ER - TY - CONF TI - Musculoskeletal model for simultaneous and proportional control of 3-DOF hand and wrist movements from EMG signals AU - Pan, Lizhi AU - Crouch, Dustin AU - Huang, He T2 - 2017 8th International IEEE/EMBS Conference on Neural Engineering (NER) AB - Recently, we proposed a musculoskeletal model to simultaneously predict motion along metacarpophalangeal (MCP) and wrist flexion/extension degrees-of-freedom (DOFs) from surface electromyography (EMG) signals. Since wrist pronation/supination is also functionally important, we extended the musculoskeletal model to simultaneously estimate wrist pronation/supination in addition to wrist and MCP flexion/extension from surface EMG signals of six corresponding muscles. Kinematic data and surface EMG signals were acquired synchronously from an able-bodied subject. The subject was instructed to perform single-DOF movements at fixed or variable speed and simultaneous 3-DOF movements at variable speed during the experiment. The model included six Hill-type actuators, each with a contractile element and a parallel elastic element. Seven parameters were optimized for each of the six muscles. The average Pearson's correlation coefficient (r) between measured and estimated joint angles across all trials was 0.91, indicating high positive correlation. The results demonstrated that the proposed model could feasibly simultaneously estimate 3-DOF joint angles during either independent-DOF or simultaneous 3-DOF movements from EMG signals. Our results promote the potential of the EMG-driven musculoskeletal model for clinical applications, such as prosthesis control. C2 - 2017/5// C3 - 2017 8th International IEEE/EMBS Conference on Neural Engineering (NER) DA - 2017/5// DO - 10.1109/ner.2017.8008356 SP - 325-328 PB - IEEE SN - 9781509046034 UR - http://dx.doi.org/10.1109/ner.2017.8008356 DB - Crossref ER - TY - CONF TI - Comparing parallel and sequential control parameter tuning for a powered knee prosthesis AU - Wen, Yue AU - Brandt, Andrea AU - Liu, Ming AU - Huang, He Helen AU - Si, Jennie T2 - 2017 IEEE International Conference on Systems, Man and Cybernetics (SMC) AB - Powered knee prostheses, compared to traditional energetically-passive knee prostheses, greatly enhance the mobility of transfemoral amputees. However, powered prostheses have a large number of control parameters that must be adjusted for individual amputee users, which presents a great challenge for clinical use. To address this challenge, we proposed and compared 2 automatic tuning strategies (i.e. parallel and sequential) using our newly developed optimal adaptive dynamic programming (ADP) tuner that objectively tuned the control parameters of an experimental powered knee prosthesis to mimic the knee profile of an able-bodied person (i.e. reference profile). With the parallel tuning strategy, we tuned all control parameters during the stance and the swing phases simultaneously. With the sequential tuning strategy, we alternately tuned stance or swing phase control parameters while fixing the remaining parameters. One able-bodied subject with a prosthesis adapter and one transfemoral amputee subject walked with the experimental powered knee prosthesis under both tuning strategies. Results show that with both tuning strategies, the ADP tuner successfully tuned the impedance parameters to match the prosthetic knee profile to the reference profile. Additionally, the parallel strategy outperformed the sequential strategy with better convergence to the reference profile. Interestingly, with the sequential tuning strategy, tuning during the swing phase greatly impacted the subsequent stance phase profile, but the impact was not as great when the order of tuning was switched. The ability to simultaneously adjust all control parameters with ADP using a parallel strategy may be a preferred solution for the current high-dimension control challenge, which may lead to more advanced, adaptive powered knee prostheses. C2 - 2017/10// C3 - 2017 IEEE International Conference on Systems, Man, and Cybernetics (SMC) DA - 2017/10// DO - 10.1109/smc.2017.8122863 VL - 2017-January SP - 1716-1721 PB - IEEE SN - 9781538616451 UR - http://dx.doi.org/10.1109/smc.2017.8122863 DB - Crossref ER - TY - CONF TI - NREL-Exo: A 4-DoFs wearable hip exoskeleton for walking and balance assistance in locomotion AU - Zhang, Ting AU - Tran, Minh AU - Huang, He Helen T2 - 2017 IEEE/RSJ International Conference on Intelligent Robots and Systems (IROS) AB - In this paper, we presented a high-power, self-balancing, passively and software-controlled active compliant, and wearable hip exoskeleton to provide walking and balance assistance. The device features powered hip abduction/adduction (HAA) and hip flexion/extension (HFE) modules to provide assistance in both sagittal and frontal planes. Each module's actuation unit employs a Series Elastic Actuator (SEA) to achieve passive compliance. The hip exoskeleton can work in two basic operation modes: human-in-charge and robot-in-charge. Both modes are integrated into the low-level controller based on the admittance control, making transitions smooth and stable. A new balance controller based on the “extrapolated center of mass” (XCoM) concept is presented for real-time control hip abduction/adduction to keep the center of mass (CoM) within the support polygon. The exoskeleton controller is designed to encourage participation in walking instead of overriding users' intrinsic behavior to achieve effective assistance and training. Our preliminary experiments on a healthy subject using the hip exoskeleton demonstrated the potential effectiveness of the device and controller in assisting locomotion. C2 - 2017/9// C3 - 2017 IEEE/RSJ International Conference on Intelligent Robots and Systems (IROS) DA - 2017/9// DO - 10.1109/iros.2017.8202201 VL - 2017-September SP - 508-513 PB - IEEE SN - 9781538626825 UR - http://dx.doi.org/10.1109/iros.2017.8202201 DB - Crossref ER - TY - CONF TI - A scalable shear and normal force sensor for prosthetic sensing AU - Agcayazi, Talha AU - McKnight, Michael AU - Sotory, Peter AU - Huang, Helen AU - Ghosh, Tushar AU - Bozkurt, Alper T2 - 2017 IEEE SENSORS AB - Current techniques of stress measurement to assess comfort for prosthetic limbs focus on resolving different forces as well as the directions for each force. The sophistication introduced by spatially scaling these techniques for the entire interface with the difficulty of integration in the current prosthetic limbs call for a more intelligent design. In this work, we introduce the design and experimental results of a capacitive shear and normal force sensor. Our force sensor works with a single transduction point to ease the process of spatial scaling and is integrated seamlessly on the liner component of the prosthetic limb. We provide proof-of-concept results of both shear and normal force sensing with our capacitive force sensor. C2 - 2017/10// C3 - 2017 IEEE SENSORS DA - 2017/10// DO - 10.1109/icsens.2017.8233977 VL - 2017-December SP - 1-3 PB - IEEE SN - 9781509010127 UR - http://dx.doi.org/10.1109/icsens.2017.8233977 DB - Crossref ER - TY - CHAP TI - Macrophages’ role in tissue disease and regeneration AU - Gaffney, L. AU - Warren, P. AU - Wrona, E.A. AU - Fisher, M.B. AU - Freytes, D.O. T2 - Results and Problems in Cell Differentiation AB - Inflammation is an essential component of the normal mammalian host tissue response and plays an important role during cardiovascular and musculoskeletal diseases. Given the important role of inflammation on the host tissue response after injury, understanding this process represents essential aspects of biomedical research, tissue engineering, and regenerative medicine. Macrophages are central players during the inflammatory response with an extensive role during wound healing. These cells exhibit a spectrum of activation states that span from pro-inflammatory to pro-healing phenotypes. The phenotype of the macrophages can have profound influences on the progression of disease or injury. As such, understanding and subsequent modulation of macrophage phenotype represents an exciting target area for regenerative medicine therapies. In this chapter, we describe the role of macrophages in specific cases of injury and disease. After myocardial infarction, a biphasic response of pro- and anti-inflammatory macrophages are involved in the remodeling process. In volumetric muscle loss, there is an intricate communication between inflammatory cells and progenitor cells affecting repair processes. Osteoarthritis is characterized by increased levels of pro-inflammatory macrophages over an extended period of time with significant impact on the progression of the disease. By harnessing the complex role of macrophages, enhanced therapeutic treatments can be developed that enhance the normal healing response as well as help the survival of therapeutic cells delivered to the site of injury. PY - 2017/// DO - 10.1007/978-3-319-54090-0_10 VL - 62 SP - 245-271 UR - http://www.scopus.com/inward/record.url?eid=2-s2.0-85019009634&partnerID=MN8TOARS ER - TY - JOUR TI - BMP protein-mediated crosstalk between inflammatory cells and human pluripotent stem cell-derived cardiomyocytes AU - Pallotta, Isabella AU - Sun, Bruce AU - Wrona, Emily A. AU - Freytes, Donald O. T2 - Journal of Tissue Engineering and Regenerative Medicine AB - Following cardiac injury, the ischaemic heart tissue is characterized by the invasion of pro-inflammatory (M1) and pro-healing (M2) macrophages. Any engineered cardiac tissue will inevitably interact with the inflammatory environment found at the site of myocardial infarction at the time of implantation. However, the interactions between the inflammatory and the cardiac repair cells remain poorly understood. Here we recapitulated in vitro some of the important cellular events found at the site of myocardial injury, such as macrophage recruitment and their effect on cardiac differentiation and maturation, by taking into account the involvement of paracrine-mediated signalling. By using a 3D inverted invasion assay, we found that cardiomyocyte (CM) conditioned medium can trigger the recruitment of pro-inflammatory (M1) macrophages, through a mechanism that involves, in part, CM-derived BMP4. Pro-inflammatory (M1) macrophages were also found to affect CM proliferation and differentiation potential, in part due to BMP molecules secreted by macrophages. These effects involved the activation of the canonical outside-in signalling pathways, such as SMAD1,5,8, which are known to be activated during myocardial injury in vivo. In the present study we propose a new role for CM- and macrophage-derived BMP proteins during the recruitment of macrophage subtypes and the maturation of repair cells, representing an important step towards creating a functional cardiac patch with superior therapeutic properties. Copyright © 2015 John Wiley & Sons, Ltd. DA - 2017/5// PY - 2017/5// DO - 10.1002/TERM.2045 VL - 11 IS - 5 SP - 1466–1478 SN - 1932-6254 UR - http://dx.doi.org/10.1002/TERM.2045 KW - cardiomyocytes KW - macrophages KW - inflammation KW - BMP KW - migration KW - tissue engineering KW - regenerative medicine ER - TY - BOOK TI - High frequency piezo-composite micromachined ultrasound transducer array technology for biomedical imaging AU - Jiang, X. AU - Li, S. AU - Kim, J. AU - Ma, J. AB - In this monograph, the authors reports the current advancement in high frequency piezoelectric crystal micromachined ultrasound transducers and arrays and their biomedical applications. Piezoelectric ultrasound transducers operating at high frequencies (> 20 MHz) are of increasing demand in recent years for medical imaging and biological particle manipulation involved therapy. The performances of transducers greatly rely on the properties of the piezoelectric materials and transduction structures, including piezoelectric coefficient (d), electromechanical coupling coefficient (k), dielectric permittivity (e) and acoustic impedance (Z).Piezo-composite structures are preferred because of their relatively high electromechanical coupling coefficient and low acoustic impedance. A number of piezo-composite techniques have been developed, namely “dice and fill,” “tape-casting,” “stack and bond,” “interdigital phase bonding,” “laser micromachining” and “micro-molding”. However, these techniques are either difficult to achieve fine features or not suitable for manufacturing of high frequency ultrasound transducers (> 20 MHz). The piezo-composite micromachined ultrasound transducers (PC-MUT) technique discovered over the last 10 years or so has demonstrated high performance high frequency piezo-composite ultrasound transducers.In this monograph, piezoelectric materials used for high frequency transducers is introduced first. Next, the benefits and theory of piezo composites is presented, followed by the design criteria and fabrication methods. Biomedical applications using piezo composites micromachined ultrasound transducers (PC-MUT) and arrays will also be reported, in comparison with other ultrasound transducer techniques. The final part of this monograph describes challenges and future perspectives of this technique for biomedical applications. DA - 2017/// PY - 2017/// DO - 10.1115/1.860441 PB - New York, NY, USA: ASME Press ER - TY - JOUR TI - Macrophages' role in tissue disease and regeneration AU - Gaffney, L. AU - Warren, P. AU - Wrona, E. A. AU - Fisher, M. B. AU - Freytes, D. O. T2 - Macrophages: origin, functions and biointervention DA - 2017/// PY - 2017/// VL - 62 SP - 245-271 ER - TY - JOUR TI - A melanin-mediated cancer immunotherapy patch AU - Ye, Yanqi AU - Wang, Chao AU - Zhang, Xudong AU - Hu, Quanyin AU - Zhang, Yuqi AU - Liu, Qi AU - Wen, Di AU - Milligan, Joshua AU - Bellotti, Adriano AU - Huang, Leaf AU - Dotti, Gianpietro AU - Gu, Zhen T2 - SCIENCE IMMUNOLOGY AB - Melanin is capable of transforming 99.9% of the absorbed sunlight energy into heat, reducing the risk of skin cancer. We here develop a melanin-mediated cancer immunotherapy strategy through a transdermal microneedle patch. B16F10 whole tumor lysate containing melanin is loaded into polymeric microneedles that allow sustained release of the lysate upon insertion into the skin. In combination with the near-infrared light irradiation, melanin in the patch mediates the generation of heat, which further promotes tumor-antigen uptake by dendritic cells, and leads to enhanced antitumor vaccination. We found that the spatiotemporal photoresponsive immunotherapy increases infiltration of polarized T cells and local cytokine release. These immunological effects increase the survival of mice after tumor challenge and elicited antitumor effects toward established primary tumor and distant tumor. Collectively, melanin generates local heat, boosts T cell activities by transdermal vaccines, and promotes antitumor immune responses. DA - 2017/11// PY - 2017/11// DO - 10.1126/sciimmunol.aan5692 VL - 2 IS - 17 SP - SN - 2470-9468 ER - TY - JOUR TI - Smart materials and systems as artificial pancreas for diabetes treatment AU - Zhang, Y. Q. AU - Wang, M. Z. AU - Yu, J. C. AU - Gu, Z. T2 - Smart materials for tissue engineering: applications DA - 2017/// PY - 2017/// VL - 25 SP - 358-381 ER - TY - CONF TI - Enhancing gait balance via a 4-DoFs wearable hip exoskeleton AU - Zhang, T. AU - Huang, He AB - One limitation of the current lower-limb exoskeletons is that they do not provide the function of maintaining the lateral stability. During walking, beyond the forward step length regulated by hip flexion/extension (HFE), adaptation of the step width, which can be adjusted by hip abduction/adduction (HAA) motions, is also crucial for walking stability. Biomechanical studies have indicated that the step width and the mediolateral foot placement at the end of each step can be estimated based on the center of mass (CoM), which is assumed to be located at the pelvis. The extrapolated center of mass (XCoM) is obtained by vertically projecting the CoM's position to the ground in the direction of its velocity. The present study is to develop a novel, high-power, self-balancing, and passively and software-controlled actively compliant hip exoskeleton that can assist with movement and maintain balance in both the sagittal and frontal planes. C2 - 2017/// C3 - 2017 International Symposium on Wearable Robotics and Rehabilitation (WEROB) DA - 2017/// DO - 10.1109/werob.2017.8383824 SP - 23–24 ER - TY - CONF TI - Characterization of hysteresis in resistive bend sensors AU - Hollingshead, R. L. AU - Henry-Etesse, L. AU - Tankere, E. AU - Kamper, D. AU - Tan, T. AB - Sensing of finger joint rotation can be difficult due to the hand's many degrees-of-freedom within a small space. The low profile and lightweight of resistive bend sensors make their use in measuring joint rotation an option. Certain properties of the bend sensors have been investigated, however investigation of the effect of hysteresis when bending and straightening the sensor has not been investigated. In this study, two inch resistive sensors were bent from 0° to 90° and back to 0° while measuring the voltage output. Three calibration models were fitted to the measured data and used to determine the sensor's accuracy and hysteresis effects. Both the quadratic and cubic fits demonstrated strong non-monotonic behavior at low bend angles. Using the exponential model, a hysteresis effect of 9.2% was observed. Accuracy at low bend angles improved by approximately 5° when the effect of hysteresis was considered. C2 - 2017/// C3 - 2017 International Symposium on Wearable Robotics and Rehabilitation (WEROB) DA - 2017/// DO - 10.1109/werob.2017.8383842 SP - 54-55 ER - TY - JOUR TI - Engineering platelet-mimicking drug delivery vehicles AU - Hu, Quanyin AU - Bomba, Hunter N. AU - Gu, Zhen T2 - FRONTIERS OF CHEMICAL SCIENCE AND ENGINEERING DA - 2017/12// PY - 2017/12// DO - 10.1007/s11705-017-1614-6 VL - 11 IS - 4 SP - 624-632 SN - 2095-0187 KW - drug delivery KW - platelets KW - nanomedicine KW - bio-inspired KW - biomimetic ER - TY - CONF TI - Using monkey hand exoskeleton to explore finger passive joint movement response in primary motor cortex AU - Qian, K. AU - Anjos, L. A. AU - Balasubramanian, K. AU - Stilson, K. AU - Balcer, C. AU - Hatsopoulos, N. G. AU - Kamper, D. G. AB - While neurons in primary motor cortex (M1) have been shown to respond to sensory stimuli, exploration of this phenomenon has proven challenging. Accurate and repeatable presentation of sensory inputs is difficult. Here, we describe a novel paradigm to study response to joint motion and fingertip force. We employed a custom exoskeleton to drive index finger metacarpophalangeal joint (MCP) of a macaque to follow sinusoid trajectories at 4 different frequencies (0.2, 0.5, 1, 2Hz) and 2 movement ranges (68.4, 34.2 degrees). We highlight results of a specific M1 unit that displayed sensitivity to direction (more active during flexion than extension), frequency (greater firing rate at higher frequencies), and movement amplitude (higher rate at larger amplitude). Joint movement trajectories were accurately reconstructed from this single unit with mean R2 =0.64 ± 0.13. The exoskeleton holds promise for examination of sensory feedback. In addition, it can be used as an external device controlled by a brain-machine interface (BMI) system. The proprioceptive related units in M1 may contribute to improving BMI control performance. C2 - 2017/// C3 - Proceedings of annual international conference of the ieee engineering DA - 2017/// DO - 10.1109/embc.2017.8037642 SP - 3624-3627 ER - TY - CONF TI - Effects of output speed threshold on real-time continuous EMG human-machine interface control AU - Chung, S. H. AU - Crouch, D. L. AU - Huang, He AB - Continuous EMG control of human-machine interfaces (HMIs) enables more direct and flexible control of output movements than discrete classification algorithms. However, EMG is a non-stationary signal and can add noise to continuous EMG control output. We studied the effect of an output speed threshold method to stabilize the movement prediction of a 2-DOF musculoskeletal model-based continuous EMG controller during a real-time virtual task. In each of several trials, three able-bodied subjects were instructed to move and align the palm and finger segments of a virtual hand with four different target postures on a computer screen. Three different thresholds on the model's predicted angular speed were applied in a randomized order across trials: no threshold, medium threshold (15 °/sec), and high threshold (30 °/sec); the virtual hand did not move if the predicted angular speed at the next timepoint did not exceed the threshold. We recorded completion time, overshoot, jerk, and number of failed trials to quantify task performance. In a separate block of trials, subjects reported their threshold preference following multiple pairwise comparisons. The number of overshoots decreased and jerk magnitude increased with higher threshold levels. The average completion time was lowest with the medium threshold for 2 subjects. All 3 subjects had lower failed trials with either the medium or high threshold. The subject preference score showed an inverse trend with the number of failed trials. In summary, the presented threshold method was successful in reducing overshoot and trial failures, and a threshold was preferred by all subjects over no threshold. Thus, an output speed threshold may improve the functional performance and user satisfaction of continuous EMG control for HMIs, such as powered upper limb prostheses. C2 - 2017/// C3 - Ieee international conference on systems man and cybernetics conference DA - 2017/// DO - 10.1109/smc.2017.8122805 VL - 2017-January SP - 1375–1380 UR - http://www.scopus.com/inward/record.url?eid=2-s2.0-85044244968&partnerID=MN8TOARS ER - TY - CONF TI - ARFI variance of acceleration (VoA) for noninvasive characterization of human carotid plaques in vivo AU - Torres, G. AU - Czernuszewicz, T. J. AU - Homeister, J. W. AU - Farber, M. A. AU - Gallippi, C. M. AB - Rather than degree of stenosis, assessing plaque structure and composition is relevant to discerning risk for plaque rupture with downstream ischemic event. The structure and composition of carotid plaque has been assessed noninvasively using Acoustic Radiation Force Impulse (ARFI) ultrasound imaging. In particular, ARFI-derived peak displacement (PD) estimations have been demonstrated for discriminating soft (lipid rich necrotic core (LRNC) or intraplaque hemorrhage (IPH)) from stiff (collagen (COL) or calcium (CAL)) plaque features; however, PD did not differentiate LRNC from IPH or COL from CAL. The purpose of this study is to evaluate a new ARFI-based measurement, the variance of acceleration (VoA), for differentiating among soft and stiff plaque components. Both PD and VoA results were obtained in vivo for a human carotid plaque acquired in a previous study and matched to a histological standard analyzed by a pathologist. With VoA, plaque feature contrast was increased by an average of 60% in comparison to PD. C2 - 2017/// C3 - Proceedings of annual international conference of the ieee engineering DA - 2017/// DO - 10.1109/embc.2017.8037484 SP - 2984-2987 ER - TY - JOUR TI - Self-renewing monolayer of primary colonic or rectal epithelial cells AU - Wang, Y. L. AU - DiSalvo, M. AU - Gunasekara, D. B. AU - Dutton, J. AU - Proctor, A. AU - Lebhar, M. S. AU - Williamson, I. A. AU - Speer, J. AU - Howard, R. L. AU - Smiddy, N. M. AU - Bultman, S. J. AU - Sims, C. E. AU - Magness, S. T. AU - Allbritton, N. L. T2 - Cellular and Molecular Gastroenterology and Hepatology DA - 2017/// PY - 2017/// VL - 4 IS - 1 SP - 165- ER - TY - JOUR TI - Rise of the Pigs: Utilization of the Porcine Model to Study Musculoskeletal Biomechanics and Tissue Engineering During Skeletal Growth AU - Cone, Stephanie G. AU - Warren, Paul B. AU - Fisher, Matthew B. T2 - TISSUE ENGINEERING PART C-METHODS AB - Large animal models play an essential role in the study of tissue engineering and regenerative medicine (TERM), as well as biomechanics. The porcine model has been increasingly used to study the musculoskeletal system, including specific joints, such as the knee and temporomandibular joints, and tissues, such as bone, cartilage, and ligaments. In particular, pigs have been utilized to evaluate the role of skeletal growth on the biomechanics and engineered replacements of these joints and tissues. In this review, we explore the publication history of the use of pig models in biomechanics and TERM discuss interspecies comparative studies, highlight studies on the effect of skeletal growth and other biological considerations in the porcine model, and present challenges and emerging opportunities for using this model to study functional TERM. DA - 2017/11// PY - 2017/11// DO - 10.1089/ten.tec.2017.0227 VL - 23 IS - 11 SP - 763-780 SN - 1937-3392 KW - animal models KW - ligament and tendon KW - cartilage KW - bone KW - skeletal muscle ER - TY - JOUR TI - Quantifying center of pressure variability in chondrodystrophoid dogs AU - Blau, S. R. AU - Davis, L. M. AU - Gorney, A. M. AU - Dohse, C. S. AU - Williams, K. D. AU - Lim, J-H AU - Pfitzner, W. G. AU - Laber, E. AU - Sawicki, G. S. AU - Olby, N. J. T2 - VETERINARY JOURNAL AB - The center of pressure (COP) position reflects a combination of proprioceptive, motor and mechanical function. As such, it can be used to quantify and characterize neurologic dysfunction. The aim of this study was to describe and quantify the movement of COP and its variability in healthy chondrodystrophoid dogs while walking to provide a baseline for comparison to dogs with spinal cord injury due to acute intervertebral disc herniations. Fifteen healthy adult chondrodystrophoid dogs were walked on an instrumented treadmill that recorded the location of each dog’s COP as it walked. Center of pressure (COP) was referenced from an anatomical marker on the dogs’ back. The root mean squared (RMS) values of changes in COP location in the sagittal (y) and horizontal (x) directions were calculated to determine the range of COP variability. Three dogs would not walk on the treadmill. One dog was too small to collect interpretable data. From the remaining 11 dogs, 206 trials were analyzed. Mean RMS for change in COPx per trial was 0.0138 (standard deviation, SD 0.0047) and for COPy was 0.0185 (SD 0.0071). Walking speed but not limb length had a significant effect on COP RMS. Repeat measurements in six dogs had high test retest consistency in the x and fair consistency in the y direction. In conclusion, COP variability can be measured consistently in dogs, and a range of COP variability for normal chondrodystrophoid dogs has been determined to provide a baseline for future studies on dogs with spinal cord injury. DA - 2017/8// PY - 2017/8// DO - 10.1016/j.tvjl.2017.07.001 VL - 226 SP - 26-31 SN - 1532-2971 KW - Locomotion KW - Kinematics KW - Center of gravity ER - TY - JOUR TI - Locally Induced Adipose Tissue Browning by Microneedle Patch for Obesity Treatment AU - Zhang, Yuqi AU - Liu, Qiongming AU - Yu, Jicheng AU - Yu, Shuangjiang AU - Wang, Jinqiang AU - Qiang, Li AU - Gu, Zhen T2 - ACS NANO AB - Obesity is one of the most serious public health problems in the 21st century that may lead to many comorbidities such as type-2 diabetes, cardiovascular diseases, and cancer. Current treatments toward obesity including diet, physical exercise, pharmacological therapy, as well as surgeries are always associated with low effectiveness or undesired systematical side effects. In order to enhance treatment efficiency with minimized side effects, we developed a transcutaneous browning agent patch to locally induce adipose tissue transformation. This microneedle-based patch can effectively deliver browning agents to the subcutaneous adipocytes in a sustained manner and switch on the “browning” at the targeted region. It is demonstrated that this patch reduces treated fat pad size, increases whole body energy expenditure, and improves type-2 diabetes in vivo in a diet-induced obesity mouse model. DA - 2017/9// PY - 2017/9// DO - 10.1021/acsnano.7b04348 VL - 11 IS - 9 SP - 9223-9230 SN - 1936-086X KW - drug delivery KW - microneedle patch KW - obesity KW - browning agent KW - adipose tissue ER - TY - JOUR TI - KO of 5-InsP(7) kinase activity transforms the HCT116 colon cancer cell line into a hypermetabolic, growth-inhibited phenotype AU - Gu, Chunfang AU - Nguyen, Hoai-Nghia AU - Ganini, Douglas AU - Chen, Zhaowei AU - Jessen, Henning J. AU - Gu, Zhen AU - Wang, Huanchen AU - Shears, Stephen B. T2 - PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA AB - The inositol pyrophosphates 5-InsP7 (diphosphoinositol pentakisphosphate) and 1,5-InsP8 (bis-diphosphoinositol tetrakisphosphate) are highly energetic cellular signals interconverted by the diphosphoinositol pentakisphosphate kinases (PPIP5Ks). Here, we used CRISPR to KO PPIP5Ks in the HCT116 colon cancer cell line. This procedure eliminates 1,5-InsP8 and raises 5-InsP7 levels threefold. Expression of p53 and p21 was up-regulated; proliferation and G1/S cell-cycle transition slowed. Thus, PPIP5Ks are potential targets for tumor therapy. Deletion of the PPIP5Ks elevated [ATP] by 35%; both [ATP] and [5-InsP7] were restored to WT levels by overexpression of PPIP5K1, and a kinase-compromised PPIP5K1 mutant had no effect. This covariance of [ATP] with [5-InsP7] provides direct support for an energy-sensing attribute (i.e., 1 mM Km for ATP) of the 5-InsP7-generating inositol hexakisphosphate kinases (IP6Ks). We consolidate this conclusion by showing that 5-InsP7 levels are elevated on direct delivery of ATP into HCT116 cells using liposomes. Elevated [ATP] in PPIP5K-/- HCT116 cells is underpinned by increased mitochondrial oxidative phosphorylation and enhanced glycolysis. To distinguish between 1,5-InsP8 and 5-InsP7 as drivers of the hypermetabolic and p53-elevated phenotypes, we used IP6K2 RNAi and the pan-IP6K inhibitor, N2-(m-trifluorobenzyl), N6-(p-nitrobenzyl) purine (TNP), to return 5-InsP7 levels in PPIP5K-/- cells to those of WT cells without rescuing 1,5-InsP8 levels. Attenuation of IP6K restored p53 expression but did not affect the hypermetabolic phenotype. Thus, we conclude that 5-InsP7 regulates p53 expression, whereas 1,5-InsP8 regulates ATP levels. These findings attribute hitherto unsuspected functionality for 1,5-InsP8 to bioenergetic homeostasis. DA - 2017/11/7/ PY - 2017/11/7/ DO - 10.1073/pnas.1702370114 VL - 114 IS - 45 SP - 11968-11973 SN - 0027-8424 KW - bioenergetics KW - signaling KW - inositol pyrophosphates ER - TY - JOUR TI - Creation and Evaluation of New Porcine Model for Investigation of Treatments of Surgical Site Infection AU - Mohiti-Asli, Mahsa AU - Risselada, Marije AU - Jacob, Megan AU - Pourdeyhimi, Behnam AU - Loboa, Elizabeth G. T2 - TISSUE ENGINEERING PART C-METHODS AB - Surgical site infection (SSI) is the most common cause of surgical failure, increasing the risks of postoperative mortality and morbidity. Recently, it has been reported that the use of antimicrobial dressings at the incision site help with prevention of SSI. Despite the increased body of research on the development of different types of antimicrobial dressings for this application, to our knowledge, nobody has reported a reliable large animal model to evaluate the efficacy of developed materials in a preclinical SSI model. In this study, we developed a porcine full-thickness incision model to investigate SSI caused by methicillin-resistant Staphylococcus aureus (MRSA), the leading cause of SSI in the United States. Using this model, we then evaluated the efficacy of our newly developed silver releasing nanofibrous dressings for preventing and inhibiting MRSA infection. Our results confirmed the ease and practicality of a new porcine model as an in vivo platform for evaluation of biomaterials for SSI. Using this model, we found that our silver releasing scaffolds significantly reduced bacterial growth in wounds inoculated with MRSA relative to nontreated controls and to wounds treated with the gold standard, silver sulfadiazine, without causing inflammation at the wound site. Findings from this study confirm the potential of our silver-releasing nanofibrous scaffolds for treatment/prevention of SSI, and introduce a new porcine model for in vivo evaluation of additional SSI treatment approaches. DA - 2017/11// PY - 2017/11// DO - 10.1089/ten.tec.2017.0024 VL - 23 IS - 11 SP - 795-803 SN - 1937-3392 KW - surgical site infection KW - porcine model KW - antimicrobial scaffold KW - silver KW - electrospinning KW - MRSA ER - TY - JOUR TI - Bioresponsive transcutaneous patches AU - Yu, Jicheng AU - Zhang, Yuqi AU - Kahkoska, Anna R. AU - Gu, Zhen T2 - CURRENT OPINION IN BIOTECHNOLOGY AB - Transdermal drug delivery systems that utilize transcutaneous patches of arrayed microneedles have attracted increasing interest in medical practice as an alternative method to hypodermic injection. Over the past ten years, research has focused on leveraging physiological signals associated with diseases or skin-specific tissues to create bioresponsive patches that release drug directly in response to an internally-generated stimulus. This review surveys the recent advances in the development and use of bioresponsive transcutaneous patches for on-demand smart and precise drug delivery, exploiting different physiological signals including pH, serum glucose levels, and enzyme activity. The clinical potential of these devices, including challenges and opportunities, is also discussed. DA - 2017/12// PY - 2017/12// DO - 10.1016/j.copbio.2017.03.001 VL - 48 SP - 28-32 SN - 1879-0429 ER - TY - JOUR TI - Age-Dependent Subchondral Bone Remodeling and Cartilage Repair in a Minipig Defect Model AU - Pfeifer, Christian G. AU - Fisher, Matthew B. AU - Saxena, Vishal AU - Kim, Minwook AU - Henning, Elizabeth A. AU - Steinberg, David A. AU - Dodge, George R. AU - Mauck, Robert L. T2 - TISSUE ENGINEERING PART C-METHODS AB - After cartilage injury and repair, the subchondral bone plate remodels. Skeletal maturity likely impacts both bone remodeling and inherent cartilage repair capacity. The objective of this study was to evaluate subchondral bone remodeling as a function of injury type, repair scenario, and skeletal maturity in a Yucatan minipig model. Cartilage defects (4 mm) were created bilaterally in the trochlear groove. Treatment conditions included a full thickness chondral defect (full chondral defect, n = 3 adult/3 juvenile), a partial thickness (∼50%) chondral defect (PCD, n = 3/3), and FCD treated with microfracture (MFX, n = 3/3). At 6 weeks postoperatively, osteochondral samples containing the lesion site were imaged by micro-computed tomography (CT) and analyzed by histology and immunohistochemistry. Via micro-CT, FCD and MFX groups showed increased bone loss in juveniles compared with adults. Quantification of histology using the ICRS II scoring system showed equal overall assessment for the FCD groups and better overall assessment in juvenile animals treated with MFX compared with adults. All FCD and MFX groups were inferior to control samples. For the PCD injury, both age groups had values close to the control values. For the FCD groups, there were greater alterations in the subchondral bone in juveniles compared with adults. Staining for collagen II showed more intense signals in juvenile FCD and MFX groups compared with adults. This large animal study of cartilage repair shows the significant impact of skeletal maturity on the propensity of subchondral bone to remodel as a result of chondral injury. This will improve selection criteria for animal models for studying cartilage injury, repair, and treatment. DA - 2017/11// PY - 2017/11// DO - 10.1089/ten.tec.2017.0109 VL - 23 IS - 11 SP - 745-753 SN - 1937-3392 KW - subchondral bone KW - cartilage KW - microfracture KW - skeletal maturity ER - TY - JOUR TI - Tailoring non-viral delivery vehicles for transporting genome-editing tools AU - Sun, W. J. AU - Gu, Z. T2 - Science China-Materials AB - The CRISPR-Cas system, especially the type II CRISPR-Cas9 system from Streptococcuspyogenes, has rapidly emerged as a popular genome editing tool. The development of Cas9 derivatives further expanded the toolbox of CRISPRCas9 based genome editing kit. However, therapeutic translation of the CRISPR-Cas9 system in vivo is severely impeded by the absence of an appropriate delivery carrier. The complexity and high molecular weight of the CRISPR-Cas9 system, together with the physiological barriers for nucleus targeted cargo transportation have made it a huge challenge for in vivo therapeutic CRISPR-Cas9 delivery. Currently, the main stream carriers for systemic delivery of CRISPR-Cas9 are viral based, such as adeno-associated virus. However, the safety concerns surrounding viral vectors call for the development of non-viral nanocarriers. In this review, we survey the recent advances in the development of non-viral delivery systems for CRISPR-Cas9. Challenges and future directions in this field are also discussed. DA - 2017/// PY - 2017/// DO - 10.1007/s40843-016-5154-4 VL - 60 IS - 6 SP - 511-515 ER - TY - JOUR TI - Shear Shock Waves Observed in the Brain AU - Espindola, David AU - Lee, Stephen AU - Pinton, Gianmarco T2 - PHYSICAL REVIEW APPLIED AB - Traumatic brain injury (TBI), particularly in athletes, has finally come to public attention as a widespread medical problem. To advance TBI research, the authors develop a high-frame-rate ultrasound technique that can track motion at subcellular scale, offering a unique combination of scanning speed, accuracy, and penetration. Their slow-motion movies reveal that at accelerations routinely observed in sports, shear waves easily develop into even worse shear $s\phantom{\rule{0}{0ex}}h\phantom{\rule{0}{0ex}}o\phantom{\rule{0}{0ex}}c\phantom{\rule{0}{0ex}}k$ $w\phantom{\rule{0}{0ex}}a\phantom{\rule{0}{0ex}}v\phantom{\rule{0}{0ex}}e\phantom{\rule{0}{0ex}}s$ within the brain. These observations closely match theoretical predictions, and could direct $e.g.$ the design of helmets that dampen frequencies likely to generate shear shocks. DA - 2017/10/31/ PY - 2017/10/31/ DO - 10.1103/physrevapplied.8.044024 VL - 8 IS - 4 SP - SN - 2331-7019 ER - TY - JOUR TI - Safety and Efficacy of Allogeneic Lung Spheroid Cells in a Mismatched Rat Model of Pulmonary Fibrosis AU - Cores, Jhon AU - Hensley, M. Taylor AU - Kinlaw, Kathryn AU - Rikard, S. Michaela AU - Dinh, Phuong-Uyen AU - Paudel, Dipti AU - Tang, Junnan AU - Vandergriff, Adam C. AU - Allen, Tyler A. AU - Li, Yazhou AU - Liu, Jianhua AU - Niu, Bo AU - Chi, Yuepeng AU - Caranasos, Thomas AU - Lobo, Leonard J. AU - Cheng, Ke T2 - STEM CELLS TRANSLATIONAL MEDICINE AB - Idiopathic pulmonary fibrosis is a devastating interstitial lung disease characterized by the relentless deposition of extracellular matrix causing lung distortions and dysfunctions. The prognosis after detection is merely 3-5 years and the only two Food and Drug Administration-approved drugs treat the symptoms, not the disease, and have numerous side effects. Stem cell therapy is a promising treatment strategy for pulmonary fibrosis. Current animal and clinical studies focus on the use of adipose or bone marrow-derived mesenchymal stem cells. We, instead, have established adult lung spheroid cells (LSCs) as an intrinsic source of therapeutic lung stem cells. In the present study, we compared the efficacy and safety of syngeneic and allogeneic LSCs in immuno-competent rats with bleomycin-induced pulmonary inflammation in an effort to mitigate fibrosis development. We found that infusion of allogeneic LSCs reduces the progression of inflammation and fibrotic manifestation and preserves epithelial and endothelial health without eliciting significant immune rejection. Our study sheds light on potential future developments of LSCs as an allogeneic cell therapy for humans with pulmonary fibrosis. Stem Cells Translational Medicine 2017;9:1905-1916. DA - 2017/10// PY - 2017/10// DO - 10.1002/sctm.16-0374 VL - 6 IS - 10 SP - 1905-1916 SN - 2157-6580 KW - Fibrosis KW - Pulmonary KW - Syngeneic KW - Allogeneic KW - Stem cells ER - TY - JOUR TI - Motor Unit Activity during Fatiguing Isometric Muscle Contraction in Hemispheric Stroke Survivors AU - McManus, Lara AU - Hu, Xiaogang AU - Rymer, William Z. AU - Suresh, Nina L. AU - Lowery, Madeleine M. T2 - FRONTIERS IN HUMAN NEUROSCIENCE AB - Enhanced muscle weakness is commonly experienced following stroke and may be accompanied by increased susceptibility to fatigue. To examine the contributions of central and peripheral factors to isometric muscle fatigue in stroke survivors, this study investigates changes in motor unit (MU) mean firing rate and action potential duration during, and directly following, a sustained submaximal fatiguing contraction at 30% maximum voluntary contraction (MVC). A series of short contractions of the first dorsal interosseous muscle were performed pre- and postfatigue at 20% MVC, and again following a 10-minute recovery period, by twelve chronic stroke survivors. Individual MU firing times were extracted using surface EMG decomposition and used to obtain the spike-triggered average MU action potential waveforms. During the sustained fatiguing contraction, the mean rate of change of the firing rate across all detected motor units was greater on the affected side (-0.02 ± 0.03 Hz/s) than on the less-affected side (-0.004 ± 0.003 Hz/s, p = .045). The change in firing rate immediately postfatigue was also greater on the affected side than less-affected side (-13.5 ± 20 % and 0.1 ± 19 %, p = .04). Mean MU firing rates increased following the recovery period on the less-affected side (19.3 ± 17 %), but not on the affected side (0.5 ± 20 %, p = .03). MU action potential duration increased postfatigue on both sides (10.3 ± 1.2 ms to 11.2 ± 1.3 ms on the affected side and 9.9 ± 1.7 ms to 11.2 ± 1.9 ms on the less-affected side, p = .001 and p = .02, respectively), and changes in MU action potential duration tended to be smaller in subjects with greater impairment (p = .04). This study presents evidence of both central and peripheral fatigue at the motor unit level during isometric fatiguing contraction for the first time in stroke survivors. Together, these preliminary observations indicate that the response to an isometric fatiguing contraction differs between the affected and less-affected side post-stroke, and may suggest that central mechanisms observed here as changes in firing rate are the dominant processes leading to task failure on the affected side. DA - 2017/11/24/ PY - 2017/11/24/ DO - 10.3389/fnhum.2017.00569 VL - 11 SP - SN - 1662-5161 KW - motor unit KW - stroke KW - isometric fatigue KW - surface EMG decomposition KW - motor unit action potential KW - motor unit firing rate ER - TY - JOUR TI - In Vitro Generation of Mouse Colon Crypts AU - Wang, Yuli AU - Gunasekara, Dulan. B. AU - Attayek, Peter J. AU - Reed, Mark I. AU - DiSalvo, Matthew AU - Nguyen, Daniel L. AU - Dutton, Johanna S. AU - Lebhar, Michael S. AU - Bultman, Scott J. AU - Sims, Christopher E. AU - Magness, Scott T. AU - Allbritton, Nancy L. T2 - ACS BIOMATERIALS SCIENCE & ENGINEERING AB - Organoid culture has had a significant impact on in vitro studies of the intestinal epithelium; however, the exquisite architecture, luminal accessibility, and lineage compartmentalization found in vivo has not been recapitulated in the organoid systems. We have used a microengineered platform with suitable extracellular matrix contacts and stiffness to generate a self-renewing mouse colonic epithelium that replicates key architectural and physiological functions found in vivo, including a surface lined with polarized crypts. Chemical gradients applied to the basal–luminal axis compartmentalized the stem/progenitor cells and promoted appropriate lineage differentiation along the in vitro crypt axis so that the tissue possessed a crypt stem cell niche as well as a layer of differentiated cells covering the luminal surface. This new approach combining microengineered scaffolds, native chemical gradients, and biophysical cues to control primary epithelium ex vivo can serve as a highly functional and physiologically relevant in vitro tissue model. DA - 2017/10// PY - 2017/10// DO - 10.1021/acsbiomaterials.7b00368 VL - 3 IS - 10 SP - 2502-2513 SN - 2373-9878 KW - intestinal epithelial stem cells KW - differentiation KW - intestine-on-a-chip KW - microfabrication KW - gradient KW - tissue mimics ER - TY - JOUR TI - Glucose-responsive insulin by molecular and physical design AU - Bakh, Naveed A. AU - Cortinas, Abel B. AU - Weiss, Michael A. AU - Langer, Robert S. AU - Anderson, Daniel G. AU - Gu, Zhen AU - Dutta, Sanjoy AU - Strano, Michael S. T2 - NATURE CHEMISTRY DA - 2017/10// PY - 2017/10// DO - 10.1038/nchem.2857 VL - 9 IS - 10 SP - 937-943 SN - 1755-4349 ER - TY - JOUR TI - Exploration of Hand Grasp Patterns Elicitable Through Non-Invasive Proximal Nerve Stimulation AU - Shin, Henry AU - Watkins, Zach AU - Hu, Xiaogang T2 - SCIENTIFIC REPORTS AB - Various neurological conditions, such as stroke or spinal cord injury, result in an impaired control of the hand. One method of restoring this impairment is through functional electrical stimulation (FES). However, traditional FES techniques often lead to quick fatigue and unnatural ballistic movements. In this study, we sought to explore the capabilities of a non-invasive proximal nerve stimulation technique in eliciting various hand grasp patterns. The ulnar and median nerves proximal to the elbow joint were activated transcutanously using a programmable stimulator, and the resultant finger flexion joint angles were recorded using a motion capture system. The individual finger motions averaged across the three joints were analyzed using a cluster analysis, in order to classify the different hand grasp patterns. With low current intensity (<5 mA and 100 µs pulse width) stimulation, our results show that all of our subjects demonstrated a variety of consistent hand grasp patterns including single finger movement and coordinated multi-finger movements. This study provides initial evidence on the feasibility of a proximal nerve stimulation technique in controlling a variety of finger movements and grasp patterns. Our approach could also be developed into a rehabilitative/assistive tool that can result in flexible movements of the fingers. DA - 2017/11/29/ PY - 2017/11/29/ DO - 10.1038/s41598-017-16824-1 VL - 7 SP - SN - 2045-2322 ER - TY - JOUR TI - Strategic Directions in Immunoresponsive Biomaterials in Tissue Engineering INTRODUCTION AU - Zaharoff, David A. AU - Jewell, Christopher M. T2 - TISSUE ENGINEERING PART A AB - Tissue Engineering Part AVol. 23, No. 19-20 Special Focus Issue:Strategic Directions in Immunoresponsive Biomaterials in Tissue EngineeringDavid A. Zaharoff and Christopher M. JewellDavid A. ZaharoffJoint Department of Biomedical Engineering, University of North Carolina - Chapel Hill & North Carolina State University, Raleigh, North Carolina.Search for more papers by this author and Christopher M. JewellFischell Department of Bioengineering, University of Maryland, College Park, Maryland.Search for more papers by this authorPublished Online:1 Oct 2017https://doi.org/10.1089/ten.tea.2017.0395AboutSectionsView articleView Full TextPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View article"Strategic Directions in Immunoresponsive Biomaterials in Tissue Engineering*." Tissue Engineering Part A, 23(19-20), pp. 1042–1043FiguresReferencesRelatedDetailsCited byTissue engineering meets immunoengineering: Prospective on personalized in situ tissue engineering strategiesCurrent Opinion in Biomedical Engineering, Vol. 6 Volume 23Issue 19-20Oct 2017 InformationCopyright 2017, Mary Ann Liebert, Inc.To cite this article:David A. Zaharoff and Christopher M. Jewell.Strategic Directions in Immunoresponsive Biomaterials in Tissue Engineering.Tissue Engineering Part A.Oct 2017.1042-1043.http://doi.org/10.1089/ten.tea.2017.0395Published in Volume: 23 Issue 19-20: October 1, 2017Online Ahead of Editing: September 19, 2017PDF download DA - 2017/10// PY - 2017/10// DO - 10.1089/ten.tea.2017.0395 VL - 23 IS - 19-20 SP - 1042-1043 SN - 1937-335X ER - TY - JOUR TI - Piecewise parabolic method for simulating one-dimensional shear shock wave propagation in tissue-mimicking phantoms AU - Tripathi, B. B. AU - Espindola, D. AU - Pinton, G. F. T2 - SHOCK WAVES DA - 2017/11// PY - 2017/11// DO - 10.1007/s00193-017-0734-8 VL - 27 IS - 6 SP - 879-888 SN - 1432-2153 KW - Shear shock waves KW - Traumatic brain injury KW - Piecewise parabolic method KW - Nonlinear shear waves ER - TY - JOUR TI - Performance of acoustic radiation force impulse ultrasound imaging for carotid plaque characterization with histologic validation AU - Czernuszewicz, Tomasz J. AU - Homeister, Jonathon W. AU - Caughey, Melissa C. AU - Wang, Yue AU - Zhu, Hongtu AU - Huang, Benjamin Y. AU - Lee, Ellie R. AU - Zamora, Carlos A. AU - Farber, Mark A. AU - Fulton, Joseph J. AU - Ford, Peter F. AU - Marston, William A. AU - Vallabhaneni, Raghuveer AU - Nichols, Timothy C. AU - Gallippi, Caterina M. T2 - JOURNAL OF VASCULAR SURGERY AB - Stroke is commonly caused by thromboembolic events originating from ruptured carotid plaque with vulnerable composition. This study assessed the performance of acoustic radiation force impulse (ARFI) imaging, a noninvasive ultrasound elasticity imaging method, for delineating the composition of human carotid plaque in vivo with histologic validation.Carotid ARFI images were captured before surgery in 25 patients undergoing clinically indicated carotid endarterectomy. The surgical specimens were histologically processed with sectioning matched to the ultrasound imaging plane. Three radiologists, blinded to histology, evaluated parametric images of ARFI-induced peak displacement to identify plaque features such as necrotic core (NC), intraplaque hemorrhage (IPH), collagen (COL), calcium (CAL), and fibrous cap (FC) thickness. Reader performance was measured against the histologic standard using receiver operating characteristic curve analysis, linear regression, Spearman correlation (ρ), and Bland-Altman analysis.ARFI peak displacement was two-to-four-times larger in regions of NC and IPH relative to regions of COL or CAL. Readers detected soft plaque features (NC/IPH) with a median area under the curve of 0.887 (range, 0.867-0.924) and stiff plaque features (COL/CAL) with median area under the curve of 0.859 (range, 0.771-0.929). FC thickness measurements of two of the three readers correlated with histology (reader 1: R2 = 0.64, ρ = 0.81; reader 2: R2 = 0.89, ρ = 0.75).This study suggests that ARFI is capable of distinguishing soft from stiff atherosclerotic plaque components and delineating FC thickness. DA - 2017/12// PY - 2017/12// DO - 10.1016/j.jvs.2017.04.043 VL - 66 IS - 6 SP - 1749-+ SN - 0741-5214 ER - TY - JOUR TI - Origins of Common Neural Inputs to Different Compartments of the Extensor Digitorum Communis Muscle AU - Dai, Chenyun AU - Shin, Henry AU - Davis, Bradley AU - Hu, Xiaogang T2 - SCIENTIFIC REPORTS AB - The extensor digitorum communis (EDC) is a multi-compartment muscle that allows dexterous extension of the four digits. However, the level of common input shared across different compartments of this muscle is not well understood. We seek to systematically characterize the common and independent neural input, originated from different levels of the central nervous system, to the different compartments. A motor unit (MU) coherence analysis was used to capture the different sources of common and independent input, by quantifying the coherence of MU discharge between different compartments. The MU activities were obtained from decomposition of surface electromyogram recordings. Our results showed that the MU coherence across different muscle compartments accounted for only a small proportion (<20%) of the total input in the alpha (5-12 Hz) and beta (15-30 Hz) bands, but was a major driver (>60%) in the delta (1-4 Hz) band. Additionally, cross-compartment coherence between the middle and ring-little fingers tended to be higher as compared with other finger combinations. Overall, the common input shared across different fingers are found to be at low to moderate levels, in comparison with the total input, which allows dexterous control of individual digits with some degree of coordinated control of multiple digits. DA - 2017/10/24/ PY - 2017/10/24/ DO - 10.1038/s41598-017-14555-x VL - 7 SP - SN - 2045-2322 ER - TY - JOUR TI - Orientation changes in the cruciate ligaments of the knee during skeletal growth: A porcine model AU - Cone, Stephanie G. AU - Simpson, Sean G. AU - Piedrahita, Jorge A. AU - Fordham, Lynn A. AU - Spang, Jeffrey T. AU - Fisher, Matthew B. T2 - JOURNAL OF ORTHOPAEDIC RESEARCH AB - ABSTRACT Musculoskeletal injuries in pediatric patients are on the rise, including significant increases in anterior cruciate ligament (ACL) injuries. Previous studies have found major anatomical changes during skeletal growth in the soft tissues of the knee. Specifically, the ACL and the posterior cruciate ligament (PCL) change in their relative orientation to the tibial plateau throughout growth. In order to develop age‐specific treatments for ACL injuries, the purpose of this study was to characterize orientation changes in the cruciate ligaments of the Yorkshire pig, a common pre‐clinical model, during skeletal growth in order to verify the applicability of this model for pediatric musculoskeletal studies. Hind limbs were isolated from female Yorkshire pigs ranging in age from newborn to late adolescence and were then imaged using high field strength magnetic resonance imaging. Orientation changes were quantified from the magnetic resonance images using image segmentation software. Statistically significant increases were found in the coronal and sagittal angles of the ACL relative to the tibial plateau during pre‐adolescent growth. Additional changes were observed in the PCL angle, Blumensaat angle, intercondylar roof angle, and the aspect ratio of the intercondylar notch. Only the sagittal angle of the ACL relative to the tibial plateau experienced statistically significant changes through late adolescence. The age‐dependent properties of the ACL and PCL in the female pig mirrored results found in female human patients, suggesting that the porcine model may provide a pre‐clinical platform to study the cruciate ligaments during skeletal growth. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2725–2732, 2017. DA - 2017/12// PY - 2017/12// DO - 10.1002/jor.23594 VL - 35 IS - 12 SP - 2725-2732 SN - 1554-527X KW - anterior cruciate ligament KW - posterior cruciate ligament KW - adolescent KW - porcine KW - MRI ER - TY - JOUR TI - Composition and structure of porcine digital flexor tendon-bone insertion tissues AU - Chandrasekaran, Sandhya AU - Pankow, Mark AU - Peters, Kara AU - Huang, Hsiao-Ying Shadow T2 - JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A AB - Tendon-bone insertion is a functionally graded tissue, transitioning from 200 MPa tensile modulus at the tendon end to 20 GPa tensile modulus at the bone, across just a few hundred micrometers. In this study, we examine the porcine digital flexor tendon insertion tissue to provide a quantitative description of its collagen orientation and mineral concentration by using Fast Fourier Transform (FFT) based image analysis and mass spectrometry, respectively. Histological results revealed uniformity in global collagen orientation at all depths, indicative of mechanical anisotropy, although at mid-depth, the highest fiber density, least amount of dispersion, and least cellular circularity were evident. Collagen orientation distribution obtained through 2D FFT of histological imaging data from fluorescent microscopy agreed with past measurements based on polarized light microscopy. Results revealed global fiber orientation across the tendon-bone insertion to be preserved along direction of physiologic tension. Gradation in the fiber distribution orientation index across the insertion was reflective of a decrease in anisotropy from the tendon to the bone. We provided elemental maps across the fibrocartilage for its organic and inorganic constituents through time-of-flight secondary ion mass spectrometry (TOF-SIMS). The apatite intensity distribution from the tendon to bone was shown to follow a linear trend, supporting past results based on Raman microprobe analysis. The merit of this study lies in the image-based simplified approach to fiber distribution quantification and in the high spatial resolution of the compositional analysis. In conjunction with the mechanical properties of the insertion tissue, fiber, and mineral distribution results for the insertion from this may potentially be incorporated into the development of a structural constitutive approach toward computational modeling. Characterizing the properties of the native insertion tissue would provide the microstructural basis for developing biomimetic scaffolds to recreate the graded morphology of a fibrocartilaginous insertion. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 3050-3058, 2017. DA - 2017/11// PY - 2017/11// DO - 10.1002/jbm.a.36162 VL - 105 IS - 11 SP - 3050-3058 SN - 1552-4965 KW - tendon-bone insertion KW - collagen fiber orientation KW - fast fourier transform KW - time-of-flight secondary ion mass spectrometry ER - TY - JOUR TI - A pH-sensitive methenamine mandelate-loaded nanoparticle induces DNA damage and apoptosis of cancer cells AU - Zhang, L. H. AU - Hao, W. B. AU - Xu, L. AU - Gao, Y. F. AU - Wang, X. S. AU - Zhu, D. W. AU - Chen, Z. AU - Zhang, X. D. AU - Chen, H. B. AU - Mei, L. T2 - Acta Biomaterialia DA - 2017/// PY - 2017/// VL - 62 SP - 246-256 ER - TY - JOUR TI - Usability Comparison of Conventional Direct Control Versus Pattern Recognition Control of Transradial Prostheses AU - White, Melissa Mae AU - Zhang, Wenjuan AU - Winslow, Anna T. AU - Zahabi, Maryam AU - Zhang, Fan AU - Huang, He AU - Kaber, David B. T2 - IEEE TRANSACTIONS ON HUMAN-MACHINE SYSTEMS AB - The goal of this study was to compare the usability of two control schemes for a transradial myoelectric prosthesis, including conventional direct control (DC) and pattern recognition (PR) control, when used by able-bodied individuals. Three types of response measures were captured to assess the control schemes, including learnability, performance, and cognitive workload. Prior research has applied performance and cognitive workload metrics for evaluation of prosthetics; however, workload measures applied in these studies (e.g., heart rate, electroencephalography, and respiration rate) have many limitations. This study used eye tracking to compare cognitive load implications of the different control schemes for a two degrees-of-freedom myoelectric prosthesis. In total, 12 participants were assigned to either control condition (six persons each) or perform a clothespin relocation task. Results revealed the PR scheme to be more intuitive for users and superior to DC across all response measures. We observed a lower learning percentage (i.e., greater learning potential), lower cognitive load, and greater productivity in task performance. This preliminary study illustrates efficacy of using eye-tracking-based measures of cognitive load and standardize test paradigms for assessment of upper limb prosthetic usability and supports PR prosthetic device control as an intuitive alternative to DC. DA - 2017/12// PY - 2017/12// DO - 10.1109/thms.2017.2759762 VL - 47 IS - 6 SP - 1146-1157 SN - 2168-2305 UR - http://www.scopus.com/inward/record.url?eid=2-s2.0-85032257100&partnerID=MN8TOARS KW - Biomedical signal KW - Human factors KW - Man-machine systems KW - prosthetics ER - TY - JOUR TI - Three-dimensional assessment of curvature, torsion, and canal flare index of the humerus of skeletally mature nonchondrodystrophic dogs AU - Smith, E. J. AU - Marcellin-Little, D. J. AU - Harrysson, O. L. A. AU - Griffith, E. H. T2 - American Journal of Veterinary Research AB - OBJECTIVE To assess 3-D geometry of the humerus of dogs and determine whether the craniocaudal canal flare index (CFI) is associated with specific geometric features. SAMPLE CT images (n = 40) and radiographs (38) for 2 groups of skeletally mature nonchondrodystrophic dogs. PROCEDURES General dimensions (length, CFI, cortical thickness, and humeral head offset), curvature (shaft, humeral head, and glenoid cavity), version (humeral head and greater tubercle), and torsion were evaluated on CT images. Dogs were allocated into 3 groups on the basis of the craniocaudal CFI, and results were compared among these 3 groups. The CT measurements were compared with radiographic measurements obtained for another group of dogs. RESULTS Mean ± SD humeral head version was -75.9 ± 9.6° (range, -100.7° to -59.4°). Mean mechanical lateral distal humeral angle, mechanical caudal proximal humeral angle, and mechanical cranial distal humeral angle were 89.5 ± 3.5°, 50.2 ± 4.5°, and 72.9 ± 7.8°, respectively, and did not differ from corresponding radiographic measurements. Mean humeral curvature was 20.4 ± 4.4° (range, 9.6° to 30.5°). Mean craniocaudal CFI was 1.74 ± 0.18 (range, 1.37 to 2.10). Dogs with a high craniocaudal CFI had thicker cranial and medial cortices than dogs with a low craniocaudal CFI. Increased body weight was associated with a lower craniocaudal CFI. Radiographic and CT measurements of craniocaudal CFI and curvature differed significantly. CONCLUSIONS AND CLINICAL RELEVANCE CT-based 3-D reconstructions allowed the assessment of shaft angulation, torsion, and CFI. Radiographic and CT measurements of shaft curvature and CFI may differ. DA - 2017/// PY - 2017/// DO - 10.2460/ajvr.78.10.1140 VL - 78 IS - 10 SP - 1140-1149 ER - TY - JOUR TI - Room Temperature Growth of Epitaxial Titanium Nitride Films by Pulsed Laser Deposition AU - Rasic, Daniel AU - Sachan, Ritesh AU - Chisholm, Matthew F. AU - Prater, John AU - Narayan, Jagdish T2 - CRYSTAL GROWTH & DESIGN AB - Reducing the thermal budget of epitaxial thin film growth has been one of the biggest challenges for the electronics industry. In this report, the room-temperature epitaxial growth of titanium nitride (TiN) thin films (∼75 nm) on (0001) Al2O3 substrates is demonstrated using a pulsed laser deposition technique. In TiN thin films, the epitaxial relationship is established by X-ray diffraction for (111)TiN//(0001) Al2O3 and <11̅0>TiN // < 101̅0> Al2O3 which corresponds to a 30° rotation of titanium and nitrogen atoms with respect to the hexagon arrangement of aluminum atoms. An increase in the defect concentration is shown in the room-temperature thin film growth as compared to the ones grown at elevated temperature. A shift and broadening of the diffraction peaks is observed in the thin films as compared to the bulk value, indicating a higher residual tensile strain with decreasing growth temperature and an increase in defect concentration at room temperature. The increased defect concentration observed at lower growth temperature is explained by the lower energy budget that limits defect recombination and film relaxation. The residual strain in all films is dominated by the lattice mismatch (∼8.46% misfit) and defects, and not due to the thermal expansion mismatch, as Al2O3 and TiN have similar coefficients of thermal expansion. Raman spectroscopy measurements also confirm an increased concentration of vacancies in TiN films grown at lower temperature. Using atomic resolution scanning transmission electron microscopy, it is shown that the room-temperature grown films contain a lower density of periodic dislocations at the film/substrate interface, a characteristic of the large misfit systems, but have more dislocations trapped within the film. The lower density of dislocations near the film–substrate interface signifies incomplete relaxation at lower temperatures. In view of more defects in the film, resistivity of the film grown at room temperature is ∼55 μΩ·cm as compared to ∼22 μΩ·cm for films grown at 650 °C, showing a similar performance at a reduced thermal budget. DA - 2017/12// PY - 2017/12// DO - 10.1021/acs.cgd.7b01278 VL - 17 IS - 12 SP - 6634-6640 SN - 1528-7505 ER - TY - JOUR TI - Required hydrophobicity of fluorescent reporters for phosphatidylinositol family of lipid enzymes AU - Waybright, Jarod AU - Huang, Weigang AU - Proctor, Angela AU - Wang, Xiaoyang AU - Allbritton, Nancy L. AU - Zhang, Qisheng T2 - ANALYTICAL AND BIOANALYTICAL CHEMISTRY AB - The phosphatidylinositol (PtdIns) family of lipids plays important roles in cell differentiation, proliferation, and migration. Abnormal expression, mutation, or regulation of their metabolic enzymes has been associated with various human diseases such as cancer, diabetes, and bipolar disorder. Recently, fluorescent derivatives have increasingly been used as chemical probes to monitor either lipid localization or enzymatic activity. However, the requirements of a good probe have not been well defined, particularly modifications on the diacylglycerol side chain partly due to challenges in generating PtdIns lipids. We have synthesized a series of fluorescent PtdIns(4,5)P2 (PIP2) and PtdIns (PI) derivatives with various lengths of side chains and tested their capacity as substrates for PI3KIα and PI4KIIα, respectively. Both capillary electrophoresis and thin-layer chromatography were used to analyze enzymatic reactions. For both enzymes, the fluorescent probe with a longer side chain functions as a better substrate than that with a shorter chain and works well in the presence of the endogenous lipid, highlighting the importance of hydrophobicity of side chains in fluorescent phosphoinositide reporters. This comparison is consistent with their interactions with lipid vesicles, suggesting that the binding of a fluorescent lipid with liposome serves as a standard for assessing its utility as a chemical probe for the corresponding endogenous lipid. These findings are likely applicable to other lipid enzymes where the catalysis takes place at the lipid-water interface. DA - 2017/11// PY - 2017/11// DO - 10.1007/s00216-017-0633-y VL - 409 IS - 29 SP - 6781-6789 SN - 1618-2650 KW - Fluorescent reporter KW - Chemical cytometry KW - Lipid enzyme KW - Phosphatidylinositol ER - TY - JOUR TI - Neutron-activatable needles for radionuclide therapy of solid tumors AU - Kim, Junghyun AU - Narayan, Roger J. AU - Lu, Xiuling AU - Jay, Michael T2 - JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A AB - Abstract Various approaches have been undertaken to enhance the delivery of therapeutic agents, including tissue‐killing radionuclides, into solid tumors. Here, we describe the preparation of conical needles composed of Ti and Mo coated by pulsed laser deposition or chemical vapor deposition with elements (Ho and Re) that can readily yield radioactive isotopes following irradiation in a neutron flux. The radioactive needles, whose design were based on solid microneedle arrays used in transdermal drug delivery, can be produced with minimal handling of radioactivity and subsequently inserted into tumors as a means of internal radiation therapy. Ho and Re were specifically chosen because of their large neutron capture cross‐sections as well as the desirable radiotherapeutic properties of the resultant radionuclides. Neutron‐absorbing shields were also developed to prevent the production of unwanted radionuclides after neutron irradiation of the needle base materials. Neutron activation calculations showed that therapeutically significant amounts of radionuclides can be produced for treating solid tumors. Stability studies demonstrated that Re did not leach off the Mo needles. These coated neutron‐activatable needles offer a new approach to internal radiation therapy of tumors that allows precise tailoring of the absorbed radiation dose delivered to the tumor by controlling the coating thickness and the irradiation time. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 3273–3280, 2017. DA - 2017/12// PY - 2017/12// DO - 10.1002/jbm.a.36185 VL - 105 IS - 12 SP - 3273-3280 SN - 1552-4965 KW - neutron-activation KW - brachytherapy KW - rhenium-molybdenum alloy KW - pulsed laser deposition KW - chemical vapor deposition ER - TY - JOUR TI - KO of 5-InsP(7) kinase activity transforms the HCT116 colon cancer cell line into a hypermetabolic, growth-inhibited phenotype AU - Gu, C. F. AU - Nguyen, H. N. AU - Ganini, D. AU - Chen, Z. W. AU - Jessen, H. J. AU - Gu, Z. AU - Wang, H. C. AU - Shears, S. B. T2 - Proceedings of the National Academy of Sciences of the United States of America DA - 2017/// PY - 2017/// VL - 114 IS - 45 SP - 11968-11973 ER - TY - JOUR TI - KIDNEY PHYSIOLOGYA size bandpass filter AU - Lu, Yue AU - Gu, Zhen T2 - NATURE NANOTECHNOLOGY DA - 2017/11// PY - 2017/11// DO - 10.1038/nnano.2017.200 VL - 12 IS - 11 SP - 1023-1025 SN - 1748-3395 ER - TY - JOUR TI - Interactions Between Transfemoral Amputees and a Powered Knee Prosthesis During Load Carriage AU - Brandt, Andrea AU - Wen, Yue AU - Liu, Ming AU - Stallings, Jonathan AU - Huang, He Helen T2 - Scientific Reports AB - Abstract Machines and humans become mechanically coupled when lower limb amputees walk with powered prostheses, but these two control systems differ in adaptability. We know little about how they interact when faced with real-world physical demands (e.g. carrying loads). Here, we investigated how each system (i.e. amputee and powered prosthesis) responds to changes in the prosthesis mechanics and gravitational load. Five transfemoral amputees walked with and without load (i.e. weighted backpack) and a powered knee prosthesis with two pre-programmed controller settings (i.e. for load and no load). We recorded subjects’ kinematics, kinetics, and perceived exertion. Compared to the no load setting, the load setting reduced subjects’ perceived exertion and intact-limb stance time when they carried load. When subjects did not carry load, their perceived exertion and gait performance did not significantly change with controller settings. Our results suggest transfemoral amputees could benefit from load-adaptive powered knee controllers, and controller adjustments affect amputees more when they walk with (versus without) load. Further understanding of the interaction between powered prostheses, amputee users, and various environments may allow researchers to expand the utility of prostheses beyond simple environments (e.g. firm level ground without load) that represent only a subset of real-world environments. DA - 2017/11/3/ PY - 2017/11/3/ DO - 10.1038/S41598-017-14834-7 VL - 7 IS - 1 J2 - Sci Rep LA - en OP - SN - 2045-2322 UR - http://dx.doi.org/10.1038/S41598-017-14834-7 DB - Crossref ER - TY - JOUR TI - First-in-Human Study of Acoustic Angiography in the Breast and Peripheral Vasculature AU - Shelton, Sarah E. AU - Lindsey, Brooks D. AU - Dayton, Paul A. AU - Lee, Yueh Z. T2 - Ultrasound in Medicine & Biology AB - Screening with mammography has been found to increase breast cancer survival rates by about 20%. However, the current system in which mammography is used to direct patients toward biopsy or surgical excision also results in relatively high rates of unnecessary biopsy, as 66.8% of biopsies are benign. A non-ionizing radiation imaging approach with increased specificity might reduce the rate of unnecessary biopsies. Quantifying the vascular characteristics within and surrounding lesions represents one potential target for assessing likelihood of malignancy via imaging. In this clinical note, we describe the translation of a contrast-enhanced ultrasound technique, acoustic angiography, to human imaging. We illustrate the feasibility of this technique with initial studies in imaging the hand, wrist and breast using Definity microbubble contrast agent and a mechanically steered prototype dual-frequency transducer in healthy volunteers. Finally, this approach was used to image pre-biopsy Breast Imaging Reporting and Data System (BI-RADS) 4 and 5 lesions <2 cm in depth in 11 patients. Results indicate that sensitivity and spatial resolution are sufficient to image vessels as small as 0.2 mm in diameter at depths of ~15 mm in the human breast. Challenges observed include motion artifacts, as well as limited depth of field and sensitivity, which could be improved by correction algorithms and improved transducer technologies. DA - 2017/12// PY - 2017/12// DO - 10.1016/j.ultrasmedbio.2017.08.1881 VL - 43 IS - 12 SP - 2939-2946 J2 - Ultrasound in Medicine & Biology LA - en OP - SN - 0301-5629 UR - http://dx.doi.org/10.1016/j.ultrasmedbio.2017.08.1881 DB - Crossref KW - Contrast-enhanced ultrasound KW - Breast imaging KW - Angiography KW - Superharmonic KW - Microbubble KW - Micro-vasculature KW - Dual frequency ER - TY - JOUR TI - Does dynamic stability govern propulsive force generation in human walking? AU - Browne, Michael G. AU - Franz, Jason R. T2 - ROYAL SOCIETY OPEN SCIENCE AB - Before succumbing to slower speeds, older adults may walk with a diminished push-off to prioritize stability over mobility. However, direct evidence for trade-offs between push-off intensity and balance control in human walking, independent of changes in speed, has remained elusive. As a critical first step, we conducted two experiments to investigate: (i) the independent effects of walking speed and propulsive force (FP) generation on dynamic stability in young adults, and (ii) the extent to which young adults prioritize dynamic stability in selecting their preferred combination of walking speed and FP generation. Subjects walked on a force-measuring treadmill across a range of speeds as well as at constant speeds while modulating their FP according to a visual biofeedback paradigm based on real-time force measurements. In contrast to improvements when walking slower, walking with a diminished push-off worsened dynamic stability by up to 32%. Rather, we find that young adults adopt an FP at their preferred walking speed that maximizes dynamic stability. One implication of these findings is that the onset of a diminished push-off in old age may independently contribute to poorer balance control and precipitate slower walking speeds. DA - 2017/11// PY - 2017/11// DO - 10.1098/rsos.171673 VL - 4 IS - 11 SP - SN - 2054-5703 KW - variability KW - push-off KW - balance KW - walking speed KW - biofeedback KW - ageing ER - TY - JOUR TI - Chemical fixation to arrest phospholipid signaling for chemical cytometry AU - Proctor, Angela AU - Sims, Christopher E. AU - Allbritton, Nancy L. T2 - JOURNAL OF CHROMATOGRAPHY A AB - Chemical cytometry is a powerful tool for measuring biological processes such as enzymatic signaling at the single cell level. Among these technologies, single-cell capillary zone electrophoresis (CZE) has emerged as a powerful tool to assay a wide range of cellular metabolites. However, analysis of dynamic processes within cells remains challenging as signaling pathways are rapidly altered in response to changes in the cellular environment, including cell manipulation and storage. To address these limitations, we describe a method for chemical fixation of cells to stop the cellular reactions to preserve the integrity of key signaling molecules or reporters within the cell and to enable the cell to act as a storage reservoir for the reporter and its metabolites prior to assay by single-cell CZE. Fluorescent phosphatidylinositol 4,5-bisphosphate reporters were loaded into cells and the cells were chemically fixed and stored prior to analysis. The reporter and its metabolites were electrophoretically separated by single-cell CZE. Chemical fixation parameters such as fixative, fixation time, storage solution, storage duration, and extraction solution were optimized. When cells were loaded with a fluorescent C6- or C16-PIP2 followed by glutaraldehyde fixation and immediate analysis, 24±2% and 139±12% of the lipid was recoverable, respectively, when compared to an unfixed control. Storage of the cells for 24h yielded recoverable lipid of 61±3% (C6-PIP2) and 55±5% (C16-PIP2) when compared to cells analyzed immediately after fixation. The metabolites observed with and without fixation were identical. Measurement of phospholipase C activity in single leukemic cells in response to an agonist demonstrated the capability of chemical fixation coupled to single-cell CZE to yield an accurate snapshot of cellular reactions with the probe. This methodology enables cell assay with the reporter to be separated in space and time from reporter metabolite quantification while preserving assay integrity. DA - 2017/11/10/ PY - 2017/11/10/ DO - 10.1016/j.chroma.2017.05.022 VL - 1523 SP - 97-106 SN - 1873-3778 KW - Capillary electrophoresis KW - Phospholipid KW - Phospholipase C KW - Diacylglycerol KW - Chemical cytometry KW - Chemical fixation ER - TY - JOUR TI - Characterizing Cell Migration Within Three-dimensional In Vitro Wound Environments AU - Nandi, Seema AU - Brown, Ashley C. T2 - JOVE-JOURNAL OF VISUALIZED EXPERIMENTS AB - Currently, most in vitro models of wound healing, such as well-established scratch assays, involve studying cell migration and wound closure on two-dimensional surfaces. However, the physiological environment in which in vivo wound healing takes place is three-dimensional rather than two-dimensional. It is becoming increasingly clear that cell behavior differs greatly in two-dimensional vs. three-dimensional environments; therefore, there is a need for more physiologically relevant in vitro models for studying cell migration behaviors in wound closure. The method described herein allows for the study of cell migration in a three-dimensional model that better reflects physiological conditions than previously established two-dimensional scratch assays. The purpose of this model is to evaluate cell outgrowth via the examination of cell migration away from a spheroid body embedded within a fibrin matrix in the presence of pro- or anti-migratory factors. Using this method, cell outgrowth from the spheroid body in a three-dimensional matrix can be observed and is easily quantifiable over time via brightfield microscopy and analysis of spheroid body area. The effect of pro-migratory and/or inhibitory factors on cell migration can also be evaluated in this system. This method provides researchers with a simple method of analyzing cell migration in three-dimensional wound associated matrices in vitro, thus increasing the relevance of in vitro cell studies prior to the use of in vivo animal models. DA - 2017/8// PY - 2017/8// DO - 10.3791/56099 IS - 126 SP - SN - 1940-087X KW - Bioengineering KW - Issue 126 KW - cell migration KW - three dimensional KW - fibrin KW - wound healing KW - extracellular matrix KW - integrins KW - in vitro wound healing assay ER - TY - JOUR TI - Two-photon polymerization for biological applications AU - Nguyen, Alexander K. AU - Narayan, Roger J. T2 - MATERIALS TODAY AB - Two-photon polymerization (2PP) leverages the two-photon absorption (TPA) of near-infrared (NIR) radiation for additive manufacturing with sub-diffraction limit resolution within the bulk of a photosensitive material. This technology draws heavily on photosensitive polymers from the microelectronics industry, which were not optimized for TPA or for biocompatibility. 2PP with sub 100 nm resolution has been repeatedly demonstrated; however, this level of fabrication resolution comes at the expense of long fabrication times. Manufacturing of medical devices beyond surface texturing would be prohibitively slow using the current state of the art 2PP technology. Current research into TPA-sensitive photopolymers with good biocompatibility and holographic projections using spatial light modulators address current technological limitations by providing materials specifically formulated for biological applications and by making better use of available laser power for applications in which nanoscale resolution is not required. DA - 2017/// PY - 2017/// DO - 10.1016/j.mattod.2017.06.004 VL - 20 IS - 6 SP - 314-322 SN - 1873-4103 ER - TY - JOUR TI - Transgenerational inheritance of neurobehavioral and physiological deficits from developmental exposure to benzo[a]pyrene in zebrafish AU - Knecht, Andrea L. AU - Truong, Lisa AU - Marvel, Skylar W. AU - Reif, David M. AU - Garcia, Abraham AU - Lu, Catherine AU - Simbnich, Michael T. AU - Teeguarden, Justin G. AU - Tanguay, Robert L. T2 - TOXICOLOGY AND APPLIED PHARMACOLOGY AB - Benzo[a]pyrene (B[a]P) is a well-known genotoxic polycylic aromatic compound whose toxicity is dependent on signaling via the aryl hydrocarbon receptor (AHR). It is unclear to what extent detrimental effects of B[a]P exposures might impact future generations and whether transgenerational effects might be AHR-dependent. This study examined the effects of developmental B[a]P exposure on 3 generations of zebrafish. Zebrafish embryos were exposed from 6 to 120 h post fertilization (hpf) to 5 and 10 μM B[a]P and raised in chemical-free water until adulthood (F0). Two generations were raised from F0 fish to evaluate transgenerational inheritance. Morphological, physiological and neurobehavioral parameters were measured at two life stages. Juveniles of the F0 and F2 exhibited hyper locomotor activity, decreased heartbeat and mitochondrial function. B[a]P exposure during development resulted in decreased global DNA methylation levels and generally reduced expression of DNA methyltransferases in wild type zebrafish, with the latter effect largely reversed in an AHR2-null background. Adults from the F0 B[a]P exposed lineage displayed social anxiety-like behavior. Adults in the F2 transgeneration manifested gender-specific increased body mass index (BMI), increased oxygen consumption and hyper-avoidance behavior. Exposure to benzo[a]pyrene during development resulted in transgenerational inheritance of neurobehavioral and physiological deficiencies. Indirect evidence suggested the potential for an AHR2-dependent epigenetic route. DA - 2017/8/15/ PY - 2017/8/15/ DO - 10.1016/j.taap.2017.05.033 VL - 329 SP - 148-157 SN - 1096-0333 KW - Zebrafish Benzo[a]pyrene KW - Transgenerational KW - Neurobehavioral KW - Developmental toxicity KW - Physiological deficits KW - Aryl hydrocarbon receptor ER - TY - JOUR TI - The effects of Achilles tendon compliance on triceps surae mechanics and energetics in walking AU - Orselli, Maria Isabel V. AU - Franz, Jason R. AU - Thelen, Darryl G. T2 - JOURNAL OF BIOMECHANICS AB - Achilles tendon (AT) compliance can affect the generation and transmission of triceps surae muscle forces, and thus has important biomechanical consequences for walking performance. However, the uniarticular soleus (SOL) and the biarticular (GAS) function differently during walking, with in vivo evidence suggesting that their associated fascicles and tendinous structures exhibit unique kinematics during walking. Given the strong association between muscle fiber length, velocity and force production, we conjectured that SOL and GAS mechanics and energetic behavior would respond differently to altered AT compliance. To test this, we characterized GAS and SOL muscle and tendon mechanics and energetics due to systematic changes in tendon compliance using musculoskeletal simulations of walking. Increased tendon compliance enlarged GAS and SOL tendon excursions, shortened fiber operation lengths and affected muscle excitation patterns. For both muscles, an optimal tendon compliance (tendon strains of approximately 5% with maximum isometric force) existed that minimized metabolic energy consumption. However, GAS muscle-tendon mechanics and energetics were significantly more sensitive to changes in tendon compliance than were those for SOL. In addition, GAS was not able to return stored tendon energy during push-off as effectively as SOL, particularly for larger values of tendon compliance. These fundamental differences between GAS and SOL sensitivity to altered tendon compliance seem to arise from the biarticular nature of GAS. These insights are potentially important for understanding the functional consequences of altered Achilles tendon compliance due to aging, injury, or disease. DA - 2017/7/26/ PY - 2017/7/26/ DO - 10.1016/j.jbiomech.2017.06.022 VL - 60 SP - 227-231 SN - 1873-2380 KW - Plantarflexor KW - Musculoskeletal modeling KW - Forward dynamics KW - Mechanical power KW - Metabolic energy ER - TY - JOUR TI - Tailoring Biomaterials for Cancer Immunotherapy: Emerging Trends and Future Outlook AU - Wang, Chao AU - Ye, Yanqi AU - Hu, Quanyin AU - Bellotti, Adriano AU - Gu, Zhen T2 - ADVANCED MATERIALS AB - Cancer immunotherapy, as a paradigm shift in cancer treatment, has recently received tremendous attention. The active cancer vaccination, immune checkpoint blockage (ICB) and chimeric antigen receptor (CAR) for T‐cell‐based adoptive cell transfer are among these developments that have achieved a significant increase in patient survival in clinical trials. Despite these advancements, emerging research at the interdisciplinary interface of cancer biology, immunology, bioengineering, and materials science is important to further enhance the therapeutic benefits and reduce side effects. Here, an overview of the latest studies on engineering biomaterials for the enhancement of anticancer immunity is given, including the perspectives of delivery of immunomodulatory therapeutics, engineering immune cells, and constructing immune‐modulating scaffolds. The opportunities and challenges in this field are also discussed. DA - 2017/8/4/ PY - 2017/8/4/ DO - 10.1002/adma.201606036 VL - 29 IS - 29 SP - SN - 1521-4095 KW - biomaterials KW - cancer immunotherapy KW - cell therapy KW - drug delivery ER - TY - JOUR TI - Piezoelectric Floating Element Shear Stress Sensor for the Wind Tunnel Flow Measurement AU - Kim, Taeyang AU - Saini, Aditya AU - Kim, Jinwook AU - Gopalarathnam, Ashok AU - Zhu, Yong AU - Palmieri, Frank L. AU - Wohl, Christopher J. AU - Jiang, Xiaoning T2 - IEEE TRANSACTIONS ON INDUSTRIAL ELECTRONICS AB - A piezoelectric (PE) sensor with a floating element was developed for direct measurement of flow induced shear stress. The PE sensor was designed to detect the pure shear stress while suppressing the effect of normal stress generated from the vortex lift up by applying opposite poling vectors to the PE elements. During the calibration stage, the prototyped sensor showed a high sensitivity to shear stress (91.3 ± 2.1 pC/Pa) due to the high PE coefficients (d31 = -1330 pC/N) of the constituent 0.67Pb(Mg 1/3 Nb 2/3 )O 3 - 0.33PbTiO 3 (PMN-33%PT) single crystal. By contrast, the sensor showed almost no sensitivity to normal stress (less than 1.2 pC/Pa) because of the electromechanical symmetry of the sensing structure. The usable frequency range of the sensor is up to 800 Hz. In subsonic wind tunnel tests, an analytical model was proposed based on cantilever beam theory with an end-tip-mass for verifying the resonance frequency shift in static stress measurements. For dynamic stress measurements, the signal-to-noise ratio (SNR) and ambient vibration-filtered pure shear stress sensitivity were obtained through signal processing. The developed PE shear stress sensor was found to have an SNR of 15.8 ± 2.2 dB and a sensitivity of 56.5 ± 4.6 pC/Pa in the turbulent flow. DA - 2017/9// PY - 2017/9// DO - 10.1109/tie.2016.2630670 VL - 64 IS - 9 SP - 7304-7312 SN - 1557-9948 KW - Bimorph piezoelectric (PE) structures KW - electromechanical symmetry KW - floating element (FE) KW - PMN-33% PT crystal KW - shear stress ER - TY - JOUR TI - OPTIMIZING SENSITIVITY OF ULTRASOUND CONTRAST-ENHANCED SUPER-RESOLUTION IMAGING BY TAILORING SIZE DISTRIBUTION OF MICROBUBBLE CONTRAST AGENT AU - Lin, Fanglue AU - Tsuruta, James K. AU - Rojas, Juan D. AU - Dayton, Paul A. T2 - ULTRASOUND IN MEDICINE AND BIOLOGY AB - Ultrasound contrast-enhanced super-resolution imaging has recently attracted attention because of its extraordinary ability to image vascular features much smaller than the ultrasound diffraction limit. This method requires sensitive detection of separable microbubble events despite a noisy tissue background to indicate the microvasculature, and any approach that could improve the sensitivity of the ultrasound system to individual microbubbles would be highly beneficial. In this study, we evaluated the effect of varying microbubble size on super-resolution imaging sensitivity. Microbubble preparations were size sorted into different mean diameters and then were imaged at equal concentrations. Commercially manufactured Definity and Optison were also imaged for comparison. Both in vitro experiments in phantom vessels and in vivo experiments imaging rat tumors revealed that the sensitivity of contrast-enhanced super-resolution imaging can be improved by using microbubbles with a larger diameter. DA - 2017/10// PY - 2017/10// DO - 10.1016/j.ultrasmedbio.2017.05.014 VL - 43 IS - 10 SP - 2488-2493 SN - 1879-291X KW - Super resolution KW - Microbubble contrast agent KW - Sensitivity KW - Size distribution ER - TY - JOUR TI - In vivo multienzyme complex coconstruction of N-Acetylneuraminic acid lyase and N-Acetylglucosamine-2-epimerase for Biosynthesis of N-Acetylneuraminic acid AU - Wang, Z. F. AU - Zhuang, W. AU - Cheng, J. AU - Sun, W. J. AU - Wu, J. L. AU - Chen, Y. AU - Ying, H. J. T2 - Journal of Agricultural and Food Chemistry DA - 2017/// PY - 2017/// VL - 65 IS - 34 SP - 7467-7475 ER - TY - JOUR TI - Dual-Frequency Transducer with a Wideband PVDF Receiver for Contrast-Enhanced, Adjustable Harmonic Imaging AU - Kim, Jinwook AU - Lindsey, Brooks D. AU - Li, Sibo AU - Dayton, Paul A. AU - Jiang, Xiaoning T2 - HEALTH MONITORING OF STRUCTURAL AND BIOLOGICAL SYSTEMS 2017 AB - Acoustic angiography is a contrast-enhanced, superharmonic microvascular imaging method. It has shown the capability of high-resolution and high-contrast-to-tissue-ratio (CTR) imaging for vascular structure near tumor. Dual-frequency ultrasound transducers and arrays are usually used for this new imaging technique. Stacked-type dual-frequency transducers have been developed for this vascular imaging method by exciting injected microbubble contrast agent (MCA) in the vessels with low-frequency (1-5 MHz), moderate power ultrasound burst waves and receiving the superharmonic responses from MCA by a high-frequency receiver (>10 MHz). The main challenge of the conventional dual-frequency transducers is a limited penetration depth (<25 mm) due to the insufficient receiving sensitivity for highfrequency harmonic signal detection. A receiver with a high receiving sensitivity spanning a wide superharmonic frequency range (3rd to 6th) enables selectable bubble harmonic detection considering the required penetration depth. Here, we develop a new dual-frequency transducer composed of a 2 MHz 1-3 composite transmitter and a polyvinylidene fluoride (PVDF) receiver with a receiving frequency range of 4-12 MHz for adjustable harmonic imaging. The developed transducer was tested for harmonic responses from a microbubble-injected vessel-mimicking tube positioned 45 mm away. Despite the long imaging distance (45 mm), the prototype transducer detected clear harmonic response with the contrast-to-noise ratio of 6-20 dB and the -6 dB axial resolution of 200-350 μm for imaging a 200 um-diameter cellulose tube filled with microbubbles. DA - 2017/// PY - 2017/// DO - 10.1117/12.2258571 VL - 10170 SP - SN - 0277-786X KW - Dual-frequency transducer KW - PVDF transducer KW - P(VDF-TrFE) copolymer KW - Acoustic angiography KW - superharmonic imaging KW - contrast imaging ER - TY - JOUR TI - Biphasic Finite Element Modeling Reconciles Mechanical Properties of Tissue-Engineered Cartilage Constructs Across Testing Platforms AU - Meloni, Gregory R. AU - Fisher, Matthew B. AU - Stoeckl, Brendan D. AU - Dodge, George R. AU - Mauck, Robert L. T2 - TISSUE ENGINEERING PART A AB - Cartilage tissue engineering is emerging as a promising treatment for osteoarthritis, and the field has progressed toward utilizing large animal models for proof of concept and preclinical studies. Mechanical testing of the regenerative tissue is an essential outcome for functional evaluation. However, testing modalities and constitutive frameworks used to evaluate in vitro grown samples differ substantially from those used to evaluate in vivo derived samples. To address this, we developed finite element (FE) models (using FEBio) of unconfined compression and indentation testing, modalities commonly used for such samples. We determined the model sensitivity to tissue radius and subchondral bone modulus, as well as its ability to estimate material parameters using the built-in parameter optimization tool in FEBio. We then sequentially tested agarose gels of 4%, 6%, 8%, and 10% weight/weight using a custom indentation platform, followed by unconfined compression. Similarly, we evaluated the ability of the model to generate material parameters for living constructs by evaluating engineered cartilage. Juvenile bovine mesenchymal stem cells were seeded (2 × 107 cells/mL) in 1% weight/volume hyaluronic acid hydrogels and cultured in a chondrogenic medium for 3, 6, and 9 weeks. Samples were planed and tested sequentially in indentation and unconfined compression. The model successfully completed parameter optimization routines for each testing modality for both acellular and cell-based constructs. Traditional outcome measures and the FE-derived outcomes showed significant changes in material properties during the maturation of engineered cartilage tissue, capturing dynamic changes in functional tissue mechanics. These outcomes were significantly correlated with one another, establishing this FE modeling approach as a singular method for the evaluation of functional engineered and native tissue regeneration, both in vitro and in vivo. DA - 2017/7// PY - 2017/7// DO - 10.1089/ten.tea.2016.0191 VL - 23 IS - 13-14 SP - 663-674 SN - 1937-335X KW - mechanical evaluation KW - mesenchymal stem cells KW - cartilage tissue engineering ER - TY - JOUR TI - A new powered lower limb prosthesis control framework based on adaptive dynamic programming AU - Wen, Y. AU - Si, J. AU - Gao, X. AU - Huang, S. AU - Huang, H. T2 - IEEE Transactions on Neural Networks and Learning Systems DA - 2017/// PY - 2017/// VL - 28 IS - 9 SP - 2215-2220 ER - TY - JOUR TI - Visuomotor Entrainment and the Frequency-Dependent Response of Walking Balance to Perturbations AU - Franz, Jason R. AU - Francis, Carrie A. AU - Allen, Matthew S. AU - Thelen, Darryl G. T2 - IEEE TRANSACTIONS ON NEURAL SYSTEMS AND REHABILITATION ENGINEERING AB - Visuomotor entrainment, or the synchronization of motor responses to visual stimuli, is a naturally emergent phenomenon in human standing. Our purpose was to investigate the prevalence and resolution of visuomotor entrainment in walking and the frequency-dependent response of walking balance to perturbations. We used a virtual reality environment to manipulate optical flow in ten healthy young adults during treadmill walking. A motion capture system recorded trunk, sacrum, and heel marker trajectories during a series of 3-min conditions in which we perturbed a virtual hallway mediolaterally with systematic changes in the driving frequencies of perceived motion. We quantified visuomotor entrainment using spectral analyses and balance deficits using trunk sway, gait variability, and detrended fluctuation analyses (DFA). ML kinematics were highly sensitive to visual perturbations, and instinctively synchronized (i.e., entrained) to a broad range of driving frequencies of perceived ML motion. However, the influence of visual perturbations on metrics of walking balance was frequency-dependent and governed by their proximity to stride frequency. Specifically, we found that a driving frequency nearest to subjects' average stride frequency uniquely compromised trunk sway, gait variability, and step-to-step correlations. We conclude that visuomotor entrainment is a robust and naturally emerging phenomenon during human walking, involving coordinated and frequency-dependent adjustments in trunk sway and foot placement to maintain balance at the whole-body level. These findings provide mechanistic insight into how the visuomotor control of walking balance is disrupted by visual perturbations and important reference values for the emergence of balance deficits due to age, injury, or disease. DA - 2017/8// PY - 2017/8// DO - 10.1109/tnsre.2016.2603340 VL - 25 IS - 8 SP - 1135-1142 SN - 1558-0210 KW - Gait KW - posture KW - sensorimotor KW - stability KW - virtual reality ER - TY - JOUR TI - Spectroelectrochemical Characterization of the Dynamic Carbon Fiber Surface in Response to Electrochemical Conditioning AU - Mitchell, Edwin C. AU - Dunaway, Lars E. AU - McCarty, Gregory S. AU - Sombers, Leslie A. T2 - LANGMUIR AB - The effects of electrochemical preconditioning of P-55 pitch-based carbon-fiber microelectrodes were quantitatively examined in this study. Microstructural characterization of the electrode surface was done using Raman spectroscopy and scanning electron microscopy. Electrochemical performance was evaluated using cyclic voltammetry. The data show that application of positive potentials provides beneficial structural modifications to the electrode surface. Electrodes that were preconditioned using a static potential of +1.0 V exhibited enhanced sensitivity and electron transfer properties when compared to electrodes conditioned for the same amount of time with dynamic (triangular) waveforms reaching +1.0 V. Conditioning elicited microstructural changes to the electrode surface that were dependent on the amount of time spent at potentials greater than ∼1.0 V. Importantly, the data demonstrate that the carbon-fiber microstructure is dynamic. It is able to quickly and continuously undergo rapid structural reorganization as potential is applied, repeatedly alternating between a relatively ordered state and one that exhibits greater disorder in response to applied electrochemical potentials that span the range commonly used in voltammetric experiments. DA - 2017/8/15/ PY - 2017/8/15/ DO - 10.1021/acs.langmuir.7b01443 VL - 33 IS - 32 SP - 7838-7846 SN - 0743-7463 ER - TY - JOUR TI - Prediction of Intrinsically Caused Tripping Events in Individuals With Stroke AU - Zhang, Fan AU - Bohlen, Peter AU - Lewek, Michael D. AU - Huang, He T2 - IEEE TRANSACTIONS ON NEURAL SYSTEMS AND REHABILITATION ENGINEERING AB - This study investigated the feasibility of predicting intrinsically caused trips (ICTs) in individuals with stroke. Gait kinematics collected from 12 individuals with chronic stroke, who demonstrated ICTs in treadmill walking, were analyzed. A prediction algorithm based on the outlier principle was employed. Sequential forward selection (SFS) and minimum-redundancy-maximum-relevance (mRMR) were used separately to identify the precursors for accurate ICT prediction. The results showed that it was feasible to predict ICTs around 50-260 ms before ICTs occurred in the swing phase by monitoring lower limb kinematics during the preceding stance phase. Both SFS and mRMR were effective in identifying the precursors of ICTs. For 9 out of the 12 subjects, the paretic lower limb's shank orientation in the sagittal plane and the vertical velocity of the paretic foot's center of gravity were important in predicting ICTs accurately; the averaged area under receiver operating characteristic curve achieved 0.95 and above. For the other three subjects, kinematics of the less affected limb or proximal joints in the paretic side were identified as the precursors to an ICT, potentially due to the variations of neuromotor deficits among stroke survivors. Although additional engineering efforts are still needed to address the challenges in making our design clinically practical, the outcome of this study may lead to further proactive engineering mechanisms for ICT avoidance and therefore reduce the risk of falls in individuals with stroke. DA - 2017/8// PY - 2017/8// DO - 10.1109/tnsre.2016.2614521 VL - 25 IS - 8 SP - 1202-1210 SN - 1558-0210 UR - http://www.scopus.com/inward/record.url?eid=2-s2.0-85029147114&partnerID=MN8TOARS KW - Fall prevention KW - gait KW - prediction KW - stroke rehabilitation KW - trips ER - TY - JOUR TI - It's positive to be negative: Achilles tendon work loops during human locomotion AU - Zelik, Karl E. AU - Franz, Jason R. T2 - PLOS ONE AB - Ultrasound imaging is increasingly used with motion and force data to quantify tendon dynamics during human movement. Frequently, tendon dynamics are estimated indirectly from muscle fascicle kinematics (by subtracting muscle from muscle-tendon unit length), but there is mounting evidence that this Indirect approach yields implausible tendon work loops. Since tendons are passive viscoelastic structures, when they undergo a loading-unloading cycle they must exhibit a negative work loop (i.e., perform net negative work). However, prior studies using this Indirect approach report large positive work loops, often estimating that tendons return 2-5 J of elastic energy for every 1 J of energy stored. More direct ultrasound estimates of tendon kinematics have emerged that quantify tendon elongations by tracking either the muscle-tendon junction or localized tendon tissue. However, it is unclear if these yield more plausible estimates of tendon dynamics. Our objective was to compute tendon work loops and hysteresis losses using these two Direct tendon kinematics estimates during human walking. We found that Direct estimates generally resulted in negative work loops, with average tendon hysteresis losses of 2-11% at 1.25 m/s and 33-49% at 0.75 m/s (N = 8), alluding to 0.51-0.98 J of tendon energy returned for every 1 J stored. We interpret this finding to suggest that Direct approaches provide more plausible estimates than the Indirect approach, and may be preferable for understanding tendon energy storage and return. However, the Direct approaches did exhibit speed-dependent trends that are not consistent with isolated, in vitro tendon hysteresis losses of about 5-10%. These trends suggest that Direct estimates also contain some level of error, albeit much smaller than Indirect estimates. Overall, this study serves to highlight the complexity and difficulty of estimating tendon dynamics non-invasively, and the care that must be taken to interpret biological function from current ultrasound-based estimates. DA - 2017/7/3/ PY - 2017/7/3/ DO - 10.1371/journal.pone.0179976 VL - 12 IS - 7 SP - SN - 1932-6203 ER - TY - JOUR TI - Dual-Frequency Piezoelectric Endoscopic Transducer for Imaging Vascular Invasion in Pancreatic Cancer AU - Lindsey, Brooks D. AU - Kim, Jinwook AU - Dayton, Paul A. AU - Jiang, Xiaoning T2 - IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL AB - Cancers of the pancreas have the poorest prognosis among all cancers, as many tumors are not detected until surgery is no longer a viable option. Surgical viability is typically determined via endoscopic ultrasound imaging. However, many patients who may be eligible for resection are not offered surgery due to diagnostic challenges in determining vascular or lymphatic invasion. In this paper, we describe the development of a dual-frequency piezoelectric transducer for rotational endoscopic imaging designed to transmit at 4 MHz and receive at 20 MHz in order to image microbubble-specific superharmonic signals. Imaging performance is assessed in a tissue-mimicking phantom at depths from 1 cm [contrast-to-tissue ratio (CTR) = 21.6 dB] to 2.5 cm (CTR = 11.4 dB), in ex vivo porcine vessels, and in vivo in a rodent. The prototyped 1.1-mm aperture transducer demonstrates contrast-specific imaging of microbubbles in a 200-μm-diameter tube through the wall of a 1-cm-diameter porcine artery, suggesting such a device may enable direct visualization of small vessels from within the lumen of larger vessels such as the portal vein or superior mesenteric vein. DA - 2017/7// PY - 2017/7// DO - 10.1109/tuffc.2017.2702010 VL - 64 IS - 7 SP - 1078-1086 SN - 1525-8955 KW - Acoustic angiography KW - endoscope KW - high frequency KW - interventional imaging KW - microbubble KW - superharmonic ER - TY - JOUR TI - Controlled synthesis of polyethylenimine coated gold nanoparticles: Application in glutathione sensing and nucleotide delivery AU - Pandey, Prem C. AU - Pandey, Govind AU - Narayan, Roger J. T2 - JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART B-APPLIED BIOMATERIALS AB - Synthesis of functional gold nanoparticles (AuNPs) justifying selectivity in biochemical interaction along with biocompatibility suited for in vivo biomedical applications has been a challenging issue. We report herein the role of polyethylenimine (PEI) in controlled synthesis of AuNPs under ambient conditions which has potentiality for sensing glutathione and selective interaction with DNA binding proteins facilitating endosomal escape for the nucleotide delivery. The choice of organic reducing agents like formaldehyde/acetaldehyde/acetyl acetone/tetrahydrofuran hydroperoxide and other similar compounds allow rapid conversion of PEI capped gold cations into AuNPs at room temperature thus controlling the functional ability of nanoparticles as a function of organic reducing agents. Both small and higher molecular weight PEI facilitates fast synthesis of AuNPs controlling cytotoxicity during in vivo biomedical applications. The AuNPs have been characterized by UV–Vis and transmission electron microscopy revealing excellent polycrystallinity and controlled nanogeometry. The cationic polymer coating enhances the electrocatalytic performances of nanoparticles. The typical biomedical application on glutathione (GSH) sensing based on peroxidase mimetic ability of as made AuNPs is studied. The as synthesized AuNPs are extreme salt and pH resistant and have potentiality for both homogeneous and heterogeneous biocatalysis. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1191–1199, 2017. DA - 2017/7// PY - 2017/7// DO - 10.1002/jbm.b.33647 VL - 105 IS - 5 SP - 1191-1199 SN - 1552-4981 KW - rapid synthesis of AuNPs KW - polyethylenimine KW - pH and salt resistive AuNPs KW - biocatalysis and nucleotide delivery ER - TY - JOUR TI - Bioengineering of Artificial Antigen Presenting Cells and Lymphoid Organs AU - Wang, Chao AU - Sun, Wujin AU - Ye, Yanqi AU - Bomba, Hunter N. AU - Gu, Zhen T2 - THERANOSTICS AB - The immune system protects the body against a wide range of infectious diseases and cancer by leveraging the efficiency of immune cells and lymphoid organs. Over the past decade, immune cell/organ therapies based on the manipulation, infusion, and implantation of autologous or allogeneic immune cells/organs into patients have been widely tested and have made great progress in clinical applications. Despite these advances, therapy with natural immune cells or lymphoid organs is relatively expensive and time-consuming. Alternatively, biomimetic materials and strategies have been applied to develop artificial immune cells and lymphoid organs, which have attracted considerable attentions. In this review, we survey the latest studies on engineering biomimetic materials for immunotherapy, focusing on the perspectives of bioengineering artificial antigen presenting cells and lymphoid organs. The opportunities and challenges of this field are also discussed. DA - 2017/// PY - 2017/// DO - 10.7150/thno.19017 VL - 7 IS - 14 SP - 3504-3516 SN - 1838-7640 KW - artificial immune cells KW - lymphoid organs ER - TY - JOUR TI - An In Vitro Approach for Directly Observing Muscle-Tendon Dynamics with Parallel Elastic Mechanical Assistance AU - Sawicki, Gregory S. AU - Robertson, Benjamin D. T2 - CONVERGING CLINICAL AND ENGINEERING RESEARCH ON NEUROREHABILITATION II, VOLS 1 AND 2 AB - Lower-limb exoskeletons are a promising tool for restoring or augmenting locomotion performance. While engineering advances have led to marked improvements on the machine side of the human machine interface, fundamental aspects of the physiological response of the human user remain unknown—especially at the level of individual leg muscles. One complication is that it is difficult to make direct measurements from muscles in humans without being invasive. Here we offer a novel benchtop approach by introducing a ‘smart’ robotic interface into the framework of biological muscle-tendon work loop experiments in order to simulate the local dynamical environment muscles experience in vivo during locomotion with exoskeleton assistance. Using this framework we demonstrate that providing force in parallel with a muscle-tendon using an ‘exo-tendon’ can have unintended consequences, disrupting the ‘tuned’ spring-like mechanics of the underlying biological muscle tendon unit. DA - 2017/// PY - 2017/// DO - 10.1007/978-3-319-46669-9_106 VL - 15 SP - 643-647 SN - 2195-3562 ER - TY - JOUR TI - ZnO wide bandgap semiconductors preparation for optoelectronic devices AU - Ramelan, A. H. AU - Wahyuningsih, S. AU - Munawaroh, H. AU - Narayan, R. T2 - INTERNATIONAL CONFERENCE ON ADVANCED MATERIALS FOR BETTER FUTURE 2016 AB - ZnO nanoparticles were successfully synthesized by sol-gel method. According to unique structural and optical properties of ZnO semiconductor material, there are many potential important applications based on that material, including as an anti-reflection coating (ARC) in solar cells. Antireflective coatings (ARC) made of ZnO on top to improve the optical properties of the coating. TiO2 layer have been coated on a ZnO nanoparticle layer. ZnO nanoparticle was characterized by X-ray diffraction (XRD), Scanning electron Microscopy (SEM) and UV-Vis spectroscopy. ZnO annealed at a temperature of 600 °C have the greatest crystalinity and crystal size than that at a temperature of 400 °C and 500 °C. SEM images of ZnO shown agglomeration and grain size increases with increasing annealed temperature. While, the optical properties of ZnO increase with increasing annealed temperature. The optical transmittance spectra of the ZnO are shown that the increasing annealing temperature had effectively improved the optical transmittance of the films. While, reflectance (%R) properties shows that, the higher annealing temperature of ZnO preparations can decrease of %R value of ZnO thin layer. The difference properties of ZnO are due to differences of light scattering resulting from the crystal size effect. The ZnO prepared by annealed at 600 °C gain a good performance of the lowest reflectance value and highest size crystal. By the addition of ARC ZnO 600 °C we have been capable improve cell performance so that that cells achieve an efficiency of 0.27%. DA - 2017/// PY - 2017/// DO - 10.1088/1757-899x/176/1/012008 VL - 176 SP - SN - 1757-8981 ER - TY - JOUR TI - Transit Time Difference Flowmeter for Intravenous Flow Rate Measurement Using 1-3 Piezoelectric Composite Transducers AU - Kim, Taeyang AU - Kim, Jinwook AU - Jiang, Xiaoning T2 - IEEE SENSORS JOURNAL AB - The flow rate of injected medication implemented by intravenous (IV) systems must be accurately monitored and meticulously controlled to prevent medical accidents. In this paper, an ultrasonic flowmeter (UF) with 1-3 piezoelectric composite transducers was designed, fabricated, and tested on a variety of flow rates of mimic medical injections. The transducer wedge for the angled beam propagation and an acoustic impedance matching layer were included in the design for transmission enhancement. To ensure an accurate measurement of flow rate, the effect of the flow distributions inside the IV tube was taken into account. The developed UF exhibited the capability of detecting low flow rates (<;0.005 m/s), with 1%-2% discrepancy compared with the reference rate of infusion. DA - 2017/9/1/ PY - 2017/9/1/ DO - 10.1109/jsen.2017.2727340 VL - 17 IS - 17 SP - 5741-5748 SN - 1558-1748 KW - Intravenous (IV) flow rate KW - transit time difference KW - ultrasonic flowmeter KW - 1-3 composite transducer ER - TY - JOUR TI - The role of biophysical properties of provisional matrix proteins in wound repair AU - Chester, Daniel AU - Brown, Ashley C. T2 - MATRIX BIOLOGY AB - Wound healing is a complex, dynamic process required for maintaining homeostasis in an organism. Along with being controlled biochemically, wound healing is also controlled through the transduction of biophysical stimuli through cell interactions with the extracellular matrix (ECM). This review provides an overview of the ECM's role in the wound healing process and subsequently expands on the variety of roles biophysical phenomenon play. DA - 2017/7// PY - 2017/7// DO - 10.1016/j.matbio.2016.08.004 VL - 60-61 SP - 124-140 SN - 1569-1802 KW - Wound healing KW - Extracellular matrix KW - Biophysics KW - Fibrin KW - Fibrinogen KW - Fibronectin KW - Collagen KW - Transforming growth factor beta KW - Platelets ER - TY - JOUR TI - Photoacoustic Drug Delivery AU - Zhang, Yuqi AU - Yu, Jicheng AU - Kahkoska, Anna R. AU - Gu, Zhen T2 - SENSORS AB - Photoacoustic (PA) technology holds great potential in clinical translation as a new non-invasive bioimaging modality. In contrast to conventional optical imaging, PA imaging (PAI) enables higher resolution imaging with deeper imaging depth. Besides applications for diagnosis, PA has also been extended to theranostic applications. The guidance of PAI facilitates remotely controlled drug delivery. This review focuses on the recent development of PAI-mediated drug delivery systems. We provide an overview of the design of different PAI agents for drug delivery. The challenges and further opportunities regarding PA therapy are also discussed. DA - 2017/6// PY - 2017/6// DO - 10.3390/s17061400 VL - 17 IS - 6 SP - SN - 1424-8220 KW - photoacoustic imaging KW - drug delivery KW - chemotherapy KW - photothermal therapy ER - TY - JOUR TI - Peptide Mimetic Drugs for Modulating Thrombosis and Hemostasis AU - Nellenbach, Kimberly AU - Brown, Ashley C. T2 - DRUG DEVELOPMENT RESEARCH AB - Preclinical Research Hemostasis is the complex physiological process that stems bleeding at an injury site while simultaneously maintaining unobstructed circulation in other areas of the body. This system is kept in balance with finely tuned regulation by pro- and antithrombotic agents. When this balance is thrown out of equilibrium, uncontrolled bleeding, or thrombotic complications can occur. Because of the high number of hemostatic disorders, researchers are continually searching for improved technologies for controlling coagulation. Recently, peptide mimetic strategies have been employed to target and regulate various stages of the coagulation cascade. In this review, we present an overview of the coagulation cascade and provide a summary of various peptide-mimetic approaches for its modulation. Drug Dev Res 78 : 236-244, 2017. © 2017 Wiley Periodicals, Inc. DA - 2017/9// PY - 2017/9// DO - 10.1002/ddr.21407 VL - 78 IS - 6 SP - 236-244 SN - 1098-2299 KW - thrombosis KW - hemostasis KW - peptide-mimetic KW - fibrinogen KW - thrombin KW - platelet ER - TY - JOUR TI - Modulation of Interleukin-12 activity in the presence of heparin AU - Jayanthi, Srinivas AU - Koppolu, Bhanu Prasanth AU - Nguyen, Khue G. AU - Smith, Sean G. AU - Felber, Barbara K. AU - Kumar, Thallapuranam Krishnaswamy Suresh AU - Zaharoff, David A. T2 - SCIENTIFIC REPORTS AB - Glycosaminoglycans (GAGs), especially heparin and heparan sulfate (HS), modulate the functions of numerous cytokines. The aims of this multidisciplinary research were to characterize heparin binding to interleukin-12 (IL-12) and determine the mechanism(s) by which heparin influences IL-12 bioactivity. Heparin and HS were found to bind human IL-12 (hIL-12) with low micromolar affinity and increase hIL-12 bioactivity by more than 6-fold. Conversely, other GAGs did not demonstrate significant binding, nor did their addition affect hIL-12 bioactivity. Biophysical studies demonstrated that heparin induced only minor conformational changes while size-exclusion chromatography and small angle X-ray scattering studies indicated that heparin induced dimerization of hIL-12. Heparin modestly protected hIL-12 from proteolytic degradation, however, this was not a likely mechanism for increased cytokine activity in vitro. Flow cytometry studies revealed that heparin increased the amount of hIL-12 bound to cell surfaces. Heparin also facilitated hIL-12 binding and signaling in cells in which both hIL-12 receptor subunits were functionally deleted. Results of this study demonstrate a new role for heparin in modulating the biological activity of IL-12. DA - 2017/7/13/ PY - 2017/7/13/ DO - 10.1038/s41598-017-05382-1 VL - 7 SP - SN - 2045-2322 ER - TY - JOUR TI - Intravascular forward-looking ultrasound transducers for microbubble-mediated sonothrombolysis AU - Kim, Jinwook AU - Lindsey, Brooks D. AU - Chang, Wei-Yi AU - Dai, Xuming AU - Stavas, Joseph M. AU - Dayton, Paul A. AU - Jiang, Xiaoning T2 - SCIENTIFIC REPORTS AB - Abstract Effective removal or dissolution of large blood clots remains a challenge in clinical treatment of acute thrombo-occlusive diseases. Here we report the development of an intravascular microbubble-mediated sonothrombolysis device for improving thrombolytic rate and thus minimizing the required dose of thrombolytic drugs. We hypothesize that a sub-megahertz, forward-looking ultrasound transducer with an integrated microbubble injection tube is more advantageous for efficient thrombolysis by enhancing cavitation-induced microstreaming than the conventional high-frequency, side-looking, catheter-mounted transducers. We developed custom miniaturized transducers and demonstrated that these transducers are able to generate sufficient pressure to induce cavitation of lipid-shelled microbubble contrast agents. Our technology demonstrates a thrombolysis rate of 0.7 ± 0.15 percent mass loss/min in vitro without any use of thrombolytic drugs. DA - 2017/6/14/ PY - 2017/6/14/ DO - 10.1038/s41598-017-03492-4 VL - 7 SP - SN - 2045-2322 ER - TY - JOUR TI - High temperature transducer using aluminum nitride single crystal for laser ultrasound detection AU - Kim, Taeyang AU - Kim, Jinwook AU - Jiang, Xiaoning T2 - NONDESTRUCTIVE CHARACTERIZATION AND MONITORING OF ADVANCED MATERIALS, AEROSPACE, AND CIVIL INFRASTRUCTURE 2017 AB - In this work, a new ultrasound nondestructive testing (NDT) method based on laser-generated Lamb wave detection was proposed for high temperature (HT) NDT. Lamb waves were introduced to a stainless steel plate by the Nd:YAG pulsed laser at one point and detected by aluminum nitride (AlN) transducer at a distant position. The fundamental symmetric (S0) and antisymmetric (A0) mode Lamb waves were successfully propagated in the thin stainless steel plate. The time-of- flight (TOF) of the S0 and A0 mode waves proportionally increased with the distance (D) between the laser source and the sensor, and almost no attenuation of the amplitude was observed. For the HT NDT experiment, AlN single crystal was adopted as the ultrasonic sensor material due to its high thermal resistance of the dielectric and piezoelectric constants at the elevated temperature up to 800 °C. The combination of non-contact, portable laser source as a Lamb wave generator and temperature-robust NDT sensor made of AIN has shown its great capability to detect the Lamb waves at elevated temperatures. DA - 2017/// PY - 2017/// DO - 10.1117/12.2259975 VL - 10169 SP - SN - 0277-786X KW - Pulsed Nd: YAG laser KW - Lamb wave KW - AlN KW - high temperature NDT ER - TY - JOUR TI - Do kinematic metrics of walking balance adapt to perturbed optical flow? AU - Thompson, Jessica D. AU - Franz, Jason R. T2 - HUMAN MOVEMENT SCIENCE AB - Visual (i.e., optical flow) perturbations can be used to study balance control and balance deficits. However, it remains unclear whether walking balance control adapts to such perturbations over time. Our purpose was to investigate the propensity for visuomotor adaptation in walking balance control using prolonged exposure to optical flow perturbations. Ten subjects (age: 25.4 ± 3.8 years) walked on a treadmill while watching a speed-matched virtual hallway with and without continuous mediolateral optical flow perturbations of three different amplitudes. Each of three perturbation trials consisted of 8 min of prolonged exposure followed by 1 min of unperturbed walking. Using 3D motion capture, we analyzed changes in foot placement kinematics and mediolateral sacrum motion. At their onset, perturbations elicited wider and shorter steps, alluding to a more cautious, general anticipatory balance control strategy. As perturbations continued, foot placement tended toward values seen during unperturbed walking while step width variability and mediolateral sacrum motion concurrently increased. Our findings suggest that subjects progressively shifted from a general anticipatory balance control strategy to a reactive, task-specific strategy using step-to-step adjustments. Prolonged exposure to optical flow perturbations may have clinical utility to reinforce reactive, task-specific balance control through training. DA - 2017/8// PY - 2017/8// DO - 10.1016/j.humov.2017.03.004 VL - 54 SP - 34-40 SN - 1872-7646 KW - Sensorimotor KW - Virtual reality KW - Gait KW - Vision KW - Visual feedback ER - TY - JOUR TI - Detection of an Integrin-Binding Mechanoswitch within Fibronectin during Tissue Formation and Fibrosis AU - Cao, Lizhi AU - Nicosia, John AU - Larouche, Jacqueline AU - Zhang, Yuanyuan AU - Bachman, Haylee AU - Brown, Ashley C. AU - Holmgren, Lars AU - Barker, Thomas H. T2 - ACS NANO AB - Fibronectin (Fn) is an extracellular matrix protein that orchestrates complex cell adhesion and signaling through cell surface integrin receptors during tissue development, remodeling, and disease, such as fibrosis. Fn is sensitive to mechanical forces in its tandem type III repeats, resulting in extensive molecular enlongation. As such, it has long been hypothesized that cell- and tissue-derived forces may activate an “integrin switch” within the critical integrin-binding ninth and 10th type III repeats—conferring differential integrin-binding specificity, leading to differential cell responses. Yet, no direct evidence exists to prove the hypothesis nor demonstrate the physiological existence of the switch. We report direct experimental evidence for the Fn integrin switch both in vitro and ex vivo using a scFv engineered to detect the transient, force-induced conformational change, representing an opportunity for detection and targeting of early molecular signatures of cell contractile forces in tissue repair and disease. DA - 2017/7// PY - 2017/7// DO - 10.1021/acsnano.7b02755 VL - 11 IS - 7 SP - 7110-7117 SN - 1936-086X KW - mechano-biology KW - antibody phage display KW - integrins KW - fibronectin KW - fibrosis KW - angiogenesis ER - TY - JOUR TI - Analytical methods for detection of Zika virus AU - Yang, Kai-Hung AU - Narayan, Roger J. T2 - MRS COMMUNICATIONS DA - 2017/6// PY - 2017/6// DO - 10.1557/mrc.2017.20 VL - 7 IS - 2 SP - 121-130 SN - 2159-6867 ER - TY - JOUR TI - Ultrasound-triggered noninvasive regulation of blood glucose levels using microgels integrated with insulin nanocapsules AU - Di, Jin AU - Yu, Jicheng AU - Wang, Qun AU - Yao, Shanshan AU - Suo, Dingjie AU - Ye, Yanqi AU - Pless, Matthew AU - Zhu, Yong AU - Jing, Yun AU - Gu, Zhen T2 - NANO RESEARCH DA - 2017/4// PY - 2017/4// DO - 10.1007/s12274-017-1500-z VL - 10 IS - 4 SP - 1393-1402 SN - 1998-0000 KW - controlled drug delivery KW - focused ultrasound KW - diabetes KW - nanocapsule KW - microgel ER - TY - JOUR TI - Systematic investigation on the intracellular trafficking network of polymeric nanoparticles AU - Zhang, J. X. AU - Chang, D. F. AU - Yang, Y. AU - Zhang, X. D. AU - Tao, W. AU - Jiang, L. J. AU - Liang, X. AU - Tsai, H. G. AU - Huang, L. Q. AU - Mei, L. T2 - Nanoscale DA - 2017/// PY - 2017/// VL - 9 IS - 9 SP - 3269-3282 ER - TY - JOUR TI - Relay Drug Delivery for Amplifying Targeting Signal and Enhancing Anticancer Efficacy AU - Hu, Quanyin AU - Sun, Wujin AU - Qian, Chenggen AU - Bomba, Hunter N. AU - Xin, Hongliang AU - Gu, Zhen T2 - ADVANCED MATERIALS AB - A "relay drug delivery" system based on two distinct modules, which is composed of a signal transmission nanocarrier A (NCA ) that can specifically induce tumor blood vessel inflammation generation and an execution biomimetic nanocarrier B (NCB ) that can accumulate at the tumor site by receiving the broadcasting signals generated by NCA , is developed for amplifying active tumor targeting signal and enhancing antitumor therapy. DA - 2017/4/4/ PY - 2017/4/4/ DO - 10.1002/adma.201605803 VL - 29 IS - 13 SP - SN - 1521-4095 ER - TY - JOUR TI - Pyruvate Kinase Inhibits Proliferation during Postnatal Cerebellar Neurogenesis and Suppresses Medulloblastoma Formation AU - Tech, Katherine AU - Tikunov, Andrey P. AU - Farooq, Hamza AU - Morrissy, A. Sorana AU - Meidinger, Jessica AU - Fish, Taylor AU - Green, Sarah C. AU - Liu, Hedi AU - Li, Yisu AU - Mungall, Andrew J. AU - Moore, Richard A. AU - Ma, Yussanne AU - Jones, Steven J. M. AU - Marra, Marco A. AU - Vander Heiden, Matthew G. AU - Taylor, Michael D. AU - Macdonald, Jeffrey M. AU - Gershon, Timothy R. T2 - CANCER RESEARCH AB - Abstract Aerobic glycolysis supports proliferation through unresolved mechanisms. We have previously shown that aerobic glycolysis is required for the regulated proliferation of cerebellar granule neuron progenitors (CGNP) and for the growth of CGNP-derived medulloblastoma. Blocking the initiation of glycolysis via deletion of hexokinase-2 (Hk2) disrupts CGNP proliferation and restricts medulloblastoma growth. Here, we assessed whether disrupting pyruvate kinase-M (Pkm), an enzyme that acts in the terminal steps of glycolysis, would alter CGNP metabolism, proliferation, and tumorigenesis. We observed a dichotomous pattern of PKM expression, in which postmitotic neurons throughout the brain expressed the constitutively active PKM1 isoform, while neural progenitors and medulloblastomas exclusively expressed the less active PKM2. Isoform-specific Pkm2 deletion in CGNPs blocked all Pkm expression. Pkm2-deleted CGNPs showed reduced lactate production and increased SHH-driven proliferation. 13C-flux analysis showed that Pkm2 deletion reduced the flow of glucose carbons into lactate and glutamate without markedly increasing glucose-to-ribose flux. Pkm2 deletion accelerated tumor formation in medulloblastoma-prone ND2:SmoA1 mice, indicating the disrupting PKM releases CGNPs from a tumor-suppressive effect. These findings show that distal and proximal disruptions of glycolysis have opposite effects on proliferation, and that efforts to block the oncogenic effect of aerobic glycolysis must target reactions upstream of PKM. Cancer Res; 77(12); 3217–30. ©2017 AACR. DA - 2017/6/15/ PY - 2017/6/15/ DO - 10.1158/0008-5472.can-16-3304 VL - 77 IS - 12 SP - 3217-3230 SN - 1538-7445 ER - TY - JOUR TI - Polyethylenimine-mediated synthetic insertion of gold nanoparticles into mesoporous silica nanoparticles for drug loading and biocatalysis AU - Pandey, Prem C. AU - Pandey, Govind AU - Narayan, Roger J. T2 - BIOINTERPHASES AB - Mesoporous silica nanoparticles (MSNPs) have been used as an efficient and safe carrier for drug delivery and biocatalysis. The surface modification of MSNPs using suitable reagents may provide a robust framework in which two or more components can be incorporated to give multifunctional capabilities (e.g., synthesis of noble metal nanoparticles within mesoporous architecture along with loading of a bioactive molecule). In this study, the authors reported on a new synthetic route for the synthesis of gold nanoparticles (AuNPs) within (1) unmodified MSNPs and (2) 3-trihydroxysilylpropyl methylphosphonate-modified MSNPs. A cationic polymer, polyethylenimine (PEI), and formaldehyde were used to mediate synthetic incorporation of AuNPs within MSNPs. The AuNPs incorporated within the mesoporous matrix were characterized by transmission electron microscopy, energy dispersive x-ray analysis, and high-resolution scanning electron microscopy. PEI in the presence of formaldehyde enabled synthetic incorporation of AuNPs in both unmodified and modified MSNPs. The use of unmodified MSNPs was associated with an increase in the polycrystalline structure of the AuNPs within the MSNPs. The AuNPs within modified MSNPs showed better catalytic activity than those within unmodified MSNPs. MSNPs with an average size of 200 nm and with a pore size of 4-6 nm were used for synthetic insertion of AuNPs. It was found that the PEI coating enabled AuNPs synthesis within the mesopores in the presence of formaldehyde or tetrahydrofuran hydroperoxide at a temperature between 10 and 25 °C or at 60 °C in the absence of organic reducing agents. The as-made AuNP-inserted MSNPs exhibited enhanced catalytic activity. For example, these materials enabled rapid catalytic oxidation of the o-dianisidine substrate to produce a colored solution in proportion to the amount of H2O2 generated as a function of glucose oxidase-catalyzed oxidation of glucose; a linear concentration range from 80 to 800 μM and a detection limit as low as 80 μM were observed. The mesoscale pores of the as developed AuNP-inserted MSNPs were also used to entrap the hydrophobic drug paclitaxel. The results of this study indicate the potential use of the AuNP-inserted MSNPs in biocatalysis and drug delivery. DA - 2017/3// PY - 2017/3// DO - 10.1116/1.4979200 VL - 12 IS - 1 SP - SN - 1559-4106 ER - TY - JOUR TI - Modular pumps as programmable hydraulic batteries for microfluidic devices AU - Cummins, Brian M. AU - Chinthapatla, Rukesh AU - Lenin, Balaji AU - Ligler, Frances S. AU - Walker, Glenn M. T2 - TECHNOLOGY AB - Simple fluid pumps have been developed to improve microfluidic device portability, but they cannot be easily programmed, produce repeatable pumping performance, or generate complex flow profiles — key requirements for increasing the functionality of portable microdevices. We present a detachable, paper-based, “hydraulic battery” that can be connected to the outlet of a microfluidic channel to pump fluid at varying flow rates over time, including step changes, ramping flows, and oscillating flows. DA - 2017/3// PY - 2017/3// DO - 10.1142/s2339547817200011 VL - 5 IS - 1 SP - 21-30 SN - 2345-7740 KW - Paper Microfluidics KW - Capillary Pump KW - Microfluidic KW - Lateral Flow KW - Microfluidic Pump KW - Point of Care ER - TY - JOUR TI - Conjugated polymer nanomaterials for theranostics AU - Cheng-gen, Qian AU - Chen, Yu-lei AU - Feng, Pei-jian AU - Xiao, Xuan-zhong AU - Dong, Mei AU - Yu, Ji-cheng AU - Hu, Quan-yin AU - Shen, Qun-dong AU - Gu, Zhen T2 - ACTA PHARMACOLOGICA SINICA AB - Conjugated polymer nanomaterials (CPNs), as optically and electronically active materials, hold promise for biomedical imaging and drug delivery applications. This review highlights the recent advances in the utilization of CPNs in theranostics. Specifically, CPN-based in vivo imaging techniques, including near-infrared (NIR) imaging, two-photon (TP) imaging, photoacoustic (PA) imaging, and multimodal (MM) imaging, are introduced. Then, CPN-based photodynamic therapy (PDT) and photothermal therapy (PTT) are surveyed. A variety of stimuli-responsive CPN systems for drug delivery are also summarized, and the promising trends and translational challenges are discussed. DA - 2017/6// PY - 2017/6// DO - 10.1038/aps.2017.42 VL - 38 IS - 6 SP - 764-781 SN - 1745-7254 KW - conjugated polymer KW - theranostics KW - biomedical imaging KW - photodynamic therapy KW - photothermal therapy KW - stimuli KW - responsive drug delivery ER - TY - JOUR TI - A Pilot Clinical Study in Characterization of Malignant Renal-cell Carcinoma Subtype with Contrast-enhanced Ultrasound AU - Kasoji, Sandeep K. AU - Chang, Emily H. AU - Mullin, Lee B. AU - Chong, Wui K. AU - Rathmell, W. Kimryn AU - Dayton, Paul A. T2 - ULTRASONIC IMAGING AB - Malignant renal cell carcinoma (RCC) is a diverse set of diseases, which are independently difficult to characterize using conventional MRI and CT protocols due to low temporal resolution to study perfusion characteristics. Because different disease subtypes have different prognoses and involve varying treatment regimens, the ability to determine RCC subtype non-invasively is a clinical need. Contrast-enhanced ultrasound (CEUS) has been assessed as a tool to characterize kidney lesions based on qualitative and quantitative assessment of perfusion patterns, and we hypothesize that this technique might help differentiate disease subtypes. Twelve patients with RCC confirmed pathologically were imaged using contrast-enhanced ultrasound. Time intensity curves were generated and analyzed quantitatively using 10 characteristic metrics. Results showed that peak intensity ( p = 0.001) and time-to-80% on wash-out ( p = 0.004) provided significant differences between clear cell, papillary, and chromophobe RCC subtypes. These results suggest that CEUS may be a feasible test for characterizing RCC subtypes. DA - 2017/3// PY - 2017/3// DO - 10.1177/0161734616666383 VL - 39 IS - 2 SP - 126-136 SN - 1096-0910 KW - contrast-enhanced ultrasound KW - renal cell carcinoma KW - time intensity curve KW - renal perfusion KW - microbubbles ER - TY - JOUR TI - Stimuli-Responsive Polymersomes for Biomedical Applications AU - Hu, Xiuli AU - Zhang, Yugi AU - Xie, Zhigang AU - Jing, Xiabin AU - Bellotti, Adriano AU - Gu, Zhen T2 - BIOMACROMOLECULES AB - Polymersomes, the structural analogues of liposomes, are hollow structures enclosed by a bilayer membrane made from amphiphilic copolymers. Polymersomes have been proposed to mimic the structure and properties of cellular membranes and viral capsids. Excellent robustness and stability, chemical versatility for tunable membrane properties and surface functionalization make polymersomes attractive candidates for drug delivery, diagnostic imaging, nanoreactor vessels, and artificial organelles. In further biomimetic strategies, stimuli-responsive polymersomes that can recognize various external physical or internal biological environmental stimuli and conduct “on demand” release in dose-, spatial-, and temporal-controlled fashions have been widely developed. This Perspective focuses on recent advances in stimuli-responsive polymersomes and their potential biomedical applications. Representative examples of each stimulus, the advantages and limitations of different strategies, and the future opportunities and challenges are discussed. DA - 2017/3// PY - 2017/3// DO - 10.1021/acs.biomac.6b01704 VL - 18 IS - 3 SP - 649-673 SN - 1526-4602 ER - TY - JOUR TI - Simultaneous Voltammetric Measurements of Glucose and Dopamine Demonstrate the Coupling of Glucose Availability with Increased Metabolic Demand in the Rat Striatum AU - Smith, Samantha K. AU - Lee, Christie A. AU - Dausch, Matthew E. AU - Horman, Brian M. AU - Patisaul, Heather B. AU - McCarty, Gregory S. AU - Sombers, Leslie A. T2 - ACS CHEMICAL NEUROSCIENCE AB - Cerebral blood flow ensures delivery of nutrients, such as glucose, to brain sites with increased metabolic demand. However, little is known about rapid glucose dynamics at discrete locations during neuronal activation in vivo. Acute exposure to many substances of abuse elicits dopamine release and neuronal activation in the striatum; however, the concomitant changes in striatal glucose remain largely unknown. Recent developments have combined fast-scan cyclic voltammetry with glucose oxidase enzyme modified carbon-fiber microelectrodes to enable the measurement of glucose dynamics with subsecond temporal resolution in the mammalian brain. This work evaluates several waveforms to enable the first simultaneous detection of endogenous glucose and dopamine at single recording sites. These molecules, one electroactive and one nonelectroactive, were found to fluctuate in the dorsal striatum in response to electrical stimulation of the midbrain and systemic infusion of cocaine/raclopride. The data reveal the second-by-second dynamics of these species in a striatal microenvironment, and directly demonstrate the coupling of glucose availability with increased metabolic demand. This work provides a foundation that will enable detailed investigation of local mechanisms that regulate the coupling of cerebral blood flow with metabolic demand under normal conditions, and in animal studies of drug abuse and addiction. DA - 2017/2// PY - 2017/2// DO - 10.1021/acschemneuro.6b00363 VL - 8 IS - 2 SP - 272-280 SN - 1948-7193 KW - Biosensor KW - carbon fiber microelectrode KW - neuroenergetics KW - glucose oxidase KW - cocaine KW - fast-scan cyclic voltammetry ER - TY - JOUR TI - Musculoskeletal model-based control interface mimics physiologic hand dynamics during path tracing task AU - Crouch, Dustin L. AU - Huang, He T2 - JOURNAL OF NEURAL ENGINEERING AB - We investigated the feasibility of a novel, customizable, simplified EMG-driven musculoskeletal model for estimating coordinated hand and wrist motions during a real-time path tracing task.A two-degree-of-freedom computational musculoskeletal model was implemented for real-time EMG-driven control of a stick figure hand displayed on a computer screen. After 5-10 minutes of undirected practice, subjects were given three attempts to trace 10 straight paths, one at a time, with the fingertip of the virtual hand. Able-bodied subjects completed the task on two separate test days.Across subjects and test days, there was a significant linear relationship between log-transformed measures of accuracy and speed (Pearson's r = 0.25, p < 0.0001). The amputee subject could coordinate movement between the wrist and MCP joints, but favored metacarpophalangeal joint motion more highly than able-bodied subjects in 8 of 10 trials. For able-bodied subjects, tracing accuracy was lower at the extremes of the model's range of motion, though there was no apparent relationship between tracing accuracy and fingertip location for the amputee. Our result suggests that, unlike able-bodied subjects, the amputee's motor control patterns were not accustomed to the multi-joint dynamics of the wrist and hand, possibly as a result of post-amputation cortical plasticity, disuse, or sensory deficits.To our knowledge, our study is one of very few that have demonstrated the real-time simultaneous control of multi-joint movements, especially wrist and finger movements, using an EMG-driven musculoskeletal model, which differs from the many data-driven algorithms that dominate the literature on EMG-driven prosthesis control. Real-time control was achieved with very little training and simple, quick (~15 s) calibration. Thus, our model is potentially a practical and effective control platform for multifunctional myoelectric prostheses that could restore more life-like hand function for individuals with upper limb amputation. DA - 2017/6// PY - 2017/6// DO - 10.1088/1741-2552/aa61bc VL - 14 IS - 3 SP - SN - 1741-2552 UR - http://www.scopus.com/inward/record.url?eid=2-s2.0-85020447492&partnerID=MN8TOARS KW - electromyogram KW - prosthesis control KW - musculoskeletal model KW - dynamic simulation KW - amputation ER - TY - JOUR TI - Directed Differentiation of Human Pluripotent Stem Cells to Microglia AU - Douvaras, Panagiotis AU - Sun, Bruce AU - Wang, Minghui AU - Kruglikov, Ilya AU - Lallos, Gregory AU - Zimmer, Matthew AU - Terrenoire, Cecile AU - Zhang, Bin AU - Gandy, Sam AU - Schadt, Eric AU - Freytes, Donald O. AU - Noggle, Scott AU - Fossati, Valentina T2 - STEM CELL REPORTS AB - Microglia, the immune cells of the brain, are crucial to proper development and maintenance of the CNS, and their involvement in numerous neurological disorders is increasingly being recognized. To improve our understanding of human microglial biology, we devised a chemically defined protocol to generate human microglia from pluripotent stem cells. Myeloid progenitors expressing CD14/CX3CR1 were generated within 30 days of differentiation from both embryonic and induced pluripotent stem cells (iPSCs). Further differentiation of the progenitors resulted in ramified microglia with highly motile processes, expressing typical microglial markers. Analyses of gene expression and cytokine release showed close similarities between iPSC-derived (iPSC-MG) and human primary microglia as well as clear distinctions from macrophages. iPSC-MG were able to phagocytose and responded to ADP by producing intracellular Ca2+ transients, whereas macrophages lacked such response. The differentiation protocol was highly reproducible across several pluripotent stem cell lines. DA - 2017/6/6/ PY - 2017/6/6/ DO - 10.1016/j.stemcr.2017.04.023 VL - 8 IS - 6 SP - 1516-1524 SN - 2213-6711 ER - TY - JOUR TI - Background Signal as an in Situ Predictor of Dopamine Oxidation Potential: Improving Interpretation of Fast-Scan Cyclic Voltammetry Data AU - Meunier, Carl J. AU - Roberts, James G. AU - McCarty, Gregory S. AU - Sombers, Leslie A. T2 - ACS CHEMICAL NEUROSCIENCE AB - Background-subtracted fast-scan cyclic voltammetry (FSCV) has emerged as a powerful analytical technique for monitoring subsecond molecular fluctuations in live brain tissue. Despite increasing utilization of FSCV, efforts to improve the accuracy of quantification have been limited due to the complexity of the technique and the dynamic recording environment. It is clear that variable electrode performance renders calibration necessary for accurate quantification; however, the nature of in vivo measurements can make conventional postcalibration difficult, or even impossible. Analyte-specific voltammograms and scaling factors that are critical for quantification can shift or fluctuate in vivo. This is largely due to impedance changes, and the effects of impedance on these measurements have not been characterized. We have previously reported that the background current can be used to predict electrode-specific scaling factors in situ. In this work, we employ model circuits to investigate the impact of impedance on FSCV measurements. Additionally, we take another step toward in situ electrode calibration by using the oxidation potential of quinones on the electrode surface to accurately predict the oxidation potential for dopamine at any point in an electrochemical experiment, as both are dependent on impedance. The model, validated both in adrenal slice and live brain tissue, enables information encoded in the shape of the background voltammogram to determine electrochemical parameters that are critical for accurate quantification. This improves data interpretation and provides a significant next step toward more automated methods for in vivo data analysis. DA - 2017/2// PY - 2017/2// DO - 10.1021/acschemneuro.6b00325 VL - 8 IS - 2 SP - 411-419 SN - 1948-7193 KW - Carbon-fiber microelectrode KW - electrochemical impedance spectroscopy KW - electrochemistry KW - calibration KW - in vivo ER - TY - JOUR TI - Automated microraft platform to identify and collect non-adherent cells successfully gene-edited with CRISPR-Cas9 AU - Attayek, Peter J. AU - Waugh, Jennifer P. AU - Hunsucker, Sally A. AU - Grayeski, Philip J. AU - Sims, Christopher E. AU - Armistead, Paul M. AU - Allbritton, Nancy L. T2 - BIOSENSORS & BIOELECTRONICS AB - Microraft arrays have been used to screen and then isolate adherent and non-adherent cells with very high efficiency and excellent viability; however, manual screening and isolation limits the throughput and utility of the technology. In this work, novel hardware and software were developed to automate the microraft array platform. The developed analysis software identified microrafts on the array with greater than 99% sensitivity and cells on the microrafts with 100% sensitivity. The software enabled time-lapse imaging and the use of temporally varying characteristics as sort criteria. The automated hardware released microrafts with 98% efficiency and collected released microrafts with 100% efficiency. The automated system was used to examine the temporal variation in EGFP expression in cells transfected with CRISPR-Cas9 components for gene editing. Of 11,499 microrafts possessing a single cell, 220 microrafts were identified as possessing temporally varying EGFP-expression. Candidate cells (n=172) were released and collected from the microraft array and screened for the targeted gene mutation. Two cell colonies were successfully gene edited demonstrating the desired mutation. DA - 2017/5/15/ PY - 2017/5/15/ DO - 10.1016/j.bios.2016.12.019 VL - 91 SP - 175-182 SN - 1873-4235 KW - Microraft KW - Cell array KW - CRISPR-Cas9 KW - Cytometry KW - Cell sorting ER - TY - JOUR TI - A benchtop biorobotic platform for in vitro observation of muscle-tendon dynamics with parallel mechanical assistance from an elastic exoskeleton AU - Robertson, Benjamin D. AU - Vadakkeveedu, Siddarth AU - Sawicki, Gregory S. T2 - JOURNAL OF BIOMECHANICS AB - We present a novel biorobotic framework comprised of a biological muscle-tendon unit (MTU) mechanically coupled to a feedback controlled robotic environment simulation that mimics in vivo inertial/gravitational loading and mechanical assistance from a parallel elastic exoskeleton. Using this system, we applied select combinations of biological muscle activation (modulated with rate-coded direct neural stimulation) and parallel elastic assistance (applied via closed-loop mechanical environment simulation) hypothesized to mimic human behavior based on previously published modeling studies. These conditions resulted in constant system-level force-length dynamics (i.e., stiffness), reduced biological loads, increased muscle excursion, and constant muscle average positive power output—all consistent with laboratory experiments on intact humans during exoskeleton assisted hopping. Mechanical assistance led to reduced estimated metabolic cost and MTU apparent efficiency, but increased apparent efficiency for the MTU + Exo system as a whole. Findings from this study suggest that the increased natural resonant frequency of the artificially stiffened MTU + Exo system, along with invariant movement frequencies, may underlie observed limits on the benefits of exoskeleton assistance. Our novel approach demonstrates that it is possible to capture the salient features of human locomotion with exoskeleton assistance in an isolated muscle-tendon preparation, and introduces a powerful new tool for detailed, direct examination of how assistive devices affect muscle-level neuromechanics and energetics. DA - 2017/5// PY - 2017/5// DO - 10.1016/j.jbiomech.2017.03.009 VL - 57 SP - 8-17 SN - 1873-2380 KW - Biomechanics KW - Elastic exoskeleton KW - Muscle-tendon mechanics KW - Unconstrained work loops KW - Biorobotics ER - TY - JOUR TI - Optimizing Acoustic Activation of Phase Change Contrast Agents With the Activation Pressure Matching Method: A Review AU - Rojas, Juan D. AU - Dayton, Paul A. T2 - IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL AB - Submicrometer phase-change contrast agents (PCCAs) consist of a liquid perfluorocarbon (PFC) core that can be vaporized by ultrasound (acoustic droplet vaporization) to generate contrast with excellent spatial and temporal control. When these agents, commonly referred to as nanodroplets, are formulated with cores of low boiling-point PFCs such as decafluorobutane and octafluoropropane, they can be activated with low-mechanical-index (MI) imaging pulses for diagnostic applications. Since the utilization of minimum MI is often desirable to avoid unnecessary biological effects, enabling consistent activation of these agents in an acoustic field is a challenge because the energy that must be delivered to achieve the vaporization threshold increases with depth due to attenuation. A novel vaporization approach called activation pressure matching (APM) has been developed to deliver the same pressure throughout a field of view in order to produce uniform nanodroplet vaporization and to limit the amount of energy that is delivered. In this paper, we discuss the application of this method with a Verasonics V1 Research Ultrasound System to modulate the output pressure from an ATL L11-5 transducer. Vaporization-pulse spacing optimization can be used in addition to matching the activation pressure through depth, and we demonstrate the feasibility of this approach both in vivo and in vitro. The use of optimized vaporization parameters increases the amount of time a single bolus of nanodroplets can generate useful contrast and provides consistent image enhancement in vivo. Therefore, APM is a useful technique for maximizing the efficacy of PCCA while minimizing delivered acoustic energy. DA - 2017/1// PY - 2017/1// DO - 10.1109/tuffc.2016.2616304 VL - 64 IS - 1 SP - 264-272 SN - 1525-8955 KW - Acoustic droplet vaporization (ADV) KW - activation pressure matching (APM) KW - nanodroplet KW - optimized droplet activation KW - perfluorocarbon (PFC) KW - phase change contrast agents (PCCAs) ER - TY - JOUR TI - Neuroimaging of Human Balance Control: A Systematic Review AU - Wittenberg, Ellen AU - Thompson, Jessica AU - Nam, Chang S. AU - Franz, Jason R. T2 - FRONTIERS IN HUMAN NEUROSCIENCE AB - This review examined 83 articles using neuroimaging modalities to investigate the neural correlates underlying static and dynamic human balance control, with aims to support future mobile neuroimaging research in the balance control domain. Furthermore, this review analyzed the mobility of the neuroimaging hardware and research paradigms as well as the analytical methodology to identify and remove movement artifact in the acquired brain signal. We found that the majority of static balance control tasks utilized mechanical perturbations to invoke feet-in-place responses (27 out of 38 studies), while cognitive dual-task conditions were commonly used to challenge balance in dynamic balance control tasks (20 out of 32 studies). While frequency analysis and event related potential characteristics supported enhanced brain activation during static balance control, that in dynamic balance control studies was supported by spatial and frequency analysis. Twenty-three of the 50 studies utilizing EEG utilized independent component analysis to remove movement artifacts from the acquired brain signals. Lastly, only eight studies used truly mobile neuroimaging hardware systems. This review provides evidence to support an increase in brain activation in balance control tasks, regardless of mechanical, cognitive, or sensory challenges. Furthermore, the current body of literature demonstrates the use of advanced signal processing methodologies to analyze brain activity during movement. However, the static nature of neuroimaging hardware and conventional balance control paradigms prevent full mobility and limit our knowledge of neural mechanisms underlying balance control. DA - 2017/4/10/ PY - 2017/4/10/ DO - 10.3389/fnhum.2017.00170 VL - 11 SP - SN - 1662-5161 KW - static and dynamic balance control KW - temporal and spatial dynamics of brain activation KW - mechanical perturbation KW - sensory degradation KW - susceptibility to cognitive dual tasks KW - movement artifacts ER - TY - JOUR TI - Microfabricated blood vessels undergo neoangiogenesis AU - DiVito, Kyle A. AU - Daniele, Michael A. AU - Roberts, Steven A. AU - Ligler, Frances S. AU - Adams, Andre A. T2 - BIOMATERIALS AB - The greatest ambition and promise of tissue engineering is to manufacture human organs. Before “made-to-measure” tissues can become a reality [1], [2], [3], however, three-dimensional tissues must be reconstructed and characterized. The current inability to manufacture operational vasculature has limited the growth of engineered tissues. Here, free-standing, small diameter blood vessels with organized cell layers that recapitulate normal biological functionality are fabricated using microfluidic technology. Over time in culture, the endothelial cells form a monolayer on the luminal wall and remodel the scaffold with human extracellular matrix proteins. After integration into three-dimensional gels containing fibroblasts, the microvessels sprout and generate extended hollow branches that anastomose with neighboring capillaries to form a network. Both the microfabricated vessels and the extended sprouts support perfusion of fluids and particles. The ability to create cellularized microvessels that can be designed with a diameter of choice, produced by the meter, and undergo angiogenesis and anastomoses will be an extremely valuable tool for vascularization of engineered tissues. To summarize, ultraviolet (UV) photo-crosslinkable poly(ethylene glycol) and gelatin methacrylate polymers used in combination with sheath-flow microfluidics allow for the fabrication of small diameter blood vessels which undergo neoangiogenesis as well as other developmental processes associated with normal human blood vessel maturation. Once mature, these vessels can be embedded; perfused; cryogenically stored and respond to stimuli such as chemokines and shear stresses to mimic native human blood vessels. The applications range from tissue-on-chip systems for drug screening, characterization of normal and pathologic processes, and creation and characterization of engineered tissues for organ repair. DA - 2017/9// PY - 2017/9// DO - 10.1016/j.biomaterials.2017.05.012 VL - 138 SP - 142-152 SN - 1878-5905 KW - Sheath-flow microfluidics KW - Blood vessel KW - Angiogenesis KW - Anastomoses KW - Perfusion ER - TY - JOUR TI - Magnetic Resonance-Derived Improvements on PET Imaging AU - Lalush, David S. T2 - MAGNETIC RESONANCE IMAGING CLINICS OF NORTH AMERICA AB - Simultaneous PET-MR imaging improves deficiencies in PET images. The primary areas in which magnetic resonance (MR) has been applied to guide PET results are in correction for patient motion and in improving the effects of PET resolution and partial volume averaging. MR-guided motion correction of PET has been applied to respiratory, cardiac, and gross body movements and shown to improve lesion detectability and contrast. Partial volume correction or resolution improvement of PET governed by MR imaging anatomic information improves visualization of structures and quantitative accuracy. Evaluation in clinical applications is needed to determine their true impacts. DA - 2017/5// PY - 2017/5// DO - 10.1016/j.mric.2016.12.002 VL - 25 IS - 2 SP - 257-+ SN - 1557-9786 KW - PET-MR imaging KW - PET motion correction KW - PET partial volume correction KW - MR-based PET reconstruction ER - TY - JOUR TI - Local delivery of checkpoints antibodies AU - Wang, Chao AU - Ye, Yanqi AU - Gu, Zhen T2 - HUMAN VACCINES & IMMUNOTHERAPEUTICS AB - Immune checkpoint inhibitors (ICI) based cancer immunotherapy has recently attracted considerable interest in the field of cancer therapy. The relevant immunotherapeutic agents do not directly attack the tumor, but boost the body's immune system to recognize and kill cancer cells. In this commentary, recent efforts utilizing immunoengineering for local delivery of these immune checkpoint antibodies are introduced. Future opportunities and challenges in this research theme are also commented. DA - 2017/// PY - 2017/// DO - 10.1080/21645515.2016.1223000 VL - 13 IS - 1 SP - 245-248 SN - 2164-554X KW - biomaterials KW - cancer immunotherapy KW - drug delivery KW - immune checkpoint inhibitors KW - microneedle ER - TY - JOUR TI - Insulin-responsive glucagon delivery for prevention of hypoglycemia AU - Yu, J. C. AU - Zhang, Y. Q. AU - Sun, W. J. AU - Kahkoska, A. R. AU - Wang, J. Q. AU - Buse, J. B. AU - Gu, Z. T2 - Small (Weinheim An Der Bergstrasse, Germany) AB - In article number 1603028, by Zhen Gu and co-workers, an insulin-responsive glucagon delivery device based on a microneedle (MN)-array patch is developed. Utilizing hyperinsulinemia as a dangerous signal, this “smart glucagon patch” can release glucagon to reduce the risk of hypoglycemia during diabetes management. DA - 2017/// PY - 2017/// DO - 10.1002/smll.201770108 VL - 13 IS - 19 ER - TY - JOUR TI - Immunological mechanisms of intravesical chitosan/interleukin-12 immunotherapy against murine bladder cancer AU - Smith, Sean G. AU - Baltz, John L. AU - Koppolu, Bhanu Prasanth AU - Ravindranathan, Sruthi AU - Nguyen, Khue AU - Zaharoff, David A. T2 - ONCOIMMUNOLOGY AB - There is a critical unmet clinical need for bladder cancer immunotherapies capable of inducing durable antitumor immunity. We have shown that four intravesical treatments with a simple co-formulation of interleukin-12 and the biopolymer chitosan not only destroy orthotopic bladder tumors, but also promote a potent long-lasting systemic immune response as evidenced through tumor-specific in vitro killing assays, complete protection from rechallenge, and abscopal antitumor responses at distant non-treated tumors. This study investigates the immunological kinetics underlying these results. We show through depletion studies that CD8+ T cells are required for initial tumor rejection, but CD4+ T cells protect against rechallenge. We also show that even a single intravesical treatment can eliminate tumors in 50% of mice with 6/9 and 7/8 mice eliminating tumors after three or four treatments respectively. We then performed immunophenotyping studies to analyze shifts in immune cell populations after each treatment within the tumor itself as well as in secondary lymphoid organs. These studies demonstrated an initial infiltration of macrophages and granulocytes followed by increased CD4+ and CD8+ effector-memory cells. This was coupled with a decreased level of regulatory T cells in peripheral lymph nodes as well as decreased myeloid-derived suppressor cell infiltration in the bladder. Taken together, these data demonstrate the ability of properly delivered interleukin-12-based therapies to engage adaptive immunity within the tumor itself as well as throughout the body and strengthen the case for clinical translation of chitosan/interleukin-12 as an intravesical treatment for bladder cancer. DA - 2017/// PY - 2017/// DO - 10.1080/2162402x.2016.1259050 VL - 6 IS - 1 SP - SN - 2162-402X KW - BCG KW - bladder cancer KW - chitosan KW - immunotherapy KW - interleukin-12 KW - intratumoral KW - intravesical KW - MDSC KW - TILS KW - TReg ER - TY - JOUR TI - High Resolution Ultrasound Superharmonic Perfusion Imaging: In Vivo Feasibility and Quantification of Dynamic Contrast-Enhanced Acoustic Angiography AU - Lindsey, Brooks D. AU - Shelton, Sarah E. AU - Martin, K. Heath AU - Ozgun, Kathryn A. AU - Rojas, Juan D. AU - Foster, F. Stuart AU - Dayton, Paul A. T2 - ANNALS OF BIOMEDICAL ENGINEERING AB - Mapping blood perfusion quantitatively allows localization of abnormal physiology and can improve understanding of disease progression. Dynamic contrast-enhanced ultrasound is a low-cost, real-time technique for imaging perfusion dynamics with microbubble contrast agents. Previously, we have demonstrated another contrast agent-specific ultrasound imaging technique, acoustic angiography, which forms static anatomical images of the superharmonic signal produced by microbubbles. In this work, we seek to determine whether acoustic angiography can be utilized for high resolution perfusion imaging in vivo by examining the effect of acquisition rate on superharmonic imaging at low flow rates and demonstrating the feasibility of dynamic contrast-enhanced superharmonic perfusion imaging for the first time. Results in the chorioallantoic membrane model indicate that frame rate and frame averaging do not affect the measured diameter of individual vessels observed, but that frame rate does influence the detection of vessels near and below the resolution limit. The highest number of resolvable vessels was observed at an intermediate frame rate of 3 Hz using a mechanically-steered prototype transducer. We also demonstrate the feasibility of quantitatively mapping perfusion rate in 2D in a mouse model with spatial resolution of ~100 μm. This type of imaging could provide non-invasive, high resolution quantification of microvascular function at penetration depths of several centimeters. DA - 2017/4// PY - 2017/4// DO - 10.1007/s10439-016-1753-9 VL - 45 IS - 4 SP - 939-948 SN - 1573-9686 KW - Ultrasound KW - Perfusion KW - Microbubble KW - High frequency KW - Low flow imaging KW - Quantitative imaging KW - Angiogenesis KW - Superharmonic ER - TY - JOUR TI - Fabrication and Evaluation of Electrospun, 3D-Bioplotted, and Combination of Electrospun/3D-Bioplotted Scaffolds for Tissue Engineering Applications AU - Mellor, Liliana F. AU - Huebner, Pedro AU - Cai, Shaobo AU - Mohiti-Asli, Mahsa AU - Taylor, Michael A. AU - Spang, Jeffrey AU - Shirwaiker, Rohan A. AU - Loboa, Elizabeth G. T2 - BIOMED RESEARCH INTERNATIONAL AB - Electrospun scaffolds provide a dense framework of nanofibers with pore sizes and fiber diameters that closely resemble the architecture of native extracellular matrix. However, it generates limited three-dimensional structures of relevant physiological thicknesses. 3D printing allows digitally controlled fabrication of three-dimensional single/multimaterial constructs with precisely ordered fiber and pore architecture in a single build. However, this approach generally lacks the ability to achieve submicron resolution features to mimic native tissue. The goal of this study was to fabricate and evaluate 3D printed, electrospun, and combination of 3D printed/electrospun scaffolds to mimic the native architecture of heterogeneous tissue. We assessed their ability to support viability and proliferation of human adipose derived stem cells (hASC). Cells had increased proliferation and high viability over 21 days on all scaffolds. We further tested implantation of stacked-electrospun scaffold versus combined electrospun/3D scaffold on a cadaveric pig knee model and found that stacked-electrospun scaffold easily delaminated during implantation while the combined scaffold was easier to implant. Our approach combining these two commonly used scaffold fabrication technologies allows for the creation of a scaffold with more close resemblance to heterogeneous tissue architecture, holding great potential for tissue engineering and regenerative medicine applications of osteochondral tissue and other heterogeneous tissues. DA - 2017/// PY - 2017/// DO - 10.1155/2017/6956794 VL - 2017 SP - SN - 2314-6141 ER - TY - JOUR TI - Enhanced Endosomal Escape by Light-Fueled Liquid-Metal Transformer AU - Lu, Yue AU - Lin, Yiliang AU - Chen, Zhaowei AU - Hu, Quanyin AU - Liu, Yang AU - Yu, Shuangjiang AU - Gao, Wei AU - Dickey, Michael D. AU - Gu, Zhen T2 - NANO LETTERS AB - Effective endosomal escape remains as the "holy grail" for endocytosis-based intracellular drug delivery. To date, most of the endosomal escape strategies rely on small molecules, cationic polymers, or pore-forming proteins, which are often limited by the systemic toxicity and lack of specificity. We describe here a light-fueled liquid-metal transformer for effective endosomal escape-facilitated cargo delivery via a chemical-mechanical process. The nanoscale transformer can be prepared by a simple approach of sonicating a low-toxicity liquid-metal. When coated with graphene quantum dots (GQDs), the resulting nanospheres demonstrate the ability to absorb and convert photoenergy to drive the simultaneous phase separation and morphological transformation of the inner liquid-metal core. The morphological transformation from nanospheres to hollow nanorods with a remarkable change of aspect ratio can physically disrupt the endosomal membrane to promote endosomal escape of payloads. This metal-based nanotransformer equipped with GQDs provides a new strategy for facilitating effective endosomal escape to achieve spatiotemporally controlled drug delivery with enhanced efficacy. DA - 2017/4// PY - 2017/4// DO - 10.1021/acs.nanolett.6b04346 VL - 17 IS - 4 SP - 2138-2145 SN - 1530-6992 KW - Drug delivery KW - liquid metal KW - stimuli-responsive KW - morphological transformation KW - endosomal escape ER - TY - JOUR TI - Engineering 3D-Bioplotted scaffolds to induce aligned extracellular matrix deposition for musculoskeletal soft tissue replacement AU - Warren, Paul B. AU - Huebner, Pedro AU - Spang, Jeffrey T. AU - Shirwaiker, Rohan A. AU - Fisher, Matthew B. T2 - CONNECTIVE TISSUE RESEARCH AB - Purpose: Tissue engineering and regenerative medicine approaches have the potential to overcome the challenges associated with current treatment strategies for meniscus injuries. 3D-Bioplotted scaffolds are promising, but have not demonstrated the ability to guide the formation of aligned collagenous matrix in vivo, which is critical for generating functional meniscus tissue. In this study, we evaluate the ability of 3D-Bioplotted scaffold designs with varying interstrand spacing to induce the deposition of aligned matrix in vivo. Materials and Methods: 3D-Bioplotted polycaprolactone scaffolds with 100, 200, or 400 μm interstrand spacing were implanted subcutaneously in a rat model for 4, 8, or 12 weeks. Scaffolds were harvested, paraffin-embedded, sectioned, and stained to visualize cell nuclei and collagen. Quantitative image analysis was used to evaluate cell density, matrix fill, and collagen fiber alignment within the scaffolds. Results: By 4 weeks, cells had infiltrated the innermost scaffold regions. Similarly, collagenous matrix filled interstrand regions nearly completely by 4 weeks. By 12 weeks, aligned collagen was present in all scaffolds. Generally, alignment along the scaffold strands increased over time for all three interstrand spacing groups. Distribution of collagen fiber alignment angles narrowed as interstrand spacing decreased. Conclusions: 3D-Bioplotted scaffolds allow for complete cell infiltration and collagenous matrix production throughout the scaffold. The ability to use interstrand spacing as a means of controlling the formation of aligned collagen in vivo was demonstrated, which helps establish a design space for scaffold-based meniscus tissue engineering. DA - 2017/// PY - 2017/// DO - 10.1080/03008207.2016.1276177 VL - 58 IS - 3-4 SP - 342-354 SN - 1607-8438 KW - Biofabrication KW - meniscus KW - tissue engineering KW - scaffold KW - 3D printing ER - TY - JOUR TI - Effects of 3D-bioplotted polycaprolactone scaffold geometry on human adipose-derived stem cell viability and proliferation AU - Mehendale, Saahil V. AU - Mellor, Liliana F. AU - Taylor, Michael A. AU - Loboa, Elizabeth G. AU - Shirwaiker, Rohan A. T2 - RAPID PROTOTYPING JOURNAL AB - Purpose This study aims to investigate the effect of three-dimensional (3D)- bioplotted polycaprolactone (PCL) scaffold geometry on the biological and mechanical characteristics of human adipose-derived stem cell (hASC) seeded constructs. Design/methodology/approach Four 3D-bioplotted scaffold disc designs (Ø14.5 × 2 mm) with two levels of strand–pore feature sizes and two strand laydown patterns (0°/90° or 0°/120°/240°) were evaluated for hASC viability, proliferation and construct compressive stiffness after 14 days of in vitro cell culture. Findings Scaffolds with the highest porosity (smaller strand–pore size in 0°/120°/240°) yielded the highest hASC proliferation and viability. Further testing of this design in a 6-mm thick configuration showed that cells were able to penetrate and proliferate throughout the scaffold thickness. The design with the lowest porosity (larger strand–pore size in 0°/90°) had the highest compression modulus after 14 days of culture, but resulted in the lowest hASC viability. The strand laydown pattern by itself did not influence the compression modulus of scaffolds. The 14-day cell culture also did not cause significant changes in compressive properties in any of the four designs. Originality/value hASC hold great potential for musculoskeletal tissue engineering applications because of their relative ease of harvest, abundance and differentiation abilities. This study reports on the effects of 3D-bioplotted scaffold geometry on mechanical and biological characteristics of hASC-seeded PCL constructs. The results provide the basis for future studies which will use this optimal scaffold design to develop constructs for hASC-based osteochondral tissue engineering applications. DA - 2017/// PY - 2017/// DO - 10.1108/rpj-03-2016-0035 VL - 23 IS - 3 SP - 534-542 SN - 1758-7670 KW - 3D-Bioplotting KW - Human adipose-derived stem cells KW - Polycaprolactone KW - Tissue engineering scaffolds ER - TY - JOUR TI - Bioresponsive materials AU - Lu, Yue AU - Aimetti, Alex A. AU - Langer, Robert AU - Gu, Zhen T2 - NATURE REVIEWS MATERIALS DA - 2017/1// PY - 2017/1// DO - 10.1038/natrevmats.2016.75 VL - 2 IS - 1 SP - SN - 2058-8437 ER - TY - JOUR TI - A microengineered collagen scaffold for generating a polarized crypt-villus architecture of human small intestinal epithelium AU - Wang, Yuli AU - Gunasekara, Duian B. AU - Reed, Mark I. AU - DiSalvo, Matthew AU - Bultman, Scott J. AU - Sims, Christopher E. AU - Magness, Scott T. AU - Allbritton, Nancy L. T2 - BIOMATERIALS AB - The human small intestinal epithelium possesses a distinct crypt-villus architecture and tissue polarity in which proliferative cells reside inside crypts while differentiated cells are localized to the villi. Indirect evidence has shown that the processes of differentiation and migration are driven in part by biochemical gradients of factors that specify the polarity of these cellular compartments; however, direct evidence for gradient-driven patterning of this in vivo architecture has been hampered by limitations of the in vitro systems available. Enteroid cultures are a powerful in vitro system; nevertheless, these spheroidal structures fail to replicate the architecture and lineage compartmentalization found in vivo, and are not easily subjected to gradients of growth factors. In the current work, we report the development of a micropatterned collagen scaffold with suitable extracellular matrix and stiffness to generate an in vitro self-renewing human small intestinal epithelium that replicates key features of the in vivo small intestine: a crypt-villus architecture with appropriate cell-lineage compartmentalization and an open and accessible luminal surface. Chemical gradients applied to the crypt-villus axis promoted the creation of a stem/progenitor-cell zone and supported cell migration along the crypt-villus axis. This new approach combining microengineered scaffolds, biophysical cues and chemical gradients to control the intestinal epithelium ex vivo can serve as a physiologically relevant mimic of the human small intestinal epithelium, and is broadly applicable to model other tissues that rely on gradients for physiological function. DA - 2017/6// PY - 2017/6// DO - 10.1016/j.biomaterials.2017.03.005 VL - 128 SP - 44-55 SN - 1878-5905 KW - Scaffold KW - Microfabrication KW - Intestine KW - Stem cell KW - Crypt KW - Villus ER - TY - JOUR TI - Time-Dependent Model for Fluid Flow in Porous Materials with Multiple Pore Sizes AU - Cummins, Brian M. AU - Chinthapatla, Rukesh AU - Ligler, Frances S. AU - Walker, Glenn M. T2 - Analytical Chemistry AB - An understanding of fluid transport through porous materials is critical for the development of lateral flow assays and analytical devices based on paper microfluidics. Models of fluid transport within porous materials often assume a single capillary pressure and permeability value for the material, implying that the material comprises a single pore size and that the porous material is fully saturated behind the visible wetted front. As a result, current models can lead to inaccuracies when modeling transport over long distances and/or times. A new transport model is presented that incorporates a range of pore sizes to more accurately predict the capillary transport of fluid in porous materials. The model effectively predicts the time-dependent saturation of rectangular strips of Whatman filter no. 1 paper using the manufacturer's data, published pore-size distribution measurements, and the fluid's properties. DA - 2017/3/28/ PY - 2017/3/28/ DO - 10.1021/acs.analchem.6b04717 VL - 89 IS - 8 SP - 4377-4381 J2 - Anal. Chem. LA - en OP - SN - 0003-2700 1520-6882 UR - http://dx.doi.org/10.1021/ACS.ANALCHEM.6B04717 DB - Crossref ER - TY - JOUR TI - The springs of time-limited bullfrog jumps and slow-preparation grasshopper leaps are tuned to their muscle dynamics AU - Rosario, M. V. AU - Sutton, G. P. AU - Patek, S. N. AU - Sawicki, G. S. T2 - Integrative and Comparative Biology DA - 2017/// PY - 2017/// VL - 57 SP - E390-390 ER - TY - JOUR TI - The independent effects of speed and propulsive force on joint power generation in walking AU - Browne, Michael G. AU - Franz, Jason R. T2 - JOURNAL OF BIOMECHANICS AB - Walking speed is modulated using propulsive forces (FP) during push-off and both preferred speed and FP decrease with aging. However, even prior to walking slower, reduced FP may be accompanied by potentially unfavorable changes in joint power generation. For example, compared to young adults, older adults exhibit a redistribution of mechanical power generation from the propulsive plantarflexor muscles to more proximal muscles acting across the knee and hip. Here, we used visual biofeedback based on real-time FP measurements to decouple and investigate the interaction between joint-level coordination, whole-body FP, and walking speed. 12 healthy young subjects walked on a dual-belt instrumented treadmill at a range of speeds (0.9–1.3 m/s). We immediately calculated the average FP from each speed. Subjects then walked at 1.3 m/s while completing a series of biofeedback trials with instructions to match their instantaneous FP to their averaged FP from slower speeds. Walking slower decreased FP and total positive joint work with little effect on relative joint-level contributions. Conversely, subjects walked at a constant speed with reduced FP, not by reducing total positive joint work, but by redistributing the mechanical demands of each step from the plantarflexor muscles during push-off to more proximal leg muscles during single support. Interestingly, these naturally emergent joint- and limb-level biomechanical changes, in the absence of neuromuscular constraints, resemble those due to aging. Our findings provide important reference data to understand the presumably complex interactions between joint power generation, whole-body FP, and walking speed in our aging population. DA - 2017/4/11/ PY - 2017/4/11/ DO - 10.1016/j.jbiomech.2017.02.011 VL - 55 SP - 48-55 SN - 1873-2380 KW - Plantarflexor KW - Push-off KW - Aging KW - Gait KW - Biofeedback ER - TY - JOUR TI - The Neuromuscular Origins of Kinematic Variability during Perturbed Walking AU - Stokes, Heather E. AU - Thompson, Jessica D. AU - Franz, Jason R. T2 - SCIENTIFIC REPORTS AB - We investigated the neuromuscular contributions to kinematic variability and thus step to step adjustments in posture and foot placement across a range of walking speeds in response to optical flow perturbations of different amplitudes using a custom virtual environment. We found that perturbations significantly increased step width, decreased step length, and elicited larger trunk sway compared to normal walking. However, perturbation-induced effects on the corresponding variabilities of these measurements were much more profound. Consistent with our hypotheses, we found that: (1) perturbations increased EMG activity of the gluteus medius and postural control muscles during leg swing, and increased antagonist leg muscle coactivation during limb loading in early stance, and (2) changes in the magnitude of step to step adjustments in postural sway and lateral foot placement positively correlated with those of postural control and gluteus medius muscle activities, respectively, in response to perturbations. However, (3) interactions between walking speed and susceptibility to perturbations, when present, were more complex than anticipated. Our study provides important mechanistic neuromuscular insight into walking balance control and important reference values for the emergence of balance impairment. DA - 2017/4/11/ PY - 2017/4/11/ DO - 10.1038/s41598-017-00942-x VL - 7 SP - SN - 2045-2322 ER - TY - JOUR TI - Red Blood Cells for Glucose-Responsive Insulin Delivery AU - Wang, Chao AU - Ye, Yanqi AU - Sun, Wujin AU - Yu, Jicheng AU - Wang, Jingqiang AU - Lawrence, David S. AU - Buse, John B. AU - Gu, Zhen T2 - ADVANCED MATERIALS AB - Glucose-responsive delivery of insulin mimicking the function of pancreatic β-cells to achieve meticulous control of blood glucose (BG) would revolutionize diabetes care. Here the authors report the development of a new glucose-responsive insulin delivery system based on the potential interaction between the glucose derivative-modified insulin (Glc-Insulin) and glucose transporters on erythrocytes (or red blood cells, RBCs) membrane. After being conjugated with the glucosamine, insulin can efficiently bind to RBC membranes. The binding is reversible in the setting of hyperglycemia, resulting in fast release of insulin and subsequent drop of BG level in vivo. The delivery vehicle can be further simplified utilizing injectable polymeric nanocarriers coated with RBC membrane and loaded with Glc-Insulin. The described work is the first demonstration of utilizing RBC membrane to achieve smart insulin delivery with fast responsiveness. DA - 2017/5/10/ PY - 2017/5/10/ DO - 10.1002/adma.201606617 VL - 29 IS - 18 SP - SN - 1521-4095 ER - TY - JOUR TI - Optimizing ultrasound molecular imaging of secreted frizzled related protein 2 expression in angiosarcoma AU - Tsuruta, James K. AU - Schaub, Nicholas P. AU - Rojas, Juan D. AU - Streeter, Jason AU - Klauber-DeMore, Nancy AU - Dayton, Paul T2 - PLOS ONE AB - Secreted frizzled related protein 2 (SFRP2) is a tumor endothelial marker expressed in angiosarcoma. Previously, we showed ultrasound molecular imaging with SFRP2-targeted contrast increased average video pixel intensity (VI) of angiosarcoma vessels by 2.2 ± 0.6 VI versus streptavidin contrast. We hypothesized that redesigning our contrast agents would increase imaging performance. Improved molecular imaging reagents were created by combining NeutrAvidin™-functionalized microbubbles with biotinylated SFRP2 or IgY control antibodies. When angiosarcoma tumors in nude mice reached 8 mm, time-intensity, antibody loading, and microbubble dose experiments optimized molecular imaging. 10 minutes after injection, the control-subtracted time-intensity curve (TIC) for SFRP2-targeted contrast reached a maximum, after subtracting the contribution of free-flowing contrast. SFRP2 antibody-targeted VI was greater when contrast was formulated with 10-fold molar excess of maleimide-activated NeutrAvidin™ versus 3-fold (4.5 ± 0.18 vs. 0.32 ± 0.15, VI ± SEM, 5 x 106 dose, p < 0.001). Tumor vasculature returned greater average video pixel intensity using 5 x 107 versus 5 x 106 microbubbles (21.2 ± 2.5 vs. 4.5 ± 0.18, p = 0.0011). Specificity for tumor vasculature was confirmed by low VI for SFRP2-targeted, and control contrast in peri-tumoral vasculature (3.2 ± 0.52 vs. 1.6 ± 0.71, p = 0.92). After optimization, average video pixel intensity of tumor vasculature was 14.2 ± 3.0 VI units higher with SFRP2-targeted contrast versus IgY-targeted control (22.1 ± 2.5 vs. 7.9 ± 1.6, p < 0.001). After log decompression, 14.2 ΔVI was equal to ~70% higher signal, in arbitray acoustic units (AU), for SFRP2 versus IgY. This provided ~18- fold higher acoustic signal enhancement than provided previously by 2.2 ΔVI. Basing our targeted contrast on NeutrAvidin™-functionalized microbubbles, using IgY antibodies for our control contrast, and optimizing our imaging protocol significantly increased the SFRP2-specific signal returned from angiosarcoma vasculature, and may provide new opportunities for targeted molecular imaging. DA - 2017/3/23/ PY - 2017/3/23/ DO - 10.1371/journal.pone.0174281 VL - 12 IS - 3 SP - SN - 1932-6203 ER - TY - JOUR TI - Electrical Cell-Substrate Impedance Spectroscopy Can Monitor Age-Grouped Human Adipose Stem Cell Variability During Osteogenic Differentiation AU - Nordberg, Rachel C. AU - Zhang, Jianlei AU - Griffith, Emily H. AU - Frank, Matthew W. AU - Starly, Binil AU - Loboa, Elizabeth G. T2 - STEM CELLS TRANSLATIONAL MEDICINE AB - Abstract Human adipose stem cells (hASCs) are an attractive cell source for bone tissue engineering applications. However, a critical issue to be addressed before widespread hASC clinical translation is the dramatic variability in proliferative capacity and osteogenic potential among hASCs isolated from different donors. The goal of this study was to test our hypothesis that electrical cell-substrate impedance spectroscopy (ECIS) could track complex bioimpedance patterns of hASCs throughout proliferation and osteogenic differentiation to better understand and predict variability among hASC populations. Superlots composed of hASCs from young (aged 24–36 years), middle-aged (aged 48–55 years), and elderly (aged 60–81 years) donors were seeded on gold electrode arrays. Complex impedance measurements were taken throughout proliferation and osteogenic differentiation. During osteogenic differentiation, four impedance phases were identified: increase, primary stabilization, drop phase, and secondary stabilization. Matrix deposition was first observed 48–96 hours after the impedance maximum, indicating, for the first time, that ECIS can identify morphological changes that correspond to late-stage osteogenic differentiation. The impedance maximum was observed at day 10.0 in young, day 6.1 in middle-aged, and day 1.3 in elderly hASCs, suggesting that hASCs from younger donors require a longer time to differentiate than do hASCs from older donors, but young hASCs proliferated more and accreted more calcium long-term. This is the first study to use ECIS to predict osteogenic potential of multiple hASC populations and to show that donor age may temporally control onset of osteogenesis. These findings could be critical for development of patient-specific bone tissue engineering and regenerative medicine therapies. DA - 2017/2// PY - 2017/2// DO - 10.5966/sctm.2015-0404 VL - 6 IS - 2 SP - 502-511 SN - 2157-6580 KW - Electrical cell-substrate impedance spectroscopy KW - Adipose stem cells KW - Osteogenesis KW - Bioimpedance ER - TY - JOUR TI - Comparison of simulated microgravity and hydrostatic pressure for chondrogenesis of hASC AU - Mellor, L. F. AU - Steward, A. J. AU - Nordberg, R. C. AU - Taylor, M. A. AU - Loboa, E. G. T2 - Aerospace Medicine and Human Performance DA - 2017/// PY - 2017/// VL - 88 IS - 4 SP - 377-384 ER - TY - JOUR TI - Common and rare genetic markers of lipid variation in subjects with type 2 diabetes from the ACCORD clinical trial AU - Marvel, S. W. AU - Rotroff, D. M. AU - Wagner, M. J. AU - Buse, J. B. AU - Havener, T. M. AU - McLeod, H. L. AU - Motsinger-Reif, A. A. T2 - PeerJ DA - 2017/// PY - 2017/// VL - 5 ER - TY - JOUR TI - Blocked Elements in 1-D and 2-D Arrays-Part I: Detection and Basic Compensation on Simulated and In Vivo Targets AU - Jakovljevic, Marko AU - Pinton, Gianmarco F. AU - Dahl, Jeremy J. AU - Trahey, Gregg E. T2 - IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL AB - During a transcostal ultrasound scan, ribs and other highly attenuating and/or reflective tissue structures can block parts of the array. Blocked elements tend to limit the acoustic window and impede visualization of structures of interest. Here, we demonstrate a method to detect blocked elements and we measure the loss of image quality they introduce in simulation and in vivo. We utilize a fullwave simulation tool and a clinical ultrasound scanner to obtain element signals from fully sampled matrix arrays during simulated and in vivo transcostal liver scans, respectively. The elements that were blocked by a rib showed lower average signal amplitude and lower average nearest-neighbor cross correlation than the elements in the remainder of the 2-D aperture. The growing receive-aperture B-mode images created from the element data indicate that the signals on blocked elements are dominated by noise and that turning them OFF has a potential to improve visibility of liver vasculature. Adding blocked elements to the growing receive apertures for five in vivo transcostal acquisitions resulted in average decrease in vessel contrast and contrast to noise ratio of 19% and 10%, respectively. DA - 2017/6// PY - 2017/6// DO - 10.1109/tuffc.2017.2683559 VL - 64 IS - 6 SP - 910-921 SN - 1525-8955 KW - Blocked elements KW - 2-D arrays KW - ribs KW - transthoracic imaging KW - growing aperture KW - cross-correlation KW - full-wave simulation ER - TY - JOUR TI - Assessment of Molecular Acoustic Angiography for Combined Microvascular and Molecular Imaging in Preclinical Tumor Models AU - Lindsey, Brooks D. AU - Shelton, Sarah E. AU - Foster, F. Stuart AU - Dayton, Paul A. T2 - Molecular Imaging and Biology AB - The purposes of the present study is to evaluate a new ultrasound molecular imaging approach in its ability to image a preclinical tumor model and to investigate the capacity to visualize and quantify co-registered microvascular and molecular imaging volumes.Molecular imaging using the new technique was compared with a conventional ultrasound molecular imaging technique (multi-pulse imaging) by varying the injected microbubble dose and scanning each animal using both techniques. Each of the 14 animals was randomly assigned one of three doses; bolus dose was varied, and the animals were imaged for three consecutive days so that each animal received every dose. A microvascular scan was also acquired for each animal by administering an infusion of nontargeted microbubbles. These scans were paired with co-registered molecular images (VEGFR2-targeted microbubbles), the vessels were segmented, and the spatial relationships between vessels and VEGFR2 targeting locations were analyzed. In five animals, an additional scan was performed in which the animal received a bolus of microbubbles targeted to E- and P-selectins. Vessel tortuosity as a function of distance from VEGF and selectin targeting was analyzed in these animals.Although resulting differences in image intensity due to varying microbubble dose were not significant between the two lowest doses, superharmonic imaging had significantly higher contrast-to-tissue ratio (CTR) than multi-pulse imaging (mean across all doses 13.98 dB for molecular acoustic angiography vs. 0.53 dB for multi-pulse imaging; p = 4.9 × 10-10). Analysis of registered microvascular and molecular imaging volumes indicated that vessel tortuosity decreases with increasing distance from both VEGFR2- and selectin-targeting sites.Molecular acoustic angiography (superharmonic molecular imaging) exhibited a significant increase in CTR at all doses tested due to superior rejection of tissue artifact signals. Due to the high resolution of acoustic angiography molecular imaging, it is possible to analyze spatial relationships in aligned microvascular and molecular superharmonic imaging volumes. Future studies are required to separate the effects of biomarker expression and blood flow kinetics in comparing local tortuosity differences between different endothelial markers such as VEGFR2, E-selectin, and P-selectin. DA - 2017/// PY - 2017/// DO - 10.1007/s11307-016-0991-4 VL - 19 IS - 2 SP - 194–202 SN - 1536-1632 1860-2002 UR - http://dx.doi.org/10.1007/s11307-016-0991-4 KW - Microbubble KW - Superharmonic KW - Microvasculature KW - Angiogenesis KW - Tortuosity KW - Targeted imaging KW - Ultrasound KW - Contrast imaging KW - VEGFR2 KW - Selectin ER - TY - JOUR TI - Altered Motor Unit Discharge Coherence in Paretic Muscles of Stroke Survivors AU - Dai, Chenyun AU - Suresh, Nina L. AU - Suresh, Aneesha K. AU - Rymer, William Zev AU - Hu, Xiaogang T2 - FRONTIERS IN NEUROLOGY AB - After a cerebral stroke, a series of changes at the supraspinal and spinal nervous system can alter the control of muscle activation, leading to persistent motor impairment. However, the relative contribution of these different levels of the nervous system to impaired muscle activation is not well understood. The coherence of motor unit (MU) spike trains is considered to partly reflect activities of higher level control, with different frequency band representing different levels of control. Accordingly, the objective of this study was to quantify the different sources of contribution to altered muscle activation. We examined the coherence of MU spike trains decomposed from surface electromyogram (sEMG) of the first dorsal interosseous muscle on both paretic and contralateral sides of 14 hemispheric stroke survivors. sEMG was obtained over a range of force contraction levels at 40, 50, and 60% of maximum voluntary contraction. Our results showed that MU coherence increased significantly in delta (1-4 Hz), alpha (8-12 Hz), and beta (15-30 Hz) bands on the affected side compared with the contralateral side, but was maintained at the same level in the gamma (30-60 Hz) band. In addition, no significant alteration was observed across medium-high force levels (40-60%). These results indicated that the common synaptic input to motor neurons increased on the paretic side, and the increased common input can originate from changes at multiple levels, including spinal and supraspinal levels following a stroke. All these changes can contribute to impaired activation of affected muscles in stroke survivors. Our findings also provide evidence regarding the different origins of impaired muscle activation poststroke. DA - 2017/5/15/ PY - 2017/5/15/ DO - 10.3389/fneur.2017.00202 VL - 8 SP - SN - 1664-2295 KW - motor unit KW - coherence KW - stroke KW - synchronization KW - surface electromyogram ER - TY - JOUR TI - Acoustic Radiation Force Impulse-Induced Peak Displacements Reflect Degree of Anisotropy in Transversely Isotropic Elastic Materials AU - Hossain, Md Murad AU - Moore, Christopher J. AU - Gallippi, Caterina M. T2 - IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL AB - In transversely isotropic (TI) materials, mechanical properties (Young's modulus, shear modulus, and Poisson's ratio) are different along versus across the axis of symmetry (AoS). In this paper, the feasibility of interrogating such directional mechanical property differences using acoustic radiation force impulse (ARFI) imaging is investigated. We herein test the hypotheses that: 1) ARFI-induced peak displacements (PDs) vary with TI material orientations when an asymmetrical ARFI excitation point spread function (PSF) is used, but not when a symmetrical ARFI PSF is employed and 2) the ratio of PDs induced with the long axis of an asymmetrical ARFI PSF oriented along versus across the material's AoS is related to the degree of anisotropy of the material. These hypotheses were tested in silico using finite-element method (FEM) models and Field II. ARFI excitations had F/1.5, 3, 4, or 5 focal configurations, with the F/1.5 and F/5 cases having the most asymmetrical and symmetrical PSFs at the focal depth, respectively. These excitations were implemented for ARFI imaging in 52 different simulated TI materials with varying degrees of anisotropy, and the ratio of ARFI-induced PDs was calculated. The change in the ratio of PDs with respect to the anisotropy of the materials was highest for the F/1.5, indicating that PD was most strongly impacted by the material orientation when the ARFI excitation was the most asymmetrical. On the contrary, the ratio of PDs did not depend on the anisotropy of the material for the F/5 ARFI excitation, suggesting that PD did not depend on material orientation when the ARFI excitation was symmetrical. Finally, the ratio of PDs achieved using asymmetrical ARFI PSF reflected the degree of anisotropy in TI materials. These results support that symmetrical ARFI focal configurations are desirable when the orientation of the ARFI excitation to the AoS is not specifically known and measurement standardization is important, such as for longitudinal or cross-sectional studies of anisotropic organs. However, asymmetrical focal configurations are useful for exploiting anisotropy, which may be diagnostically relevant. Feasibility for future experimental implementation is demonstrated by simulating ultrasonic displacement tracking and by varying the ARF duration. DA - 2017/6// PY - 2017/6// DO - 10.1109/tuffc.2017.2690223 VL - 64 IS - 6 SP - 989-1001 SN - 1525-8955 KW - Anisotropy KW - ARFI KW - fractional anisotropy KW - peak displacement KW - strain KW - transversely isotropic material ER - TY - JOUR TI - Variation in the human Achilles tendon moment arm during walking AU - Rasske, Kristen AU - Thelen, Darryl G. AU - Franz, Jason R. T2 - COMPUTER METHODS IN BIOMECHANICS AND BIOMEDICAL ENGINEERING AB - The Achilles tendon (AT) moment arm is an important determinant of ankle moment and power generation during locomotion. Load and depth-dependent variations in the AT moment arm are generally not considered, but may be relevant given the complex triceps surae architecture. We coupled motion analysis and ultrasound imaging to characterize AT moment arms during walking in 10 subjects. Muscle loading during push-off amplified the AT moment arm by 10% relative to heel strike. AT moment arms also varied by 14% over the tendon thickness. In walking, AT moment arms are not strictly dependent on kinematics, but exhibit important load and spatial dependencies. DA - 2017/// PY - 2017/// DO - 10.1080/10255842.2016.1213818 VL - 20 IS - 2 SP - 201-205 SN - 1476-8259 KW - Gait KW - plantarflexors KW - triceps surae KW - ultrasound KW - musculoskeletal model ER - TY - JOUR TI - Subresolution Displacements in Finite Difference Simulations of Ultrasound Propagation and Imaging AU - Pinton, Gianmarco F. T2 - IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL AB - Time domain finite difference simulations are used extensively to simulate wave propagation. They approximate the wave field on a discrete domain with a grid spacing that is typically on the order of a tenth of a wavelength. The smallest displacements that can be modeled by this type of simulation are thus limited to discrete values that are integer multiples of the grid spacing. This paper presents a method to represent continuous and subresolution displacements by varying the impedance of individual elements in a multielement scatterer. It is demonstrated that this method removes the limitations imposed by the discrete grid spacing by generating a continuum of displacements as measured by the backscattered signal. The method is first validated on an ideal perfect correlation case with a single scatterer. It is subsequently applied to a more complex case with a field of scatterers that model an acoustic radiation force-induced displacement used in ultrasound elasticity imaging. A custom finite difference simulation tool is used to simulate propagation from ultrasound imaging pulses in the scatterer field. These simulated transmit-receive events are then beamformed into images, which are tracked with a correlation-based algorithm to determine the displacement. A linear predictive model is developed to analytically describe the relationship between element impedance and backscattered phase shift. The error between model and simulation is λ/1364, where λ is the acoustical wavelength. An iterative method is also presented that reduces the simulation error to λ/5556 over one iteration. The proposed technique therefore offers a computationally efficient method to model continuous subresolution displacements of a scattering medium in ultrasound imaging. This method has applications that include ultrasound elastography, blood flow, and motion tracking. This method also extends generally to finite difference simulations of wave propagation, such as electromagnetic or seismic waves. DA - 2017/3// PY - 2017/3// DO - 10.1109/tuffc.2016.2638801 VL - 64 IS - 3 SP - 537-543 SN - 1525-8955 KW - Biomedical acoustics KW - biomedical imaging KW - elastography KW - numerical simulation ER - TY - JOUR TI - Semisupervised Tripled Dictionary Learning for Standard-Dose PET Image Prediction Using Low-Dose PET and Multimodal MRI AU - Wang, Yan AU - Ma, Guangkai AU - An, Le AU - Shi, Feng AU - Zhang, Pei AU - Lalush, David S. AU - Wu, , Xi AU - Pu, Yifei AU - Zhou, Jiliu AU - Shen, Dinggang T2 - IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING AB - Objective: To obtain high-quality positron emission tomography (PET) image with low-dose tracer injection, this study attempts to predict the standard-dose PET (S-PET) image from both its low-dose PET (L-PET) counterpart and corresponding magnetic resonance imaging (MRI). Methods: It was achieved by patch-based sparse representation (SR), using the training samples with a complete set of MRI, L-PET and S-PET modalities for dictionary construction. However, the number of training samples with complete modalities is often limited. In practice, many samples generally have incomplete modalities (i.e., with one or two missing modalities) that thus cannot be used in the prediction process. In light of this, we develop a semisupervised tripled dictionary learning (SSTDL) method for S-PET image prediction, which can utilize not only the samples with complete modalities (called complete samples) but also the samples with incomplete modalities (called incomplete samples), to take advantage of the large number of available training samples and thus further improve the prediction performance. Results: Validation was done on a real human brain dataset consisting of 18 subjects, and the results show that our method is superior to the SR and other baseline methods. Conclusion: This paper proposed a new S-PET prediction method, which can significantly improve the PET image quality with low-dose injection. Significance: The proposed method is favorable in clinical application since it can decrease the potential radiation risk for patients. DA - 2017/3// PY - 2017/3// DO - 10.1109/tbme.2016.2564440 VL - 64 IS - 3 SP - 569-579 SN - 1558-2531 KW - Local coordinate coding (LCC) KW - positron emission tomography (PET) KW - semisupervised tripled dictionary learning (SSTDL) KW - sparse representation (SR) ER - TY - JOUR TI - LEVERAGING PHYSIOLOGY FOR PRECISION DRUG DELIVERY AU - Sun, Wujin AU - Hu, Quanyin AU - Ji, Wenyan AU - Wright, Grace AU - Gu, Zhen T2 - PHYSIOLOGICAL REVIEWS AB - Physiological characteristics of diseases bring about both challenges and opportunities for targeted drug delivery. Various drug delivery platforms have been devised ranging from macro- to micro- and further into the nanoscopic scale in the past decades. Recently, the favorable physicochemical properties of nanomaterials, including long circulation, robust tissue and cell penetration attract broad interest, leading to extensive studies for therapeutic benefits. Accumulated knowledge about the physiological barriers that affect the in vivo fate of nanomedicine has led to more rational guidelines for tailoring the nanocarriers, such as size, shape, charge, and surface ligands. Meanwhile, progresses in material chemistry and molecular pharmaceutics generate a panel of physiological stimuli-responsive modules that are equipped into the formulations to prepare “smart” drug delivery systems. The capability of harnessing physiological traits of diseased tissues to control the accumulation of or drug release from nanomedicine has further improved the controlled drug release profiles with a precise manner. Successful clinical translation of a few nano-formulations has excited the collaborative efforts from the research community, pharmaceutical industry, and the public towards a promising future of smart drug delivery. DA - 2017/1// PY - 2017/1// DO - 10.1152/physrev.00015.2016 VL - 97 IS - 1 SP - 189-225 SN - 1522-1210 ER - TY - JOUR TI - H2O2-Responsive Vesicles Integrated with Transcutaneous Patches for Glucose-Mediated Insulin Delivery AU - Hu, Xiuli AU - Yu, Jicheng AU - Qian, Chenggen AU - Lu, Yue AU - Kahkoska, Anna R. AU - Xie, Zhigang AU - Jing, Xiabin AU - Buse, John B. AU - Gu, Zhen T2 - ACS NANO AB - A self-regulated "smart" insulin administration system would be highly desirable for diabetes management. Here, a glucose-responsive insulin delivery device, which integrates H2O2-responsive polymeric vesicles (PVs) with a transcutaneous microneedle-array patch was prepared to achieve a fast response, excellent biocompatibility, and painless administration. The PVs are self-assembled from block copolymer incorporated with polyethylene glycol (PEG) and phenylboronic ester (PBE)-conjugated polyserine (designated mPEG-b-P(Ser-PBE)) and loaded with glucose oxidase (GOx) and insulin. The polymeric vesicles function as both moieties of the glucose sensing element (GOx) and the insulin release actuator to provide basal insulin release as well as promote insulin release in response to hyperglycemic states. In the current study, insulin release responds quickly to elevated glucose and its kinetics can be modulated by adjusting the concentration of GOx loaded into the microneedles. In vivo testing indicates that a single patch can regulate glucose levels effectively with reduced risk of hypoglycemia. DA - 2017/1// PY - 2017/1// DO - 10.1021/acsnano.6b06892 VL - 11 IS - 1 SP - 613-620 SN - 1936-086X KW - drug delivery KW - vesicles KW - polymersome KW - glucose-responsive KW - insulin KW - diabetes ER - TY - JOUR TI - Electrical switching of antiferromagnets via strongly spin-orbit coupled materials AU - Li, Xi-Lai AU - Duan, Xiaopeng AU - Semenov, Yuriy G. AU - Kim, Ki Wook T2 - JOURNAL OF APPLIED PHYSICS AB - Electrically controlled ultra-fast switching of an antiferromagnet (AFM) is shown to be realizable by interfacing it with a material of strong spin-orbit coupling. The proximity interaction between the sublattice magnetic moments of a layered AFM and the spin-polarized free electrons at the interface offers an efficient way to manipulate antiferromagnetic states. A quantitative analysis, using the combination with a topological insulator as an example, demonstrates highly reliable 90° and 180° rotations of AFM magnetic states under two different mechanisms of effective torque generation at the interface. The estimated switching speed and energy requirement are in the ps and aJ ranges, respectively, which are about two-three orders of magnitude better than the ferromagnetic counterparts. The observed differences in the magnetization dynamics may explain the disparate characteristic responses. Unlike the usual precessional/chiral motions in the ferromagnets, those of the AFMs can essentially be described as a damped oscillator with a more direct path. The impact of random thermal fluctuations is also examined. DA - 2017/1/14/ PY - 2017/1/14/ DO - 10.1063/1.4974027 VL - 121 IS - 2 SP - SN - 1089-7550 ER - TY - JOUR TI - Contrast Enhanced Superharmonic Imaging for Acoustic Angiography Using Reduced Form-Factor Lateral Mode Transmitters for Intravascular and Intracavity Applications AU - Wang, Zhuochen AU - Martin, K. Heath AU - Huang, Wenbin AU - Dayton, Paul A. AU - Jiang, Xiaoning T2 - IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL AB - Techniques to image the microvasculature may play an important role in imaging tumor-related angiogenesis and vasa vasorum associated with vulnerable atherosclerotic plaques. However, the microvasculature associated with these pathologies is difficult to detect using traditional B-mode ultrasound or even harmonic imaging due to small vessel size and poor differentiation from surrounding tissue. Acoustic angiography, a microvascular imaging technique that utilizes superharmonic imaging (detection of higher order harmonics of microbubble response), can yield a much higher contrast-to-tissue ratio than second harmonic imaging methods. In this paper, two dual-frequency transducers using lateral mode transmitters were developed for superharmonic detection and acoustic angiography imaging in intracavity applications. A single element dual-frequency intravascular ultrasound transducer was developed for concept validation, which achieved larger signal amplitude, better contrast-to-noise ratio (CNR), and pulselength compared to the previous work. A dual-frequency [Pb(Mg1/3Nb2/3)O3]-x[PbTiO3] array transducer was then developed for superharmonic imaging with dynamic focusing. The axial and lateral sizes of the microbubbles in a 200- [Formula: see text] tube were measured to be 269 and [Formula: see text], respectively. The maximum CNR was calculated to be 22 dB. These results show that superharmonic imaging with a low frequency lateral mode transmitter is a feasible alternative to thickness mode transmitters when the final transducer size requirements dictate design choices. DA - 2017/2// PY - 2017/2// DO - 10.1109/tuffc.2016.2619687 VL - 64 IS - 2 SP - 311-319 SN - 1525-8955 KW - Dual frequency KW - lateral mode transducer KW - superharmonic KW - ultrasound transducer ER - TY - JOUR TI - Common genetic variants in neurobeachin (nbea) are associated with metformin drug response in individuals with type 2 diabetes in the accord clinical trial AU - Rotroff, D. M. AU - Marvel, S. W. AU - Jack, J. R. AU - Havener, T. M. AU - Doria, A. AU - Shah, H. S. AU - Mychaleckyi, J. C. AU - McLeod, H. L. AU - Buse, J. B. AU - Wagner, M. J. AU - Motsinger-Reif, A. A. T2 - Clinical Pharmacology & Therapeutics DA - 2017/// PY - 2017/// VL - 101 IS - S1 SP - S9-9 ER - TY - JOUR TI - Anaerobe-Inspired Anticancer Nanovesicles AU - Qian, Chenggen AU - Feng, Peijian AU - Yu, Jicheng AU - Chen, Yulei AU - Hu, Quanyin AU - Sun, Wujin AU - Xiao, Xuanzhong AU - Hu, Xiuli AU - Bellotti, Adriano AU - Shen, Qun-Dong AU - Gu, Zhen T2 - ANGEWANDTE CHEMIE-INTERNATIONAL EDITION AB - Abstract Anaerobic bacteria, such as Clostridium and Salmonella , can selectively invade and colonize in tumor hypoxic regions (THRs) and deliver therapeutic products to destroy cancer cells. Herein, we present an anaerobe nanovesicle mimic that can not only be activated in THRs but also induce hypoxia in tumors by themselves. Moreover, inspired by the oxygen metabolism of anaerobes, we construct a light‐induced hypoxia‐responsive modality to promote dissociation of vehicles and activation of bioreductive prodrugs simultaneously. In vitro and in vivo experiments indicate that this anaerobe‐inspired nanovesicle can efficiently induce apoptotic cell death and significantly inhibit tumor growth. Our work provides a new strategy for engineering stimuli‐responsive drug delivery systems in a bioinspired and synergistic fashion. DA - 2017/3/1/ PY - 2017/3/1/ DO - 10.1002/anie.201611783 VL - 56 IS - 10 SP - 2588-2593 SN - 1521-3773 KW - drug delivery KW - nanomedicines KW - photodynamic therapy ER - TY - JOUR TI - An evaluation of the sonoporation potential of low-boiling point phase-change ultrasound contrast agents in vitro AU - Fix, Samantha M. AU - Novell, Anthony AU - Yun, Yeoheung AU - Dayton, Paul A. AU - Arena, Christopher B. T2 - JOURNAL OF THERAPEUTIC ULTRASOUND AB - Phase-change ultrasound contrast agents (PCCAs) offer a solution to the inherent limitations associated with using microbubbles for sonoporation; they are characterized by prolonged circulation lifetimes, and their nanometer-scale sizes may allow for passive accumulation in solid tumors. As a first step towards the goal of extravascular cell permeabilization, we aim to characterize the sonoporation potential of a low-boiling point formulation of PCCAs in vitro.Parameters to induce acoustic droplet vaporization and subsequent microbubble cavitation were optimized in vitro using high-speed optical microscopy. Sonoporation of pancreatic cancer cells in suspension was then characterized at a range of pressures (125-600 kPa) and pulse lengths (5-50 cycles) using propidium iodide as an indicator molecule.We achieved sonoporation efficiencies ranging from 8 ± 1% to 36 ± 4% (percent of viable cells), as evidenced by flow cytometry. Increasing sonoporation efficiency trended with increasing pulse length and peak negative pressure.We conclude that PCCAs can be used to induce the sonoporation of cells in vitro, and our results warrant further investigation into the use of PCCAs as extravascular sonoporation agents in vivo. DA - 2017/1/24/ PY - 2017/1/24/ DO - 10.1186/s40349-017-0085-z VL - 5 SP - 1-11 SN - 2050-5736 KW - Sonoporation KW - Ultrasound KW - Drug delivery KW - Acoustic droplet vaporization KW - Nanodroplet ER - TY - JOUR TI - Thrombin-responsive transcutaneous patch for auto-anticoagulant regulation AU - Zhang, Y. Q. AU - Yu, J. C. AU - Wang, J. Q. AU - Hanne, N. J. AU - Cui, Z. AU - Qian, C. G. AU - Wang, C. AU - Xin, H. L. AU - Cole, Jacqueline AU - Gallippi, C. M. AU - Zhu, Y. AU - Gu, Z. T2 - Advanced Materials AB - A thrombin-responsive microneedle-based transcutaneous patch is developed by C. M. Gallippi, Y. Zhu, Z. Gu, and co-workers, as demonstrated in article 1604043. The anticoagulant drug heparin is loaded into the hyaluronic acid needles through a thrombin cleavable peptide linker. This heparin patch can sense the thrombin level in blood vessels and autoregulate blood coagulation in a long-term manner. Cover design credit: Yuqi Zhang. DA - 2017/// PY - 2017/// DO - 10.1002/adma.201770028 VL - 29 IS - 4 ER - TY - JOUR TI - Investigation and intervention of autophagy to guide cancer treatment with nanogels AU - Zhang, Xudong AU - Liang, Xin AU - Gu, Jianjun AU - Chang, Danfeng AU - Zhang, Jinxie AU - Chen, Zhaowei AU - Ye, Yanqi AU - Wang, Chao AU - Tao, Wei AU - Zeng, Xiaowei AU - Liu, Gan AU - Zhang, Yongjun AU - Mei, Lin AU - Gu, Zhen T2 - NANOSCALE AB - Cancer cells use autophagy to resist poor survival environmental conditions such as low PH, poor nutrients as well as chemical therapy. Nanogels have been used as efficient chemical drug carriers for cancer treatment. However, the effect of nanogels on autophagy is still unknown. Here, we used Rab proteins as the marker of multiple trafficking vesicles in endocytosis and LC3 as the marker of autophagy to investigate the intracellular trafficking network of Rhodamine B (Rho)-labeled nanogels. The nanogels were internalized by the cells through multiple protein dependent endocytosis and micropinocytosis. After inception by the cells, the nanogels were transported into multiple Rab positive vesicles including early endosomes (EEs), late endosomes (LEs), recycling endosomes (REs) and lipid droplets. Finally, these Rab positive vesicles were transported to lysosome. In addition, GLUT4 exocytosis vesicles could transport the nanogels out of the cells. Moreover, nanogels could induce autophagy and be sequestered in autophagosomes. The crosstalk between autophagosomes and Rab positive vesicles were investigated, we found that autophagosomes may receive nanogels through multiple Rab positive vesicles. Co-delivery of autophagy inhibitors such as chloroquine (CQ) and the chemotherapeutic drug doxorubicin (DOX) by nanogels blocked the autophagy induced by DOX greatly decreasing both of the volume and weight of the tumors in mice tumor models. Investigation and intervention of the autophagy pathway could provide a new method to improve the therapeutic effect of anticancer nanogels. DA - 2017/1/7/ PY - 2017/1/7/ DO - 10.1039/c6nr07866d VL - 9 IS - 1 SP - 150-163 SN - 2040-3372 ER - TY - JOUR TI - Ibuprofen loaded PLA nanofibrous scaffolds increase proliferation of human skin cells in vitro and promote healing of full thickness incision wounds in vivo AU - Mohiti-Asli, M. AU - Saha, S. AU - Murphy, S. V. AU - Gracz, H. AU - Pourdeyhimi, B. AU - Atala, A. AU - Loboa, E. G. T2 - JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART B-APPLIED BIOMATERIALS AB - This article presents successful incorporation of ibuprofen in polylactic acid (PLA) nanofibers to create scaffolds for the treatment of both acute and chronic wounds. Nanofibrous PLA scaffolds containing 10, 20, or 30 wt % ibuprofen were created and ibuprofen release profiles quantified. In vitro cytotoxicity to human epidermal keratinocytes (HEK) and human dermal fibroblasts (HDF) of the three scaffolds with varying ibuprofen concentrations were evaluated and compared to pure PLA nanofibrous scaffolds. Thereafter, scaffolds loaded with ibuprofen at the concentration that promoted human skin cell viability and proliferation (20 wt %) were evaluated in vivo in nude mice using a full thickness skin incision model to determine the ability of these scaffolds to promote skin regeneration and/or assist with scarless healing. Both acellular and HEK and HDF cell-seeded 20 wt % ibuprofen loaded nanofibrous bandages reduced wound contraction compared with wounds treated with Tegaderm™ and sterile gauze. Newly regenerated skin on wounds treated with cell-seeded 20 wt % ibuprofen bandages exhibited significantly greater blood vessel formation relative to acellular ibuprofen bandages. We have found that degradable anti-inflammatory scaffolds containing 20 wt % ibuprofen promote human skin cell viability and proliferation in vitro, reduce wound contraction in vivo, and when seeded with skin cells, also enhance new blood vessel formation. The approaches and results reported here hold promise for multiple skin tissue engineering and wound healing applications. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 327-339, 2017. DA - 2017/2// PY - 2017/2// DO - 10.1002/jbm.b.33520 VL - 105 IS - 2 SP - 327-339 SN - 1552-4981 KW - controlled release KW - drug delivery/release KW - inflammation KW - PLLA KW - wound healing ER - TY - JOUR TI - Effects of nanotopography on the in vitro hemocompatibility of nanocrystalline diamond coatings AU - Skoog, Shelby A. AU - Lu, Qijin AU - Malinauskas, Richard A. AU - Sumant, Anirudha V. AU - Zheng, Jiwen AU - Goering, Peter L. AU - Narayan, Roger J. AU - Casey, Brendan J. T2 - JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A AB - Abstract Nanocrystalline diamond (NCD) coatings have been investigated for improved wear resistance and enhanced hemocompatibility of cardiovascular devices. The goal of this study was to evaluate the effects of NCD surface nanotopography on in vitro hemocompatibility. NCD coatings with small (NCD‐S) and large (NCD‐L) grain sizes were deposited using microwave plasma chemical vapor deposition and characterized using scanning electron microscopy, atomic force microscopy, contact angle testing, and Raman spectroscopy. NCD‐S coatings exhibited average grain sizes of 50–80 nm (RMS 5.8 nm), while NCD‐L coatings exhibited average grain sizes of 200–280 nm (RMS 23.1 nm). In vitro hemocompatibility testing using human blood included protein adsorption, hemolysis, nonactivated partial thromboplastin time, platelet adhesion, and platelet activation. Both NCD coatings demonstrated low protein adsorption, a nonhemolytic response, and minimal activation of the plasma coagulation cascade. Furthermore, the NCD coatings exhibited low thrombogenicity with minimal platelet adhesion and aggregation, and similar morphological changes to surface‐bound platelets (i.e., activation) in comparison to the HDPE negative control material. For all assays, there were no significant differences in the blood–material interactions of NCD‐S versus NCD‐L. The two tested NCD coatings, regardless of nanotopography, had similar hemocompatibility profiles compared to the negative control material (HDPE) and should be further evaluated for use in blood‐contacting medical devices. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 253–264, 2017. DA - 2017/1// PY - 2017/1// DO - 10.1002/jbm.a.35872 VL - 105 IS - 1 SP - 253-264 SN - 1552-4965 KW - nanocrystalline diamond KW - hemocompatibility KW - cardiovascular devices KW - nanostructured topography KW - blood ER - TY - JOUR TI - 3-D Ultrasound Localization Microscopy for Identifying Microvascular Morphology Features of Tumor Angiogenesis at a Resolution Beyond the Diffraction Limit of Conventional Ultrasound AU - Lin, Fanglue AU - Shelton, Sarah E. AU - Espíndola, David AU - Rojas, Juan D. AU - Pinton, Gianmarco AU - Dayton, Paul A. T2 - Theranostics AB - Angiogenesis has been known as a hallmark of solid tumor cancers for decades, yet ultrasound has been limited in its ability to detect the microvascular changes associated with malignancy. Here, we demonstrate the potential of 'ultrasound localization microscopy' applied volumetrically in combination with quantitative analysis of microvascular morphology, as an approach to overcome this limitation. This pilot study demonstrates our ability to image complex microvascular patterns associated with tumor angiogenesis in-vivo at a resolution of tens of microns - substantially better than the diffraction limit of traditional clinical ultrasound, yet using an 8 MHz clinical ultrasound probe. Furthermore, it is observed that data from healthy and tumor-bearing tissue exhibit significant differences in microvascular pattern and density. Results suggests that with continued development of these novel technologies, ultrasound has the potential to detect biomarkers of cancer based on the microvascular 'fingerprint' of malignant angiogenesis rather than through imaging of blood flow dynamics or the tumor mass itself. DA - 2017/// PY - 2017/// DO - 10.7150/thno.16899 VL - 7 IS - 1 SP - 196-204 J2 - Theranostics LA - en OP - SN - 1838-7640 UR - http://dx.doi.org/10.7150/thno.16899 DB - Crossref KW - Angiogenesis KW - super-resolution KW - ultrasound localization microscopy KW - microbubble contrast agent KW - acoustic angiography KW - biomarker ER - TY - JOUR TI - Single-platelet nanomechanics measured by high-throughput cytometry AU - Myers, David R. AU - Qiu, Yongzhi AU - Fay, Meredith E. AU - Tennenbaum, Michael AU - Chester, Daniel AU - Cuadrado, Jonas AU - Sakurai, Yumiko AU - Baek, Jong AU - Tran, Reginald AU - Ciciliano, Jordan C. AU - Ahn, Byungwook AU - Mannino, Robert G. AU - Bunting, Silvia T. AU - Bennett, Carolyn AU - Briones, Michael AU - Fernandez-Nieves, Alberto AU - Smith, Michael L. AU - Brown, Ashley C. AU - Sulchek, Todd AU - Lam, Wilbur A. T2 - NATURE MATERIALS AB - Haemostasis occurs at sites of vascular injury, where flowing blood forms a clot, a dynamic and heterogeneous fibrin-based biomaterial. Paramount in the clot's capability to stem haemorrhage are its changing mechanical properties, the major drivers of which are the contractile forces exerted by platelets against the fibrin scaffold. However, how platelets transduce microenvironmental cues to mediate contraction and alter clot mechanics is unknown. This is clinically relevant, as overly softened and stiffened clots are associated with bleeding and thrombotic disorders. Here, we report a high-throughput hydrogel-based platelet-contraction cytometer that quantifies single-platelet contraction forces in different clot microenvironments. We also show that platelets, via the Rho/ROCK pathway, synergistically couple mechanical and biochemical inputs to mediate contraction. Moreover, highly contractile platelet subpopulations present in healthy controls are conspicuously absent in a subset of patients with undiagnosed bleeding disorders, and therefore may function as a clinical diagnostic biophysical biomarker. DA - 2017/2// PY - 2017/2// DO - 10.1038/nmat4772 VL - 16 IS - 2 SP - 230-235 SN - 1476-4660 ER - TY - JOUR TI - Hypoxia and H2O2 Dual-Sensitive Vesicles for Enhanced Glucose-Responsive Insulin Delivery AU - Yu, Jicheng AU - Qian, Chenggen AU - Zhang, Yuqi AU - Cui, Zheng AU - Zhu, Yong AU - Shen, Qundong AU - Ligler, Frances S. AU - Buse, John B. AU - Gu, Zhen T2 - NANO LETTERS AB - A glucose-responsive closed-loop insulin delivery system mimicking pancreas activity without long-term side effect has the potential to improve diabetic patients' health and quality of life. Here, we developed a novel glucose-responsive insulin delivery device using a painless microneedle-array patch containing insulin-loaded vesicles. Formed by self-assembly of hypoxia and H2O2 dual-sensitive diblock copolymer, the glucose-responsive polymersome-based vesicles (d-GRPs) can disassociate and subsequently release insulin triggered by H2O2 and hypoxia generated during glucose oxidation catalyzed by glucose specific enzyme. Moreover, the d-GRPs were able to eliminate the excess H2O2, which may lead to free radical-induced damage to skin tissue during the long-term usage and reduce the activity of GOx. In vivo experiments indicated that this smart insulin patch could efficiently regulate the blood glucose in the chemically induced type 1 diabetic mice for 10 h. DA - 2017/2// PY - 2017/2// DO - 10.1021/acs.nanolett.6b03848 VL - 17 IS - 2 SP - 733-739 SN - 1530-6992 KW - Drug delivery KW - diabetes KW - insulin KW - glucose-responsive KW - hypoxia-sensitive KW - H2O2-sensitive ER - TY - JOUR TI - Enhanced Cisplatin Chemotherapy by Iron Oxide Nanocarrier-Mediated Generation of Highly Toxic Reactive Oxygen Species AU - Ma, Ping'an AU - Xiao, Haihua AU - Yu, Chang AU - Liu, Jianhua AU - Cheng, Ziyong AU - Song, Haiqin AU - Zhang, Xinyang AU - Li, Chunxia AU - Wang, Jinqiang AU - Gu, Zhen AU - Lin, Jun T2 - NANO LETTERS AB - Reactive oxygen species (ROS) plays a key role in therapeutic effects as well as side effects of platinum drugs. Cisplatin mediates activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX), which triggers oxygen (O2) to superoxide radical (O2•–) and its downstream H2O2. Through the Fenton’s reaction, H2O2 could be catalyzed by Fe2+/Fe3+ to the toxic hydroxyl radicals (•OH), which cause oxidative damages to lipids, proteins, and DNA. By taking the full advantage of Fenton’s chemistry, we herein demonstrated tumor site-specific conversion of ROS generation induced by released cisplatin and Fe2+/Fe3+ from iron-oxide nanocarriers with cisplatin(IV) prodrugs for enhanced anticancer activity but minimized systemic toxicity. DA - 2017/2// PY - 2017/2// DO - 10.1021/acs.nanolett.6b04269 VL - 17 IS - 2 SP - 928-937 SN - 1530-6992 KW - Drug delivery KW - cisplatin KW - iron oxide KW - Fenton's reaction KW - reactive oxygen species ER -