@article{krissanaprasit_mihalko_meinhold_simpson_sollinger_pandit_dupont_kjems_brown_labean_2024, title={A Functional RNA-Origami as Direct Thrombin Inhibitor with Fast-acting and Specific Single-Molecule Reversal Agents in vivo model}, volume={5}, ISSN={1525-0016}, url={http://dx.doi.org/10.1016/j.ymthe.2024.05.002}, DOI={10.1016/j.ymthe.2024.05.002}, abstractNote={Injectable anticoagulants are widely used in medical procedures to prevent unwanted blood clotting. However, many lack safe, effective reversal agents. Here, we present new data on a previously described RNA origami-based, direct thrombin inhibitor (HEX01). We describe a new, fast-acting, specific, single-molecule reversal agent (antidote) and present in vivo data for the first time, including efficacy, reversibility, preliminary safety, and initial biodistribution studies. HEX01 contains multiple thrombin-binding aptamers appended on an RNA origami. It exhibits excellent anticoagulation activity in vitro and in vivo. The new single-molecule, DNA antidote (HEX02) reverses anticoagulation activity of HEX01 in human plasma within 30 seconds in vitro and functions effectively in a murine liver laceration model. Biodistribution studies of HEX01 in whole mice using ex vivo imaging show accumulated mainly in the liver over 24 hours and with 10-fold lower concentrations in the kidneys. Additionally, we show that the HEX01/HEX02 system is non-cytotoxic to epithelial cell lines and non-hemolytic in vitro. Furthermore, we found no serum cytokine response to HEX01/HEX02 in a murine model. HEX01 and HEX02 represent a safe and effective coagulation control system with a fast-acting, specific reversal agent showing promise for potential drug development.}, journal={Molecular Therapy}, publisher={Elsevier BV}, author={Krissanaprasit, Abhichart and Mihalko, Emily and Meinhold, Katherine and Simpson, Aryssa and Sollinger, Jennifer and Pandit, Sanika and Dupont, Daniel M. and Kjems, Jørgen and Brown, Ashley C. and LaBean, Thomas H.}, year={2024}, month={May} }
 @article{sheridan_nellenbach_pandit_byrnes_hardy_lutz_moiseiwitsch_scull_mihalko_levy_et al._2024, title={Clot-Targeted Nanogels for Dual-Delivery of AntithrombinIII and Tissue Plasminogen Activator to Mitigate Disseminated Intravascular Coagulation Complications}, volume={6}, ISSN={["1936-086X"]}, DOI={10.1021/acsnano.4c00162}, abstractNote={Disseminated intravascular coagulation (DIC) is a pathologic state that follows systemic injury and other diseases. Often a complication of sepsis or trauma, DIC causes coagulopathy associated with paradoxical thrombosis and hemorrhage. DIC upregulates the thrombotic pathways while simultaneously downregulating the fibrinolytic pathways that cause excessive fibrin deposition, microcirculatory thrombosis, multiorgan dysfunction, and consumptive coagulopathy with excessive bleeding. Given these opposing disease phenotypes, DIC management is challenging and includes treating the underlying disease and managing the coagulopathy. Currently, no therapies are approved for DIC. We have developed clot-targeted therapeutics that inhibit clot polymerization and activate clot fibrinolysis to manage DIC. We hypothesize that delivering both an anticoagulant and a fibrinolytic agent directly to clots will inhibit active clot polymerization while also breaking up pre-existing clots; therefore, reversing consumptive coagulopathy and restoring hemostatic balance. To test this hypothesis, we single- and dual-loaded fibrin-specific nanogels (FSNs) with antithrombinIII (ATIII) and/or tissue plasminogen activator (tPA) and evaluated their clot preventing and clot lysing abilities in vitro and in a rodent model of DIC. In vivo, single-loaded ATIII-FSNs decreased fibrin deposits in DIC organs and reduced blood loss when DIC rodents were injured. We also observed that the addition of tPA in dual-loaded ATIII-tPA-FSNs intensified the antithrombotic and fibrinolytic mechanisms, which proved advantageous for clot lysis and restoring platelet counts. However, the addition of tPA may have hindered wound healing capabilities when an injury was introduced. Our data supports the benefits of delivering both anticoagulants and fibrinolytic agents directly to clots to reduce the fibrin load and restore hemostatic balance in DIC.}, journal={ACS NANO}, author={Sheridan, Anastasia and Nellenbach, Kimberly and Pandit, Sanika and Byrnes, Elizabeth and Hardy, Grace and Lutz, Halle and Moiseiwitsch, Nina and Scull, Grant and Mihalko, Emily and Levy, Jerrold and et al.}, year={2024}, month={Jun} }
 @article{davis_koch_watson_scull_brown_schnabel_fisher_2024, title={Controlled Stiffness of Direct-Write, Near-Field Electrospun Gelatin Fibers Generates Differences in Tenocyte Morphology and Gene Expression}, volume={146}, ISSN={0148-0731 1528-8951}, url={http://dx.doi.org/10.1115/1.4065163}, DOI={10.1115/1.4065163}, abstractNote={Tendinopathy is a leading cause of mobility issues. Currently, the cell-matrix interactions involved in the development of tendinopathy are not fully understood. In vitro tendon models provide a unique tool for addressing this knowledge gap as they permit fine control over biochemical, micromechanical, and structural aspects of the local environment to explore cell-matrix interactions. In this study, direct-write, near-field electrospinning of gelatin solution was implemented to fabricate micron-scale fibrous scaffolds that mimic native collagen fiber size and orientation. The stiffness of these fibrous scaffolds was found to be controllable between 1MPa and 8MPa using different crosslinking methods (EDC, DHT, DHT+EDC) or through altering the duration of crosslinking with EDC (1hr to 24hrs). EDC crosslinking provided the greatest fiber stability surviving up to 3 weeks in vitro. Differences in stiffness resulted in phenotypic changes for equine tenocytes with low stiffness fibers (~1MPa) promoting an elongated nuclear aspect ratio while those on high stiffness fibers (~8MPa) were rounded. High stiffness fibers resulted in the upregulation of MMPs and proteoglycans (possible indicators for tendinopathy) relative to low stiffness fibers. These results demonstrate the feasibility of direct-written gelatin scaffolds as tendon in vitro models and provide evidence that matrix mechanical properties may be crucial factors in cell-matrix interactions during tendinopathy formation.}, number={9}, journal={Journal of Biomechanical Engineering}, publisher={ASME International}, author={Davis, Zachary G. and Koch, Drew W. and Watson, Samantha L. and Scull, Grant M. and Brown, Ashley C. and Schnabel, Lauren V. and Fisher, Matthew B.}, year={2024}, month={Apr} }
 @article{scull_aligwekwe_rey_koch_nellenbach_sheridan_pandit_sollinger_pierce_flick_et al._2024, title={Fighting fibrin with fibrin: Vancomycin delivery into coagulase-mediated <i>Staphylococcus aureus</i> biofilms via fibrin-based nanoparticle binding}, volume={6}, ISSN={["1552-4965"]}, DOI={10.1002/jbm.a.37760}, abstractNote={Abstract Staphylococcus aureus skin and soft tissue infection is a common ailment placing a large burden upon global healthcare infrastructure. These bacteria are growing increasingly recalcitrant to frontline antimicrobial therapeutics like vancomycin due to the prevalence of variant populations such as methicillin‐resistant and vancomycin‐resistant strains, and there is currently a dearth of novel antibiotics in production. Additionally, S. aureus has the capacity to hijack the host clotting machinery to generate fibrin‐based biofilms that confer protection from host antimicrobial mechanisms and antibiotic‐based therapies, enabling immune system evasion and significantly reducing antimicrobial efficacy. Emphasis is being placed on improving the effectiveness of therapeutics that are already commercially available through various means. Fibrin‐based nanoparticles (FBNs) were developed and found to interact with S. aureus through the clumping factor A (ClfA) fibrinogen receptor and directly integrate into the biofilm matrix. FBNs loaded with antimicrobials such as vancomycin enabled a targeted and sustained release of antibiotic that increased drug contact time and reduced the therapeutic dose required for eradicating the bacteria, both in vitro and in vivo. Collectively, these findings suggest that FBN‐antibiotic delivery may be a novel and potent therapeutic tool for the treatment of S. aureus biofilm infections.}, journal={JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A}, author={Scull, Grant and Aligwekwe, Adrian and Rey, Ysabel and Koch, Drew and Nellenbach, Kimberly and Sheridan, Ana and Pandit, Sanika and Sollinger, Jennifer and Pierce, Joshua G. and Flick, Matthew J. and et al.}, year={2024}, month={Jun} }
 @article{ward_curry_el-ekiaby_jurk_versteeg_keragala_burstyn-cohen_antoniak_suzuki_baker_et al._2024, title={Illustrated State-of-the-Art Capsules of the ISTH 2024 Congress}, volume={8}, ISSN={["2475-0379"]}, DOI={10.1016/j.rpth.2024.102432}, abstractNote={Here, we present a series of illustrated capsules from the State of the Art (SOA) speakers at the 2024 International Society on Thrombosis and Haemostasis Congress in Bangkok, Thailand. This year's Congress marks the first time that the International Society on Thrombosis and Haemostasis has held its flagship scientific meeting in Southeast Asia and is the first to be organized by an international Planning Committee. The Bangkok program will feature innovative science and clinical updates from around the world, reflecting the diversity and multidisciplinary growth of our field. In these illustrated SOA capsules, you will find an exploration of novel models of thrombosis and bleeding and biomaterial discoveries that can trigger or block coagulation. Thromboinflammation is now understood to drive many disease states, and the SOA speakers cover cellular and coagulation responses to COVID-19 and other infections. The theme of crosstalk between coagulation and inflammation expands with capsules on protein S signaling, complement, and fibrinolytic inhibitors. Novel agents for hemophilia and thrombosis prevention are introduced. Challenging clinical conditions are also covered, such as inherited platelet disorders and antiphospholipid antibody syndrome. The scientific program in Bangkok will also showcase the work of clinicians and scientists from all parts of the world and chronicle real-world challenges. For example, 2 SOA capsules address the diagnosis and management of von Willebrand disease in low-income settings. Take some time to browse through these short illustrated reviews; we're sure that you'll be entertained, educated, and inspired to further explore the world of thrombosis and hemostasis.}, number={4}, journal={RESEARCH AND PRACTICE IN THROMBOSIS AND HAEMOSTASIS}, author={Ward, Chris and Curry, Nicola and El-Ekiaby, Magdy and Jurk, Kerstin and Versteeg, Henri H. and Keragala, Charithani and Burstyn-Cohen, Tal and Antoniak, Silvio and Suzuki, Yuko and Baker, Ross I. and et al.}, year={2024}, month={May} }
 @article{nellenbach_mihalko_nandi_koch_shetty_moretti_sollinger_moiseiwitsch_sheridan_pandit_et al._2024, title={Ultrasoft platelet-like particles stop bleeding in rodent and porcine models of trauma}, volume={16}, ISSN={["1946-6242"]}, DOI={10.1126/scitranslmed.adi4490}, abstractNote={Uncontrolled bleeding after trauma represents a substantial clinical problem. The current standard of care to treat bleeding after trauma is transfusion of blood products including platelets; however, donated platelets have a short shelf life, are in limited supply, and carry immunogenicity and contamination risks. Consequently, there is a critical need to develop hemostatic platelet alternatives. To this end, we developed synthetic platelet-like particles (PLPs), formulated by functionalizing highly deformable microgel particles composed of ultralow cross-linked poly ( N -isopropylacrylamide) with fibrin-binding ligands. The fibrin-binding ligand was designed to target to wound sites, and the cross-linking of fibrin polymers was designed to enhance clot formation. The ultralow cross-linking of the microgels allows the particles to undergo large shape changes that mimic platelet shape change after activation; when coupled to fibrin-binding ligands, this shape change facilitates clot retraction, which in turn can enhance clot stability and contribute to healing. Given these features, we hypothesized that synthetic PLPs could enhance clotting in trauma models and promote healing after clotting. We first assessed PLP activity in vitro and found that PLPs selectively bound fibrin and enhanced clot formation. In murine and porcine models of traumatic injury, PLPs reduced bleeding and facilitated healing of injured tissue in both prophylactic and immediate treatment settings. We determined through biodistribution experiments that PLPs were renally cleared, possibly enabled by ultrasoft particle properties. The performance of synthetic PLPs in the preclinical studies shown here supports future translational investigation of these hemostatic therapeutics in a trauma setting.}, number={742}, journal={SCIENCE TRANSLATIONAL MEDICINE}, author={Nellenbach, Kimberly and Mihalko, Emily and Nandi, Seema and Koch, Drew W. and Shetty, Jagathpala and Moretti, Leandro and Sollinger, Jennifer and Moiseiwitsch, Nina and Sheridan, Ana and Pandit, Sanika and et al.}, year={2024}, month={Apr} }
 @article{simpson_krissanaprasit_chester_koehler_labean_brown_2024, title={Utilizing multiscale engineered biomaterials to examine <scp>TGF‐β</scp>‐mediated myofibroblastic differentiation}, volume={3}, ISSN={1067-1927 1524-475X}, url={http://dx.doi.org/10.1111/wrr.13168}, DOI={10.1111/wrr.13168}, abstractNote={Abstract}, journal={Wound Repair and Regeneration}, publisher={Wiley}, author={Simpson, Aryssa and Krissanaprasit, Abhichart and Chester, Daniel and Koehler, Cynthia and LaBean, Thomas H. and Brown, Ashley C.}, year={2024}, month={Mar} }
 @article{lutz_brown_2023, title={Biomaterials for treating sepsis-induced thromboinflammation}, url={https://cdr.lib.unc.edu/concern/articles/bc386v80n}, DOI={10.17615/64a5-2g37}, journal={Frontiers Media SA}, publisher={Frontiers Media SA}, author={Lutz, Halle and Brown, Ashley C.}, year={2023} }
 @article{pandit_nellenbach_brown_2023, title={Characteristics of Fetal Wound Healing and Inspiration for Pro-healing Materials}, volume={2}, ISSN={2731-4812 2731-4820}, url={http://dx.doi.org/10.1007/s44174-023-00093-w}, DOI={10.1007/s44174-023-00093-w}, abstractNote={Chronic non-healing wounds are a significant healthcare challenge. Various biomaterials have been developed to treat chronic wounds but there are still opportunities for improvement of biomaterial therapeutics. This review discusses how fetal wound healing could be used as inspiration to develop pro-healing materials. Compared to adults, fetuses have enhanced wound healing outcomes and healing without scarring. Scarless fetal wound healing is associated with various key differences in several growth factors, cytokines, extracellular matrix components, and coagulation parameters. Mimicking the fetal wound healing environment through bioinspired materials could create improved therapeutics to treat chronic wounds. This review addresses the key differences between adult and fetal wound healing that allow for enhanced scarless fetal healing and discusses how these differences can be used to develop pro-healing materials.}, number={1}, journal={Biomedical Materials & Devices}, publisher={Springer Science and Business Media LLC}, author={Pandit, Sanika and Nellenbach, Kimberly and Brown, Ashley C.}, year={2023}, month={Jun}, pages={158–167} }
 @article{zhang_gluck_brown_zaharoff_king_2023, title={Heparin Affinity-Based IL-4 Delivery to Modulate Macrophage Phenotype and Endothelial Cell Activity In Vitro}, volume={15}, ISSN={1944-8244 1944-8252}, url={http://dx.doi.org/10.1021/acsami.3c00489}, DOI={10.1021/acsami.3c00489}, abstractNote={Macrophages play a pivotal role in wound healing and tissue regeneration, as they are rapidly recruited to the site of injury or implanted foreign material. Depending on their interaction with the material, macrophages can develop different phenotypes, with the M1 pro-inflammatory and M2 pro-regenerative phenotypes being highly involved in tissue regeneration. M2 macrophages mitigate inflammation and promote tissue regeneration and extracellular matrix remodeling. In this study, we engineered a gelatin-heparin-methacrylate (GelMA-HepMA) hydrogel that gradually releases interleukin-4 (IL-4), a cytokine that modulates macrophages to adopt the M2 phenotype. Methacrylation of heparin improved the retention of both heparin and IL-4 within the hydrogel. The GelMA-HepMA hydrogel and IL-4 synergistically downregulated M1 gene expression and upregulated M2 gene expression in macrophages within 48 h of in vitro cell culture. However, the M2-like macrophage phenotype induced by the GelMA-HepMA-IL-4 hydrogel did not necessarily further improve endothelial cell proliferation and migration in vitro.}, number={23}, journal={ACS Applied Materials & Interfaces}, publisher={American Chemical Society (ACS)}, author={Zhang, Fan and Gluck, Jessica M. and Brown, Ashley C. and Zaharoff, David A. and King, Martin W.}, year={2023}, month={Jun}, pages={27457–27470} }
 @article{moiseiwitsch_nellenbach_downey_boorman_brown_guzzetta_2023, title={Influence of Fibrinogen Concentrate on Neonatal Clot Structure When Administered Ex Vivo After Cardiopulmonary Bypass}, volume={137}, ISSN={0003-2999}, url={http://dx.doi.org/10.1213/ANE.0000000000006357}, DOI={10.1213/ANE.0000000000006357}, abstractNote={
            BACKGROUND:
            Bleeding is a serious complication of cardiopulmonary bypass (CPB) in neonates. Blood product transfusions are often needed to adequately restore hemostasis, but are associated with significant risks. Thus, neonates would benefit from other effective, and safe, hemostatic therapies. The use of fibrinogen concentrate (FC; RiaSTAP, CSL Behring, Marburg, Germany) is growing in popularity, but has not been adequately studied in neonates. Here, we characterize structural and degradation effects on the neonatal fibrin network when FC is added ex vivo to plasma obtained after CPB.
          }, number={3}, journal={Anesthesia & Analgesia}, publisher={Ovid Technologies (Wolters Kluwer Health)}, author={Moiseiwitsch, Nina and Nellenbach, Kimberly A. and Downey, Laura A. and Boorman, David and Brown, Ashley C. and Guzzetta, Nina A.}, year={2023}, month={Jan}, pages={682–690} }
 @article{tigner_scull_brown_alge_2023, title={Microparticle Hydrogel Material Properties Emerge from Mixing-Induced Homogenization in a Poly(ethylene glycol) and Dextran Aqueous Two-Phase System}, volume={56}, ISSN={0024-9297 1520-5835}, url={http://dx.doi.org/10.1021/acs.macromol.3c00557}, DOI={10.1021/acs.macromol.3c00557}, abstractNote={Polymer–polymer aqueous two-phase systems (ATPSs) are attractive for microgel synthesis, but given the complexity of phase separation, predicting microgel material properties from ATPS formulations is not trivial. The objective of this study was to determine how the phase diagram of a poly(ethylene glycol) (PEG) and dextran ATPS is related to the material properties of PEG microgel products. PEG-dextran ATPSs were prepared from four-arm 20 kDa PEG-norbornene and 40 kDa dextran in phosphate buffered saline (PBS), and the phase diagram was constructed. PEG microgels were synthesized from five ATPS formulations using an oligopeptide cross-linker and thiol-norbornene photochemistry. Thermogravimetric analysis (TGA) revealed that the polymer concentration of microgel pellets linearly correlates with the average concentration of PEG in the ATPS rather than the separated phase compositions, as determined from the phase diagram. Atomic force microscopy (AFM) and bulk rheology studies demonstrated that the mechanical properties of microgels rely on both the average concentration of PEG in the ATPS and the ATPS volume ratio as determined from the phase diagram. These findings suggest that PEG-dextran ATPSs undergo homogenization upon mixing, which principally determines the material properties of the microgels upon gelation.}, number={21}, journal={Macromolecules}, publisher={American Chemical Society (ACS)}, author={Tigner, Thomas J. and Scull, Grant and Brown, Ashley C. and Alge, Daniel L.}, year={2023}, month={Oct}, pages={8518–8528} }
 @article{prodromou_moore_chu_deal_san miguel_brown_daniele_pozdin_menegatti_2023, title={Molecular Engineering of Cyclic Azobenzene‐Peptide Hybrid Ligands for the Purification of Human Blood Factor VIII via Photo‐Affinity Chromatography}, volume={33}, ISSN={1616-301X 1616-3028}, url={http://dx.doi.org/10.1002/adfm.202213881}, DOI={10.1002/adfm.202213881}, abstractNote={Abstract}, number={14}, journal={Advanced Functional Materials}, publisher={Wiley}, author={Prodromou, Raphael and Moore, Brandyn David and Chu, Wenning and Deal, Halston and San Miguel, Adriana and Brown, Ashley Carson and Daniele, Michael Angelo‐Anthony and Pozdin, Vladimir Aleksandrovich and Menegatti, Stefano}, year={2023}, month={Jan} }
 @article{sheridan_brown_2023, title={Recent Advances in Blood Cell-Inspired and Clot-Targeted Thrombolytic Therapies}, volume={2023}, ISSN={1932-7005}, url={http://dx.doi.org/10.1155/2023/6117810}, DOI={10.1155/2023/6117810}, abstractNote={Myocardial infarction, stroke, and pulmonary embolism are all deadly conditions associated with excessive thrombus formation. Standard treatment for these conditions involves systemic delivery of thrombolytic agents to break up clots and restore blood flow; however, this treatment can impact the hemostatic balance in other parts of the vasculature, which can lead to excessive bleeding. To avoid this potential danger, targeted thrombolytic treatments that can successfully target thrombi and release an effective therapeutic load are necessary. Because activated platelets and fibrin make up a large proportion of clots, these two components provide ample opportunities for targeting. This review will highlight potential thrombus targeting mechanisms as well as recent advances in thrombolytic therapies which utilize blood cells and clotting proteins to effectively target and lyse clots.}, journal={Journal of Tissue Engineering and Regenerative Medicine}, publisher={Hindawi Limited}, author={Sheridan, Anastasia and Brown, Ashley C.}, editor={Kuo, Catherine K.Editor}, year={2023}, month={Feb}, pages={1–14} }
 @article{young_deal_rusch_pozdin_brown_daniele_2023, title={Simple design for membrane-free microphysiological systems to model the blood-tissue barriers}, volume={5}, ISSN={2666-1020}, url={http://dx.doi.org/10.1016/j.ooc.2023.100032}, DOI={10.1016/j.ooc.2023.100032}, abstractNote={Microphysiological systems (MPS) incorporate physiologically relevant microanatomy, mechanics, and cells to mimic tissue function. Reproducible and standardized in vitro models of tissue barriers, such as the blood-tissue interface (BTI), are critical for next-generation MPS applications in research and industry. Many models of the BTI are limited by the need for semipermeable membranes, use of homogenous cell populations, or 2D culture. These factors limit the relevant endothelial-epithelial contact and 3D transport, which would best mimic the BTI. Current models are also difficult to assemble, requiring precise alignment and layering of components. The work reported herein details the engineering of a BTI-on-a-chip (BTI Chip) that addresses current disadvantages by demonstrating a single layer, membrane-free design. Laminar flow profiles, photocurable hydrogel scaffolds, and human cell lines were used to construct a BTI Chip that juxtaposes an endothelium in direct contact with a 3D engineered tissue. A biomaterial composite, gelatin methacryloyl and 8-arm polyethylene glycol thiol, was used for in situ fabrication of a tissue structure within a Y-shaped microfluidic device. To produce the BTI, a laminar flow profile was achieved by flowing a photocurable precursor solution alongside phosphate buffered saline. Immediately after stopping flow, the scaffold underwent polymerization through a rapid exposure to UV light (<300 mJ/cm2). After scaffold formation, blood vessel endothelial cells were introduced and allowed to adhere directly to the 3D tissue scaffold, without barriers or phase guides. Fabrication of the BTI Chip was demonstrated in both an epithelial tissue model and blood-brain barrier (BBB) model. In the epithelial model, scaffolds were seeded with human dermal fibroblasts. For the BBB models, scaffolds were seeded with the immortalized glial cell line, SVGP12. The BTI Chip microanatomy was analyzed post facto by immunohistochemistry, showing the uniform production of a patent endothelium juxtaposed with a 3D engineered tissue. Fluorescent tracer molecules were used to characterize the permeability of the BTI Chip. The BTI Chips were challenged with an efflux pump inhibitor, cyclosporine A, to assess physiological function and endothelial cell activation. Operation of physiologically relevant BTI Chips and a novel means for high-throughput MPS generation was demonstrated, enabling future development for drug candidate screening and fundamental biological investigations.}, journal={Organs-on-a-Chip}, publisher={Elsevier BV}, author={Young, By Ashlyn T. and Deal, Halston and Rusch, Gabrielle and Pozdin, Vladimir A. and Brown, Ashley C. and Daniele, Michael}, year={2023}, month={Dec}, pages={100032} }
 @article{chee_mihalko_nellenbach_sollinger_huang_hon_pandit_cheng_brown_2023, title={Wound‐triggered shape change microgels for the development of enhanced biomimetic function platelet‐like particles}, volume={112}, ISSN={1549-3296 1552-4965}, url={http://dx.doi.org/10.1002/jbm.a.37625}, DOI={10.1002/jbm.a.37625}, abstractNote={Abstract}, number={4}, journal={Journal of Biomedical Materials Research Part A}, publisher={Wiley}, author={Chee, Eunice and Mihalko, Emily and Nellenbach, Kimberly and Sollinger, Jennifer and Huang, Ke and Hon, Mason and Pandit, Sanika and Cheng, Ke and Brown, Ashley}, year={2023}, month={Oct}, pages={613–624} }
 @article{londoño-zuluaga_jameel_gonzalez_nellenbach_brown_yang_lucia_2022, title={A Unique Crustacean-Based Chitin Platform to Reduce Self-Aggregation of Polysaccharide Nanofibers}, volume={10}, ISSN={2079-6439}, url={http://dx.doi.org/10.3390/fib10100087}, DOI={10.3390/fib10100087}, abstractNote={Every year, over 8 million tons of crustacean shells are discarded. However, there exists an opportunity for valorizing the chitin and calcium carbonate part of the composition of the shells. Our study revealed crustacean chitin reduces self-aggregation effects. It was shown that crustacean-based nanofibers alone or added to cellulose offer unprecedented reductions in viscosity even after drying to produce foams impossible for cellulose. Polysaccharide nanofibers suffer from increased viscosity from strong hydrogen bonding addressed by the incorporation of crustacean-based nanofibers. The ability of the nanocomposite to overcome self-aggregation and collapse was attributed to organized chitin nanofiber morphology in the crustacean matrix. As a result of enhanced surface area from reduced fiber aggregation, the chitin/crustacean-cellulose blend was tested for a biomedical application requiring a high surface area: coagulation. Preliminary experiments showed the crustacean matrices, especially those containing calcium carbonate, induced blood clotting when 35 s. A materials platform is proposed for bio-based nanofiber production overcoming intractable and difficult-to-address self-aggregation effects associated with polysaccharides.}, number={10}, journal={Fibers}, publisher={MDPI AG}, author={Londoño-Zuluaga, Carolina and Jameel, Hasan and Gonzalez, Ronalds and Nellenbach, Kimberly and Brown, Ashley and Yang, Guihua and Lucia, Lucian}, year={2022}, month={Oct}, pages={87} }
 @article{simpson_shukla_brown_2022, title={Biomaterials for Hemostasis}, volume={24}, ISSN={1523-9829 1545-4274}, url={http://dx.doi.org/10.1146/annurev-bioeng-012521-101942}, DOI={10.1146/annurev-bioeng-012521-101942}, abstractNote={ Uncontrolled bleeding is a major problem in trauma and emergency medicine. While materials for trauma applications would certainly find utility in traditional surgical settings, the unique environment of emergency medicine introduces additional design considerations, including the need for materials that are easily deployed in austere environments. Ideally, these materials would be available off the shelf, could be easily transported, and would be able to be stored at room temperature for some amount of time. Both natural and synthetic materials have been explored for the development of hemostatic materials. This review article provides an overview of classes of materials used for topical hemostats and newer developments in the area of injectable hemostats for use in emergency medicine. }, number={1}, journal={Annual Review of Biomedical Engineering}, publisher={Annual Reviews}, author={Simpson, Aryssa and Shukla, Anita and Brown, Ashley C.}, year={2022}, month={Jun}, pages={111–135} }
 @article{moiseiwitsch_zwennes_szlam_sniecinski_brown_2022, title={COVID‐19 patient fibrinogen produces dense clots with altered polymerization kinetics, partially explained by increased sialic acid}, volume={20}, ISSN={1538-7836}, url={http://dx.doi.org/10.1111/jth.15882}, DOI={10.1111/jth.15882}, abstractNote={Thrombogenicity is a known complication of COVID‐19, resulting from SARS‐CoV‐2 infection, with significant effects on morbidity and mortality.}, number={12}, journal={Journal of Thrombosis and Haemostasis}, publisher={Elsevier BV}, author={Moiseiwitsch, Nina and Zwennes, Nicole and Szlam, Fania and Sniecinski, Roman and Brown, Ashley}, year={2022}, month={Dec}, pages={2909–2920} }
 @article{zhang_scull_gluck_brown_king_2022, title={Effects of sterilization methods on gelatin methacryloyl hydrogel properties and macrophage gene expression in vitro}, volume={18}, ISSN={1748-6041 1748-605X}, url={http://dx.doi.org/10.1088/1748-605X/aca4b2}, DOI={10.1088/1748-605X/aca4b2}, abstractNote={Abstract}, number={1}, journal={Biomedical Materials}, publisher={IOP Publishing}, author={Zhang, Fan and Scull, Grant and Gluck, Jessica M and Brown, Ashley C and King, Martin W}, year={2022}, month={Dec}, pages={015015} }
 @article{chester_lee_wagner_nordberg_fisher_brown_2022, title={Elucidating the combinatorial effect of substrate stiffness and surface viscoelasticity on cellular phenotype}, volume={110}, ISSN={1549-3296 1552-4965}, url={http://dx.doi.org/10.1002/jbm.a.37367}, DOI={10.1002/jbm.a.37367}, abstractNote={Abstract}, number={6}, journal={Journal of Biomedical Materials Research Part A}, publisher={Wiley}, author={Chester, Daniel and Lee, Veronica and Wagner, Paul and Nordberg, Matthew and Fisher, Matthew B. and Brown, Ashley C.}, year={2022}, month={Feb}, pages={1224–1237} }
 @article{popowski_moatti_scull_silkstone_lutz_lópez de juan abad_george_belcher_zhu_mei_et al._2022, title={Inhalable dry powder mRNA vaccines based on extracellular vesicles}, volume={5}, ISSN={2590-2385}, url={http://dx.doi.org/10.1016/j.matt.2022.06.012}, DOI={10.1016/j.matt.2022.06.012}, abstractNote={Respiratory diseases are a global burden, with millions of deaths attributed to pulmonary illnesses and dysfunctions. Therapeutics have been developed, but they present major limitations regarding pulmonary bioavailability and product stability. To circumvent such limitations, we developed room-temperature-stable inhalable lung-derived extracellular vesicles or exosomes (Lung-Exos) as mRNA and protein drug carriers. Compared with standard synthetic nanoparticle liposomes (Lipos), Lung-Exos exhibited superior distribution to the bronchioles and parenchyma and are deliverable to the lungs of rodents and nonhuman primates (NHPs) by dry powder inhalation. In a vaccine application, severe acute respiratory coronavirus 2 (SARS-CoV-2) spike (S) protein encoding mRNA-loaded Lung-Exos (S-Exos) elicited greater immunoglobulin G (IgG) and secretory IgA (SIgA) responses than its loaded liposome (S-Lipo) counterpart. Importantly, S-Exos remained functional at room-temperature storage for one month. Our results suggest that extracellular vesicles can serve as an inhaled mRNA drug-delivery system that is superior to synthetic liposomes.}, number={9}, journal={Matter}, publisher={Elsevier BV}, author={Popowski, Kristen D. and Moatti, Adele and Scull, Grant and Silkstone, Dylan and Lutz, Halle and López de Juan Abad, Blanca and George, Arianna and Belcher, Elizabeth and Zhu, Dashuai and Mei, Xuan and et al.}, year={2022}, month={Sep}, pages={2960–2974} }
 @article{wang_sun_vallabhuneni_pawlowski_vahabi_nellenbach_brown_scholle_zhao_kota_2022, title={On-demand, remote and lossless manipulation of biofluid droplets}, volume={9}, ISSN={2051-6347 2051-6355}, url={http://dx.doi.org/10.1039/D2MH00695B}, DOI={10.1039/d2mh00695b}, abstractNote={To minimize exposure of healthcare workers and clinical laboratory personnel to infectious liquids, we designed biofluid manipulators for on-demand handling of liquid droplets, in-plane or out-of-plane, in a remote and lossless manner.}, number={11}, journal={Materials Horizons}, publisher={Royal Society of Chemistry (RSC)}, author={Wang, Wei and Sun, Jiefeng and Vallabhuneni, Sravanthi and Pawlowski, Benjamin and Vahabi, Hamed and Nellenbach, Kimberly and Brown, Ashley C. and Scholle, Frank and Zhao, Jianguo and Kota, Arun K.}, year={2022}, pages={2863–2871} }
 @article{wang_hamedi_zhang_el-shafei_brown_gluck_king_2022, title={Plasma-Induced Diallyldimethylammonium Chloride Antibacterial Hernia Mesh}, volume={5}, ISSN={2576-6422 2576-6422}, url={http://dx.doi.org/10.1021/acsabm.2c00695}, DOI={10.1021/acsabm.2c00695}, abstractNote={A hernia is a pathological condition caused by a defect or opening in the muscle wall, which leads to organs pushing through the opening or defect. Hernia recurrence, seroma, persistent pain, tissue adhesions, and wound infection are common complications following hernia repair surgery. Infection after hernia mesh implantation is the third major complication leading to hernia recurrence. In order to reduce the incidence of late infections, we developed a polypropylene mesh with antibacterial properties. In this study, knitted polypropylene meshes were exposed to radio-frequency plasma to activate their surfaces. The antibacterial monomer diallyldimethylammonium chloride (DADMAC) was then grafted onto the mesh surface using pentaerythritol tetraacrylate as the cross-linker since it is able to engage all four functional groups to form a high-density cross-linked network. The subsequent antibacterial performance showed a 2.9 log reduction toward Staphylococcus aureus and a 0.9 log reduction for Escherichia coli.}, number={12}, journal={ACS Applied Bio Materials}, publisher={American Chemical Society (ACS)}, author={Wang, Ziyu and Hamedi, Hamid and Zhang, Fan and El-Shafei, Ahmed and Brown, Ashley C. and Gluck, Jessica M. and King, Martin W.}, year={2022}, month={Nov}, pages={5645–5656} }
 @article{nellenbach_brown_2022, title={Platelet-mimicking procoagulant nanoparticles: Potential strategies for mitigating blood shortages}, volume={4}, ISSN={["1538-7836"]}, DOI={10.1111/jth.15720}, abstractNote={Bleeding can be a lifethreating event following trauma or surgery. Many factors can increase a patient's likelihood of severe bleeding, including the use of anticoagulants or having hereditary clotting disorders or thrombocytopenia. In a hospital setting, transfusion of donor blood products, including red blood cells, platelets, and/or fibrinogen concentrates, are used as a first line of defense to mitigate bleeding.1 Because of their critical roles in hemostasis, transfusion of platelets is particularly important for stopping uncontrolled bleeding. However, donor platelets have a short shelf life of approximately 5 to 7 days under standard storage conditions. The use of coldstored platelets is gaining popularity as a means to enhance platelet shelflife, but cold storage can cause platelet lesions and has not yet been widely adopted.2 Additionally, no matter the storage conditions used for platelets, because they are derived from human donors, platelet supply is dependent on donor availability and willingness, which often leads to shortages. This limitation has been particularly striking in the past year because the COVID19 pandemic has led to an unprecedented blood product storage. In fact, in 2022, for the first time, the American Red Cross declared a “blood crisis” and implored eligible donors to give blood.3 Furthermore, although risk of disease transmission is low because of current screening standards for donorderived products, this risk is still not zero.4 Finally, although platelets are a key therapeutic tool in the hospital setting, in emergency situations outside of a hospital, it is not practical to carry platelets or other blood products; therefore, many patients suffering traumatic bleeding have delays in critical treatment that could prevent morbidity and mortality.5 Overall, these limitations highlight that a great need exists to identify an alternative to natural platelets to treat bleeding. Ideally, this alternative should be readily available, have a long shelf life, have storage conditions that are amenable to use in emergency medicine, and perform in an equivalent manner to natural platelets. The creation of artificial platelets to meet these design goals has been an active area of research in recent years, and a new study by Sekhon et al. has demonstrated the creation of plateletmimicking procoagulant nanoparticles (PPNs) that have advanced platelet function compared with prior designs.6 Here, we discuss the implications for these new findings in the field of synthetic platelet design.}, journal={JOURNAL OF THROMBOSIS AND HAEMOSTASIS}, author={Nellenbach, Kimberly and Brown, Ashley C.}, year={2022}, month={Apr} }
 @article{moody_brown_massaro_patel_agarwalla_simpson_brown_zheng_pierce_brudno_2022, title={Restoring Carboxylates on Highly Modified Alginates Improves Gelation, Tissue Retention and Systemic Capture}, volume={138}, ISSN={1742-7061}, url={http://dx.doi.org/10.1016/j.actbio.2021.10.046}, DOI={10.1016/j.actbio.2021.10.046}, abstractNote={Alginate hydrogels are gaining traction for use in drug delivery, regenerative medicine, and as tissue engineered scaffolds due to their physiological gelation conditions, high tissue biocompatibility, and wide chemical versatility. Traditionally, alginate is decorated at the carboxyl group to carry drug payloads, peptides, or proteins. While low degrees of substitution do not cause noticeable mechanical changes, high degrees of substitution can cause significant losses to alginate properties including complete loss of calcium cross-linking. While most modifications used to decorate alginate deplete the carboxyl groups, we propose that alginate modifications that replenish the carboxyl groups could overcome the loss in gel integrity and mechanics. In this report, we demonstrate that restoring carboxyl groups during functionalization maintains calcium cross-links as well as hydrogel shear-thinning and self-healing properties. In addition, we demonstrate that alginate hydrogels modified to a high degree with azide modifications that restore the carboxyl groups have improved tissue retention at intramuscular injection sites and capture blood-circulating cyclooctynes better than alginate hydrogels modified with azide modifications that deplete the carboxyl groups. Taken together, alginate modifications that restore carboxyl groups could significantly improve alginate hydrogel mechanics for clinical applications. STATEMENT OF SIGNIFICANCE: Chemical modification of hydrogels provides a powerful tool to regulate cellular adhesion, immune response, and biocompatibility with local tissues. Alginate, due to its biocompatibility and easy chemical modification, is being explored for tissue engineering and drug delivery. Unfortunately, modifying alginate to a high degree of substitution consumes carboxyl group, which are necessary for ionic gelation, leading to poor hydrogel crosslinking. We introduce alginate modifications that restore the alginate's carboxyl groups. We demonstrate that modifications that reintroduce carboxyl groups restore gelation and improve gel mechanics and tissue retention. In addition to contributing to a basic science understanding of hydrogel properties, we anticipate our approach will be useful to create tissue engineered scaffolds and drug delivery platforms.}, journal={Acta Biomaterialia}, publisher={Elsevier BV}, author={Moody, CT and Brown, AE and Massaro, NP and Patel, AS and Agarwalla, PA and Simpson, AM and Brown, AC and Zheng, H and Pierce, JG and Brudno, Y}, year={2022}, month={Jan}, pages={208–217} }
 @article{nellenbach_kyu_guzzetta_brown_2021, title={Differential sialic acid content in adult and neonatal fibrinogen mediates differences in clot polymerization dynamics}, volume={5}, ISSN={["2473-9537"]}, DOI={10.1182/bloodadvances.2021004417.}, abstractNote={Neonates possess a molecular variant of fibrinogen, known as fetal fibrinogen, characterized by increased sialic acid, a greater negative charge, and decreased activity compared with adults. Despite these differences, adult fibrinogen is used for the treatment of bleeding in neonates, with mixed efficacy. To determine safe and efficacious bleeding protocols for neonates, more information on neonatal fibrin clot formation and the influence of sialic acid on these processes is needed. Here, we examine the influence of sialic acid on neonatal fibrin polymerization. We hypothesized that the increased sialic acid content of neonatal fibrinogen promotes fibrin B:b knob-hole interactions and consequently influences the structure and function of the neonatal fibrin matrix. We explored this hypothesis through analysis of structural properties and knob:hole polymerization dynamics of normal and desialylated neonatal fibrin networks and compared them with those formed with adult fibrinogen. We then characterized normal neonatal fibrin knob:hole interactions by forming neonatal and adult clots with either thrombin or snake-venom thrombin-like enzymes that preferentially cleave fibrinopeptide A or B. Sialic acid content of neonatal fibrinogen was determined to be a key determinant of resulting clot properties. Experiments analyzing knob:hole dynamics indicated that typical neonatal fibrin clots are formed with the release of more fibrinopeptide B and less fibrinopeptide A than adults. After the removal of sialic acid, fibrinopeptide release was roughly equivalent between adults and neonates, indicating the influence of sialic acid on fibrin neonatal fibrin polymerization mechanisms. These results could inform future studies developing neonatal-specific treatments of bleeding.}, number={23}, journal={BLOOD ADVANCES}, author={Nellenbach, Kimberly and Kyu, Alexander and Guzzetta, Nina and Brown, Ashley C.}, year={2021}, month={Dec}, pages={5202–5214} }
 @article{nellenbach_kyu_guzzetta_brown_2021, title={Differential sialic acid content in adult and neonatal fibrinogen mediates differences in clot polymerization dynamics}, volume={5}, ISSN={2473-9529 2473-9537}, url={http://dx.doi.org/10.1182/bloodadvances.2021004417}, DOI={10.1182/bloodadvances.2021004417}, abstractNote={Neonates possess a molecular variant of fibrinogen, known as fetal fibrinogen, characterized by increased sialic acid, a greater negative charge, and decreased activity compared with adults. Despite these differences, adult fibrinogen is used for the treatment of bleeding in neonates, with mixed efficacy. To determine safe and efficacious bleeding protocols for neonates, more information on neonatal fibrin clot formation and the influence of sialic acid on these processes is needed. Here, we examine the influence of sialic acid on neonatal fibrin polymerization. We hypothesized that the increased sialic acid content of neonatal fibrinogen promotes fibrin B:b knob-hole interactions and consequently influences the structure and function of the neonatal fibrin matrix. We explored this hypothesis through analysis of structural properties and knob:hole polymerization dynamics of normal and desialylated neonatal fibrin networks and compared them with those formed with adult fibrinogen. We then characterized normal neonatal fibrin knob:hole interactions by forming neonatal and adult clots with either thrombin or snake-venom thrombin-like enzymes that preferentially cleave fibrinopeptide A or B. Sialic acid content of neonatal fibrinogen was determined to be a key determinant of resulting clot properties. Experiments analyzing knob:hole dynamics indicated that typical neonatal fibrin clots are formed with the release of more fibrinopeptide B and less fibrinopeptide A than adults. After the removal of sialic acid, fibrinopeptide release was roughly equivalent between adults and neonates, indicating the influence of sialic acid on fibrin neonatal fibrin polymerization mechanisms. These results could inform future studies developing neonatal-specific treatments of bleeding.}, number={23}, journal={Blood Advances}, publisher={American Society of Hematology}, author={Nellenbach, Kimberly and Kyu, Alexander and Guzzetta, Nina and Brown, Ashley C.}, year={2021}, month={Dec}, pages={5202–5214} }
 @article{moiseiwitsch_nellenbach_guzzetta_brown_downey_2021, title={Ex Vivo and In Vivo Evaluation of Fibrinogen Concentrate to Mitigate Post-Surgical Bleeding in Neonates}, volume={138}, ISSN={["1528-0020"]}, DOI={10.1182/blood-2021-153823}, abstractNote={Abstract}, journal={BLOOD}, author={Moiseiwitsch, Nina and Nellenbach, Kimberly A. and Guzzetta, Nina A. and Brown, Ashley C. and Downey, Laura}, year={2021}, month={Nov} }
 @article{mihalko_sandry_mininni_nellenbach_deal_daniele_ghadimi_levy_brown_2021, title={Fibrin-modulating nanogels for treatment of disseminated intravascular coagulation}, volume={5}, ISSN={2473-9529 2473-9537}, url={http://dx.doi.org/10.1182/bloodadvances.2020003046}, DOI={10.1182/bloodadvances.2020003046}, abstractNote={Abstract}, number={3}, journal={Blood Advances}, publisher={American Society of Hematology}, author={Mihalko, Emily P. and Sandry, Megan and Mininni, Nicholas and Nellenbach, Kimberly and Deal, Halston and Daniele, Michael and Ghadimi, Kamrouz and Levy, Jerrold H. and Brown, Ashley C.}, year={2021}, month={Jan}, pages={613–627} }
 @article{mihalko_nellenbach_krishnakumar_moiseiwitsch_sollinger_cooley_brown_2021, title={Fibrin‐specific <scp>poly(N‐isopropylacrylamide)</scp> nanogels for targeted delivery of tissue‐type plasminogen activator to treat thrombotic complications are well tolerated in vivo}, volume={7}, ISSN={2380-6761 2380-6761}, url={http://dx.doi.org/10.1002/btm2.10277}, DOI={10.1002/btm2.10277}, abstractNote={Abstract}, number={2}, journal={Bioengineering & Translational Medicine}, publisher={Wiley}, author={Mihalko, Emily P. and Nellenbach, Kimberly and Krishnakumar, Manasi and Moiseiwitsch, Nina and Sollinger, Jennifer and Cooley, Brian C. and Brown, Ashley C.}, year={2021}, month={Dec} }
 @article{pearce_nellenbach_smith_brown_haider_2021, title={Modeling and Parameter Subset Selection for Fibrin Polymerization Kinetics with Applications to Wound Healing}, volume={83}, ISSN={0092-8240 1522-9602}, url={http://dx.doi.org/10.1007/s11538-021-00876-6}, DOI={10.1007/s11538-021-00876-6}, abstractNote={During the hemostatic phase of wound healing, vascular injury leads to endothelial cell damage, initiation of a coagulation cascade involving platelets, and formation of a fibrin-rich clot. As this cascade culminates, activation of the protease thrombin occurs and soluble fibrinogen is converted into an insoluble polymerized fibrin network. Fibrin polymerization is critical for bleeding cessation and subsequent stages of wound healing. We develop a cooperative enzyme kinetics model for in vitro fibrin matrix polymerization capturing dynamic interactions among fibrinogen, thrombin, fibrin, and intermediate complexes. A tailored parameter subset selection technique is also developed to evaluate parameter identifiability for a representative data curve for fibrin accumulation in a short-duration in vitro polymerization experiment. Our approach is based on systematic analysis of eigenvalues and eigenvectors of the classical information matrix for simulations of accumulating fibrin matrix via optimization based on a least squares objective function. Results demonstrate robustness of our approach in that a significant reduction in objective function cost is achieved relative to a more ad hoc curve-fitting procedure. Capabilities of this approach to integrate non-overlapping subsets of the data to enhance the evaluation of parameter identifiability are also demonstrated. Unidentifiable reaction rate parameters are screened to determine whether individual reactions can be eliminated from the overall system while preserving the low objective cost. These findings demonstrate the high degree of information within a single fibrin accumulation curve, and a tailored model and parameter subset selection approach for improving optimization and reducing model complexity in the context of polymerization experiments.}, number={5}, journal={Bulletin of Mathematical Biology}, publisher={Springer Science and Business Media LLC}, author={Pearce, Katherine J. and Nellenbach, Kimberly and Smith, Ralph C. and Brown, Ashley C. and Haider, Mansoor A.}, year={2021}, month={Mar} }
 @article{krissanaprasit_key_froehlich_pontula_mihalko_dupont_andersen_kjems_brown_labean_2021, title={Multivalent Aptamer‐Functionalized Single‐Strand RNA Origami as Effective, Target‐Specific Anticoagulants with Corresponding Reversal Agents}, volume={10}, ISSN={2192-2640 2192-2659}, url={http://dx.doi.org/10.1002/adhm.202001826}, DOI={10.1002/adhm.202001826}, abstractNote={Abstract}, number={11}, journal={Advanced Healthcare Materials}, publisher={Wiley}, author={Krissanaprasit, Abhichart and Key, Carson M. and Froehlich, Kristen and Pontula, Sahil and Mihalko, Emily and Dupont, Daniel M. and Andersen, Ebbe S. and Kjems, Jørgen and Brown, Ashley C. and LaBean, Thomas H.}, year={2021}, month={Apr} }
 @article{moiseiwitsch_brown_2021, title={Neonatal coagulopathies: A review of established and emerging treatments}, volume={246}, ISSN={1535-3702 1535-3699}, url={http://dx.doi.org/10.1177/15353702211006046}, DOI={10.1177/15353702211006046}, abstractNote={ Despite the relative frequency of both bleeding and clotting disorders among patients treated in the neonatal intensive care unit, few clear guidelines exist for treatment of neonatal coagulopathies. The study and treatment of neonatal coagulopathies are complicated by the distinct hemostatic balance and clotting components present during this developmental stage as well as the relative scarcity of studies specific to this age group. This mini-review examines the current understanding of neonatal hemostatic balance and treatment of neonatal coagulopathies, with particular emphasis on emerging treatment methods and areas in need of further investigative efforts. }, number={12}, journal={Experimental Biology and Medicine}, publisher={Frontiers Media SA}, author={Moiseiwitsch, Nina and Brown, Ashley C}, year={2021}, month={Apr}, pages={1447–1457} }
 @article{todd_bharadwaj_nellenbach_nandi_mihalko_copeland_brown_stabenfeldt_2021, title={Platelet‐like</scp> particles reduce <scp>coagulopathy‐related</scp> and neuroinflammatory pathologies <scp>post‐experimental</scp> traumatic brain injury}, volume={109}, ISSN={1552-4973 1552-4981}, url={http://dx.doi.org/10.1002/jbm.b.34888}, DOI={10.1002/jbm.b.34888}, abstractNote={Abstract}, number={12}, journal={Journal of Biomedical Materials Research Part B: Applied Biomaterials}, publisher={Wiley}, author={Todd, Jordan and Bharadwaj, Vimala N. and Nellenbach, Kimberly and Nandi, Seema and Mihalko, Emily and Copeland, Connor and Brown, Ashley C. and Stabenfeldt, Sarah E.}, year={2021}, month={Jun}, pages={2268–2278} }
 @article{roosa_muhamed_young_nellenbach_daniele_ligler_brown_2021, title={Synthesis of sonicated fibrin nanoparticles that modulate fibrin clot polymerization and enhance angiogenic responses}, volume={204}, ISSN={0927-7765}, url={http://dx.doi.org/10.1016/j.colsurfb.2021.111805}, DOI={10.1016/j.colsurfb.2021.111805}, abstractNote={Chronic wounds can occur when the healing process is disrupted and the wound remains in a prolonged inflammatory stage that leads to severe tissue damage and poor healing outcomes. Clinically used treatments, such as high density, FDA-approved fibrin sealants, do not provide an optimal environment for native cell proliferation and subsequent tissue regeneration. Therefore, new treatments outside the confines of these conventional fibrin bulk gel therapies are required. We have previously developed flowable, low-density fibrin nanoparticles that, when coupled to keratinocyte growth factor, promote cell migration and epithelial wound closure in vivo. Here, we report a new high throughput method for generating the fibrin nanoparticles using probe sonication, which is less time intensive than the previously reported microfluidic method, and investigate the ability of the sonicated fibrin nanoparticles (SFBN) to promote clot formation and cell migration in vitro. The SFBNs can form a fibrin gel when combined with fibrinogen in the absence of exogenous thrombin, and the polymerization rate and fiber density in these fibrin clots is tunable based on SFBN concentration. Furthermore, fibrin gels made with SFBNs support cell migration in an in vitro angiogenic sprouting assay, which is relevant for wound healing. In this report, we show that SFBNs may be a promising wound healing therapy that can be easily produced and delivered in a flowable formulation.}, journal={Colloids and Surfaces B: Biointerfaces}, publisher={Elsevier BV}, author={Roosa, Colleen A. and Muhamed, Ismaeel and Young, Ashlyn T. and Nellenbach, Kimberly and Daniele, Michael A. and Ligler, Frances S. and Brown, Ashley C.}, year={2021}, month={Aug}, pages={111805} }
 @article{nandi_mihalko_nellenbach_castaneda_schneible_harp_deal_daniele_menegatti_barker_et al._2021, title={Synthetic Platelet Microgels Containing Fibrin Knob B Mimetic Motifs Enhance Clotting Responses}, volume={4}, ISSN={2366-3987 2366-3987}, url={http://dx.doi.org/10.1002/adtp.202100010}, DOI={10.1002/adtp.202100010}, abstractNote={Abstract}, number={5}, journal={Advanced Therapeutics}, publisher={Wiley}, author={Nandi, Seema and Mihalko, Emily and Nellenbach, Kimberly and Castaneda, Mario and Schneible, John and Harp, Mary and Deal, Halston and Daniele, Michael and Menegatti, Stefano and Barker, Thomas H. and et al.}, year={2021}, month={Mar} }
 @article{chee_brown_2020, title={Biomimetic antimicrobial material strategies for combating antibiotic resistant bacteria}, volume={8}, ISSN={2047-4830 2047-4849}, url={http://dx.doi.org/10.1039/C9BM01393H}, DOI={10.1039/c9bm01393h}, abstractNote={Antibiotic drugs have revolutionized the field of medicine for almost 90 years. However, continued use has led to the rise of antibiotic resistant bacteria. To combat these bacteria, biomimetic material strategies have been investigated.}, number={4}, journal={Biomaterials Science}, publisher={Royal Society of Chemistry (RSC)}, author={Chee, Eunice and Brown, Ashley C.}, year={2020}, pages={1089–1100} }
 @article{nellenbach_nandi_kyu_sivadanam_guzzetta_brown_2020, title={Comparison of Neonatal and Adult Fibrin Clot Properties between Porcine and Human Plasma}, volume={132}, ISSN={0003-3022}, url={http://dx.doi.org/10.1097/ALN.0000000000003165}, DOI={10.1097/ALN.0000000000003165}, abstractNote={Abstract Background Recent studies suggest that adult-specific treatment options for fibrinogen replacement during bleeding may be less effective in neonates. This is likely due to structural and functional differences found in the fibrin network between adults and neonates. In this investigation, the authors performed a comparative laboratory-based study between immature and adult human and porcine plasma samples in order to determine if piglets are an appropriate animal model of neonatal coagulopathy. Methods Adult and neonatal human and porcine plasma samples were collected from the Children’s Hospital of Atlanta and North Carolina State University College of Veterinary Medicine, respectively. Clots were formed for analysis and fibrinogen concentration was quantified. Structure was examined through confocal microscopy and cryogenic scanning electron microscopy. Function was assessed through atomic force microscopy nanoindentation and clotting and fibrinolysis assays. Lastly, novel hemostatic therapies were applied to neonatal porcine samples to simulate treatment. Results All sample groups had similar plasma fibrinogen concentrations. Neonatal porcine and human plasma clots were less branched with lower fiber densities than the dense and highly branched networks seen in adult human and porcine clots. Neonatal porcine and human clots had faster degradation rates and lower clot stiffness values than adult clots (stiffness [mmHg] mean ± SD: neonatal human, 12.15 ± 1.35 mmHg vs. adult human, 32.25 ± 7.13 mmHg; P = 0.016; neonatal pig, 10.5 ± 8.25 mmHg vs. adult pigs, 32.55 ± 7.20 mmHg; P = 0.015). The addition of hemostatic therapies to neonatal porcine samples enhanced clot formation. Conclusions The authors identified similar age-related patterns in structure, mechanical, and degradation properties between adults and neonates in porcine and human samples. These findings suggest that piglets are an appropriate preclinical model of neonatal coagulopathy. The authors also show the feasibility of in vitro model application through analysis of novel hemostatic therapies as applied to dilute neonatal porcine plasma. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New}, number={5}, journal={Anesthesiology}, publisher={Ovid Technologies (Wolters Kluwer Health)}, author={Nellenbach, Kimberly A. and Nandi, Seema and Kyu, Alexander and Sivadanam, Supriya and Guzzetta, Nina A. and Brown, Ashley C.}, year={2020}, month={May}, pages={1091–1101} }
 @article{scull_brown_2020, title={Development of Novel Microenvironments for Promoting Enhanced Wound Healing}, volume={1}, ISSN={2662-4079}, url={http://dx.doi.org/10.1007/s43152-020-00009-6}, DOI={10.1007/s43152-020-00009-6}, abstractNote={Non-healing wounds are a significant issue facing the healthcare industry. Materials that modulate the wound microenvironment have the potential to improve healing outcomes. A variety of acellular and cellular scaffolds have been developed for regulating the wound microenvironment, including materials for controlled release of antimicrobials and growth factors, materials with inherent immunomodulative properties, and novel colloidal-based scaffolds. Scaffold construction methods include electrospinning, 3D printing, decellularization of the extracellular matrix, or a combination of techniques. Material application methods include layering or injecting at the wound site. Though these techniques show promise for repairing wounds, all material strategies thus far struggle to induce regeneration of features such as sweat glands and hair follicles. Nonetheless, innovative technologies currently in the research phase may facilitate future attainment of these features. Novel methods and materials are constantly arising for the development of microenvironments for enhanced wound healing.}, number={3}, journal={Current Tissue Microenvironment Reports}, publisher={Springer Science and Business Media LLC}, author={Scull, Grant and Brown, Ashley C.}, year={2020}, month={Jul}, pages={73–87} }
 @article{erramilli_neumann_chester_dickey_brown_genzer_2020, title={Effect of surface interactions on the settlement of particles on a sinusoidally corrugated substrate}, volume={10}, ISSN={2046-2069}, url={http://dx.doi.org/10.1039/C9RA10297C}, DOI={10.1039/C9RA10297C}, abstractNote={The interplay among the surface modulus, geometry, and interactions between the surface and the particle governs particle settlement on sinusoidally-corrugated substrates.}, number={19}, journal={RSC Advances}, publisher={Royal Society of Chemistry (RSC)}, author={Erramilli, Shreya and Neumann, Taylor V. and Chester, Daniel and Dickey, Michael D. and Brown, Ashley C. and Genzer, Jan}, year={2020}, pages={11348–11356} }
 @article{scull_fisher_brown_2020, title={Fibrin‐based biomaterial systems to enhance anterior cruciate ligament healing}, volume={4}, ISSN={2573-802X 2573-802X}, url={http://dx.doi.org/10.1002/mds3.10147}, DOI={10.1002/mds3.10147}, abstractNote={Abstract Anterior cruciate ligament (ACL) tears are a common and potentially career‐ending injury, particularly for athletes and soldiers. Partial and complete ruptures of this ligament cause instability in the knee, and the ACL does not have the capacity for healing due, in part, to its position within the highly thrombolytic synovial fluid environment of the knee joint. Traditional methods of ACL reconstruction, such as graft replacement, restore stability but do not prevent the development of post‐traumatic osteoarthritis. To enhance therapeutic treatment options, novel fibrin‐based technologies and repair techniques have been recently explored and show promise for improved patient outcomes. Through modification of existing surgical methods, such as the use of fibrin glues incorporating growth factors and cells and the implementation of scaffolds containing platelet‐rich plasma, platelet‐rich fibrin and other blood derivatives, surgeons are attempting to overcome the shortcomings of traditional treatments. This mini‐review will detail current efforts using fibrin‐based treatments and discuss opportunities to further enhance ACL healing.}, number={1}, journal={MEDICAL DEVICES & SENSORS}, publisher={Wiley}, author={Scull, Grant and Fisher, Matthew B. and Brown, Ashley C.}, year={2020}, month={Dec} }
 @article{deal_brown_daniele_2020, title={Microphysiological systems for the modeling of wound healing and evaluation of pro-healing therapies}, volume={8}, ISSN={2050-750X 2050-7518}, url={http://dx.doi.org/10.1039/D0TB00544D}, DOI={10.1039/d0tb00544d}, abstractNote={Wound healing microphysiological systems have been engineered with synthetic and natural materials and techniques such as bioprinting or viscous finger patterning. Model designs focus on particular phases of wound healing or the recapitulation of micro-anatomies.}, number={32}, journal={Journal of Materials Chemistry B}, publisher={Royal Society of Chemistry (RSC)}, author={Deal, Halston E. and Brown, Ashley C. and Daniele, Michael A.}, year={2020}, pages={7062–7075} }
 @article{chee_nandi_nellenbach_mihalko_snider_morrill_bond_sproul_sollinger_cruse_et al._2020, title={Nanosilver composite pNIPAm microgels for the development of antimicrobial platelet‐like particles}, volume={108}, ISSN={1552-4973 1552-4981}, url={http://dx.doi.org/10.1002/jbm.b.34592}, DOI={10.1002/jbm.b.34592}, abstractNote={Abstract}, number={6}, journal={Journal of Biomedical Materials Research Part B: Applied Biomaterials}, publisher={Wiley}, author={Chee, Eunice and Nandi, Seema and Nellenbach, Kimberly and Mihalko, Emily and Snider, Douglas B. and Morrill, Landon and Bond, Andrew and Sproul, Erin and Sollinger, Jennifer and Cruse, Glenn and et al.}, year={2020}, month={Feb}, pages={2599–2609} }
 @article{nellenbach_nandi_peeler_kyu_brown_2020, title={Neonatal Fibrin Scaffolds Promote Enhanced Cell Adhesion, Migration, and Wound Healing In Vivo Compared to Adult Fibrin Scaffolds}, volume={13}, ISBN={1865-5033}, ISSN={1865-5025 1865-5033}, url={http://dx.doi.org/10.1007/s12195-020-00620-5}, DOI={10.1007/s12195-020-00620-5}, abstractNote={Fibrin scaffolds are often utilized to treat chronic wounds. The monomer fibrinogen used to create such scaffolds is typically derived from adult human or porcine plasma. However, our previous studies have identified extensive differences in fibrin network properties between adults and neonates, including higher fiber alignment in neonatal networks. Wound healing outcomes have been linked to fibrin matrix structure, including fiber alignment, which can affect the binding and migration of cells. We hypothesized that fibrin scaffolds derived from neonatal fibrin would enhance wound healing outcomes compared to adult fibrin scaffolds. Fibrin scaffolds were formed from purified adult or neonatal fibrinogen and thrombin then structural analysis was conducted via confocal microscopy. Human neonatal dermal fibroblast attachment, migration, and morphology on fibrin scaffolds were assessed. A murine full thickness injury model was used to compare healing in vivo in the presence of neonatal fibrin, adult fibrin, or saline. Distinct fibrin architectures were observed between adult and neonatal scaffolds. Significantly higher fibroblast attachment and migration was observed on neonatal scaffolds compared to adults. Cell morphology on neonatal scaffolds exhibited higher spreading compared to adult scaffolds. In vivo significantly smaller wound areas and greater epidermal thickness were observed when wounds were treated with neonatal fibrin compared to adult fibrin or a saline control. Distinctions in neonatal and adult fibrin scaffold properties influence cellular behavior and wound healing. These studies indicate that fibrin scaffolds sourced from neonatal plasma could improve healing outcomes compared to scaffolds sourced from adult plasma.}, number={5}, journal={Cellular and Molecular Bioengineering}, publisher={Springer Science and Business Media LLC}, author={Nellenbach, Kimberly and Nandi, Seema and Peeler, Christopher and Kyu, Alexander and Brown, Ashley C.}, year={2020}, month={May}, pages={393–404} }
 @article{nandi_sommerville_nellenbach_mihalko_erb_freytes_hoffman_monroe_brown_2020, title={Platelet-like particles improve fibrin network properties in a hemophilic model of provisional matrix structural defects}, volume={577}, ISSN={0021-9797}, url={http://dx.doi.org/10.1016/j.jcis.2020.05.088}, DOI={10.1016/j.jcis.2020.05.088}, abstractNote={Following injury, a fibrin-rich provisional matrix is formed to stem blood loss and provide a scaffold for infiltrating cells, which rebuild the damaged tissue. Defects in fibrin network formation contribute to impaired healing outcomes, as evidenced in hemophilia. Platelet-fibrin interactions greatly influence fibrin network structure via clot contraction, which increases fibrin density over time. Previously developed hemostatic platelet-like particles (PLPs) are capable of mimicking platelet functions including binding to fibrin fibers, augmenting clotting, and inducing clot retraction. In this study, we aimed to apply PLPs within a plasma-based in vitro hemophilia B model of deficient fibrin network structure to determine the ability of PLPs to improve fibrin structure and wound healing responses within hemophilia-like abnormal fibrin network formation. PLP impact on structurally deficient clot networks was assessed via confocal microscopy, a micropost deflection model, atomic force microscopy and an in vitro wound healing model of early cell migration within a provisional fibrin matrix. PLPs improved clot network density, force generation, and stiffness, and promoted fibroblast migration within an in vitro model of early wound healing under hemophilic conditions, indicating that PLPs could provide a biomimetic platform for improving wound healing events in disease conditions that cause deficient fibrin network formation.}, journal={Journal of Colloid and Interface Science}, publisher={Elsevier BV}, author={Nandi, Seema and Sommerville, Laura and Nellenbach, Kimberly and Mihalko, Emily and Erb, Mary and Freytes, Donald O. and Hoffman, Maureane and Monroe, Dougald and Brown, Ashley C.}, year={2020}, month={Oct}, pages={406–418} }
 @article{chester_theetharappan_ngobili_daniele_brown_2020, title={Ultrasonic Microplotting of Microgel Bioinks}, volume={12}, ISSN={1944-8244 1944-8252}, url={http://dx.doi.org/10.1021/acsami.0c15056}, DOI={10.1021/acsami.0c15056}, abstractNote={Material scaffolds that mimic the structure, function, and bioactivity of native biological tissues are in constant development. Recently, material scaffolds composed of microgel particles have shown promise for applications ranging from bone regeneration to spheroid cell growth. Previous studies with poly N-isopropylacrylamide microgel scaffolds utilized a layer-by-layer (LBL) technique where individual, uniform microgel layers are built on top of each other resulting in a multilayer scaffold. However, this technique is limited in its applications due to the inability to control microscale deposition or patterning of multiple particle types within a microgel layer. In this study, an ultrasonic microplotting technique is used to address the limitations of LBL fabrication to create patterned microgel films. Printing parameters, such as bioink formulation, surface contact angle, and print head diameter, are optimized to identify the ideal parameters needed to successfully print microgel films. It was found that bioinks composed of 2 mg/mL of microgels and 20% polyethylene glycol by volume (v/v), on bovine serum albumin-coated glass, with a print head diameter of 50 μm resulted in the highest quality prints. Patterned films were created with a maximum resolution of 50 μm with the potential for finer resolutions to be achieved with alternative bioink compositions and printing parameters. Overall, ultrasonic microplotting can be used to create more complex microgel films than is possible with LBL techniques and offers the possibility of greater printing resolution in 3D with further technology development.}, number={42}, journal={ACS Applied Materials & Interfaces}, publisher={American Chemical Society (ACS)}, author={Chester, D. and Theetharappan, P. and Ngobili, T. and Daniele, M. and Brown, A. C.}, year={2020}, month={Oct}, pages={47309–47319} }
 @article{nandi_mohanty_nellenbach_erb_muller_brown_2020, title={Ultrasound Enhanced Synthetic Platelet Therapy for Augmented Wound Repair}, volume={6}, ISSN={2373-9878 2373-9878}, url={http://dx.doi.org/10.1021/acsbiomaterials.9b01976}, DOI={10.1021/acsbiomaterials.9b01976}, abstractNote={Native platelets perform a number of functions within the wound healing process, including interacting with fibrin fibers at the wound site to bring about retraction after clot formation. Clot retraction improves clot stability and enhances the function of the fibrin network as a provisional matrix to support cellular infiltration of the wound site, thus facilitating tissue repair and remodeling after hemostasis. In cases of traumatic injury or disease, platelets can become depleted and this process disrupted. To that end, our lab has developed synthetic platelet-like particles (PLPs) that recapitulate the clot retraction abilities of native platelets through a Brownian-wrench driven mechanism that drives fibrin network densification and clot retraction over time, however, this Brownian-motion driven process occurs on a longer time scale than native active actin/myosin-driven platelet-mediated clot retraction. We hypothesized that a combinatorial therapy comprised of ultrasound stimulation of PLP motion within fibrin clots would facilitate a faster induction of clot retraction on a more platelet-mimetic time scale and at a lower dosage than required for PLPs acting alone. We found that application of ultrasound in combination with a subtherapeutic dosage of PLPs resulted in increased clot density and stiffness, improved fibroblast migration in vitro and increased epidermal thickness and angiogenesis in vivo, indicating that this combination therapy has potential to facilitate multiphase pro-healing outcomes. Additionally, while these particular studies focus on the role of ultrasound in enhancing specific interactions between fibrin-binding synthetic PLPs embedded within fibrin networks, these studies have wide applicability in understanding the role of ultrasound stimulation in enhancing multi-scale colloidal interactions within fibrillar matrices.}, number={5}, journal={ACS Biomaterials Science & Engineering}, publisher={American Chemical Society (ACS)}, author={Nandi, Seema and Mohanty, Kaustav and Nellenbach, Kimberly and Erb, Mary and Muller, Marie and Brown, Ashley C.}, year={2020}, month={Apr}, pages={3026–3036} }
 @article{brown_lavik_stabenfeldt_2019, title={Biomimetic Strategies To Treat Traumatic Brain Injury by Leveraging Fibrinogen}, volume={30}, ISSN={1043-1802 1520-4812}, url={http://dx.doi.org/10.1021/acs.bioconjchem.9b00360}, DOI={10.1021/acs.bioconjchem.9b00360}, abstractNote={There were over 27 million new cases of traumatic brain injuries (TBIs) in 2016 across the globe. TBIs are often part of complicated trauma scenarios and may not be diagnosed initially as primary clinical focus is on stabilizing the patient. Interventions used to stabilize trauma patients may inadvertently impact the outcomes of TBIs. Recently, there has been a strong interest in the trauma community towards administrating fibrinogen-containing solutions intravenously to help stabilize trauma patients. While this interventional shift may benefit general trauma scenarios, fibrinogen is associated with potentially deleterious effects for TBIs. Here, we deconstruct what components of fibrinogen may be beneficial as well as, potentially harmful, following TBI and extrapolate this to biomimetic approaches to treat bleeding and trauma that may, also, lead to better outcomes following TBI.}, number={7}, journal={Bioconjugate Chemistry}, publisher={American Chemical Society (ACS)}, author={Brown, Ashley C. and Lavik, Erin and Stabenfeldt, Sarah E.}, year={2019}, month={Jun}, pages={1951–1956} }
 @article{mihalko_brown_2019, title={Clot Structure and Implications for Bleeding and Thrombosis}, volume={46}, ISSN={0094-6176 1098-9064}, url={http://dx.doi.org/10.1055/s-0039-1696944}, DOI={10.1055/s-0039-1696944}, abstractNote={Abstract}, number={01}, journal={Seminars in Thrombosis and Hemostasis}, publisher={Georg Thieme Verlag KG}, author={Mihalko, Emily and Brown, Ashley C.}, year={2019}, month={Oct}, pages={096–104} }
 @article{sproul_nandi_chee_sivadanam_igo_schreck_brown_2019, title={Development of Biomimetic Antimicrobial Platelet-Like Particles Comprised of Microgel Nanogold Composites}, volume={6}, ISSN={2364-4133 2364-4141}, url={http://dx.doi.org/10.1007/s40883-019-00121-6}, DOI={10.1007/s40883-019-00121-6}, abstractNote={A blood clot is formed in response to bleeding by platelet aggregation and adherence to fibrin fibers. Platelets contract over time, stabilizing the clot, which contributes to wound healing. We have developed platelet-like particles (PLPs) that augment clotting and induce clot retraction by mimicking the fibrin-binding capabilities and morphology of native platelets. Wound repair following hemostasis can be complicated by infection; therefore, we aim to augment wound healing by combining PLPs with antimicrobial gold to develop nanogold composites (NGCs). PLPs were synthesized with N-isopropylacrylamide (NIPAm)/co-acrylic acid in a precipitation polymerization reaction and conjugated to a fibrin-specific antibody. Two methods were employed to create NGCs: (1) noncovalent swelling with aqueous gold nanospheres, and (2) covalent seeding and growth. Since the ability of PLPs to mimic platelet morphology and clot retraction requires a high degree of particle deformability, we investigated how PLPs created from NGCs affected these properties. Cryogenic scanning electron microscopy (cryoSEM) and atomic force microscopy (AFM) demonstrated that particle deformability, platelet-mimetic morphology, and clot retraction were maintained in NGC-based PLPs. The effect of NGCs on bacterial adhesion and growth was assessed with antimicrobial assays. These results demonstrate NGCs fabricated through noncovalent and covalent methods retain deformability necessary for clot collapse and exhibit some antimicrobial potential. Therefore, NGCs are promising materials for preventing hemorrhage and infection following trauma. Following injury, a blood clot is formed by platelets aggregating and binding to fibrin fibers. Platelets contract over time, stabilizing the clot, which contributes to wound healing. We have developed PLPs that enhance clotting and stimulate clot retraction by mimicking the fibrin-binding capabilities and morphology of native platelets. Wound repair following hemostasis can be complicated by infection; therefore, we aim to amplify wound healing by combining PLPs with antimicrobial gold to develop NGCs. These NGC PLPs mimic platelet morphology, generate clot retraction, demonstrate some antimicrobial potential, and are promising materials for preventing blood loss and infection following trauma. Future work will include exploring the application of these particles to treat hemorrhage and infection following traumatic injury.}, number={3}, journal={Regenerative Engineering and Translational Medicine}, publisher={Springer Science and Business Media LLC}, author={Sproul, Erin P. and Nandi, Seema and Chee, Eunice and Sivadanam, Supriya and Igo, Benjamin J. and Schreck, Luisa and Brown, Ashley C.}, year={2019}, month={Aug}, pages={299–309} }
 @article{muhamed_sproul_ligler_brown_2019, title={Fibrin Nanoparticles Coupled with Keratinocyte Growth Factor Enhance the Dermal Wound-Healing Rate}, volume={11}, ISSN={1944-8244 1944-8252}, url={http://dx.doi.org/10.1021/acsami.8b21056}, DOI={10.1021/acsami.8b21056}, abstractNote={Expediting the wound-healing process is critical for patients chronically ill from nonhealing wounds and diseases such as hemophilia or diabetes or who have suffered trauma including easily infected open wounds. FDA-approved external tissue sealants include the topical application of fibrin gels, which can be 500 times denser than natural fibrin clots. With lower clot porosity and higher polymerization rates than physiologically formed fibrin clots, the commercial gels quickly stop blood loss but impede the later clot degradation kinetics and thus retard tissue-healing rates. The fibrin nanoparticles (FBNs) described here are constructed from physiologically relevant fibrin concentrations that support new tissue and dermal wound scaffold formation when coupled with growth factors. The FBNs, synthesized in a microfluidic droplet generator, support cell adhesion and traction generation, and when coupled to keratinocyte growth factor (KGF), support cell migration and in vivo wound healing. The FBN-KGF particles enhance cell migration in vitro greater than FBN alone or free KGF and also improve healing outcomes in a murine full thickness injury model compared to saline, bulk fibrin sealant, free KGF, or bulk fibrin mixed with KGF treatments. Furthermore, FBN can be potentially administered with other tissue-healing factors and inflammatory mediators to improve wound-healing outcomes.}, number={4}, journal={ACS Applied Materials & Interfaces}, publisher={American Chemical Society (ACS)}, author={Muhamed, Ismaeel and Sproul, Erin P. and Ligler, Frances S. and Brown, Ashley C.}, year={2019}, month={Jan}, pages={3771–3780} }
 @article{brown_levy_2019, title={Maintaining Hemostatic Balance in Treating Disseminated Intravascular Coagulation}, volume={131}, ISSN={["1528-1175"]}, DOI={10.1097/ALN.0000000000002862}, abstractNote={Disseminated intravascular coagulation (DIC) is a complex coagulopathic state that can present as a thromboinflammatory response to diverse causes that include septic shock, traumatic injury, pregnancy, and cancer. The International Society on Thrombosis and Hemostasis (Carrboro, North Carolina) defines DIC as “an acquired syndrome characterized by the intravascular activation of coagulation with loss of localization arising from different causes that can originate from and cause damage to the microvasculature, which if sufficiently severe, can produce organ dysfunction.” In DIC, endothelial injury and microcirculatory abnormalities produced by hemostatic abnormalities cause multiorgan failure. Of note is that DIC is not a primary disease state, but rather a pathophysiologic response to an underlying disease process, and is based on laboratory diagnosis. The clinical (phenotypic) manifestations can range as a spectrum of either bleeding or thrombotic manifestation due to causes that include the underlying disease process (e.g., cancer-induced DIC), or the time course of diagnosis and therapy. The basis of therapy for DIC is to treat the underlying disease, but also provide temporary support of the coagulation disorder and coagulopathy that depends on whether patients present with bleeding or thrombotic phenotypes. The complexity of managing DIC is to balance both the bleeding and thrombotic complications that occur. In the current edition of the Anesthesiology, Grottke et al. evaluated, in a porcine trauma model, whether prothrombin complex concentrate–induced DIC could be prevented by coadministering antithrombin, a physiologic anticoagulant. They evaluated multiple procoagulant and anticoagulant combinations including tranexamic acid in their multiorgan trauma model that included femur fractures, thoracic contusion, and blunt liver injury. Although prothrombin concentrates reduced bleeding, there were thromboembolic complications (pulmonary emboli) that can occur in clinical DIC. However, when antithrombin was administered in combination with prothrombin concentrate and/or fibrinogen concentrate, DIC did not occur, and there were no early deaths in the fibrinogen concentrate plus prothrombin concentrates plus antithrombin group. Collectively, these studies demonstrate that following experimental animal trauma, administration of prothrombin complex concentrates, either alone or in combination with fibrinogen concentrate, can potentially induce hypercoagulability, but coadministration of antithrombin mitigated this effect. What can we learn from this model of coagulopathy when there are multiple causes of bleeding and thrombosis that have been extensively characterized and have many of the similar characteristics of DIC? European trauma guidelines are increasingly considering prothrombin concentrates as part of a multimodal approach to managing bleeding compared to fresh frozen plasma for rapid factor administration due to their availability without the need for cross-matching. In a bleeding coagulopathic patient, the critical management strategy is to administer products that create a thrombotic milieu; the question is how to balance the risk of thrombotic complications, consumptive coagulopathy, or potentially DIC. 2019 “The complexity of managing DIC [disseminated intravascular coagulation] is to balance both the bleeding and thrombotic complications that occur.”}, number={3}, journal={ANESTHESIOLOGY}, author={Brown, Ashley C. and Levy, Jerrold H.}, year={2019}, month={Sep}, pages={459–461} }
 @article{huebner_warren_chester_spang_brown_fisher_shirwaiker_2019, title={Mechanical properties of tissue formed in vivo are affected by 3D-bioplotted scaffold microarchitecture and correlate with ECM collagen fiber alignment}, volume={61}, ISSN={0300-8207 1607-8438}, url={http://dx.doi.org/10.1080/03008207.2019.1624733}, DOI={10.1080/03008207.2019.1624733}, abstractNote={ABSTRACT Purpose: Musculoskeletal soft tissues possess highly aligned extracellular collagenous networks that provide structure and strength. Such an organization dictates tissue-specific mechanical properties but can be difficult to replicate by engineered biological substitutes. Nanofibrous electrospun scaffolds have demonstrated the ability to control cell-secreted collagen alignment, but concerns exist regarding their scalability for larger and anatomically relevant applications. Additive manufacturing processes, such as melt extrusion-based 3D-Bioplotting, allow fabrication of structurally relevant scaffolds featuring highly controllable porous microarchitectures. Materials and Methods: In this study, we investigate the effects of 3D-bioplotted scaffold design on the compressive elastic modulus of neotissue formed in vivo in a subcutaneous rat model and its correlation with the alignment of ECM collagen fibers. Polycaprolactone scaffolds featuring either 100 or 400 µm interstrand spacing were implanted for 4 or 12 weeks, harvested, cryosectioned, and characterized using atomic-force-microscopy-based force mapping. Results: The compressive elastic modulus of the neotissue formed within the 100 µm design was significantly higher at 4 weeks (p < 0.05), but no differences were observed at 12 weeks. In general, the tissue stiffness was within the same order of magnitude and range of values measured in native musculoskeletal soft tissues including the porcine meniscus and anterior cruciate ligament. Finally, a significant positive correlation was noted between tissue stiffness and the degree of ECM collagen fiber alignment (p < 0.05) resulting from contact guidance provided by scaffold strands. Conclusion: These findings demonstrate the significant effects of 3D-bioplotted scaffold microarchitectures in the organization and sub-tissue-level mechanical properties of ECM in vivo.}, number={2}, journal={Connective Tissue Research}, publisher={Informa UK Limited}, author={Huebner, Pedro and Warren, Paul B. and Chester, Daniel and Spang, Jeffrey T. and Brown, Ashley C. and Fisher, Matthew B. and Shirwaiker, Rohan A.}, year={2019}, month={Jul}, pages={190–204} }
 @article{nandi_sproul_nellenbach_erb_gaffney_freytes_brown_2019, title={Platelet-like particles dynamically stiffen fibrin matrices and improve wound healing outcomes}, volume={7}, ISSN={2047-4830 2047-4849}, url={http://dx.doi.org/10.1039/C8BM01201F}, DOI={10.1039/c8bm01201f}, abstractNote={PLPs increase fibrin stiffness, promote cell migration, and improve healing outcomes.}, number={2}, journal={Biomaterials Science}, publisher={Royal Society of Chemistry (RSC)}, author={Nandi, Seema and Sproul, Erin P. and Nellenbach, Kimberly and Erb, Mary and Gaffney, Lewis and Freytes, Donald O. and Brown, Ashley C.}, year={2019}, pages={669–682} }
 @article{chester_marrow_daniele_brown_2019, title={Wound Healing and the Host Response in Regenerative Engineering}, DOI={10.1016/B978-0-12-801238-3.99896-9}, abstractNote={Wound healing is a complex and highly controlled process responsible for maintaining and reestablishing the homeostatic structure, function, and properties of tissues. This process becomes substantially more complicated upon the introduction of a foreign material. The purpose of this book chapter is to highlight the cellular processes and bioactive agents that encompass the wound healing process and to discuss how these processes change in the presence of a biomaterial. Common biomaterials that are used to direct the wound healing process are also discussed.}, journal={ENCYCLOPEDIA OF BIOMEDICAL ENGINEERING, VOL 1}, author={Chester, Daniel and Marrow, Ethan A. and Daniele, Michael A. and Brown, Ashley C.}, year={2019}, pages={707–718} }
 @article{nellenbach_guzzetta_brown_2018, title={Analysis of the structural and mechanical effects of procoagulant agents on neonatal fibrin networks following cardiopulmonary bypass}, volume={16}, ISSN={1538-7836}, url={http://dx.doi.org/10.1111/jth.14280}, DOI={10.1111/jth.14280}, abstractNote={Essentials The standard of care (SOC) for treating neonatal bleeding is transfusion of adult blood products. We compared neonatal clots formed with cryoprecipitate (SOC) to two procoagulant therapies. The current SOC resulted in clots with increased stiffness and decreased fibrinolytic properties. Procoagulant therapies may be a viable alternative to SOC treatment for neonatal bleeding.}, number={11}, journal={Journal of Thrombosis and Haemostasis}, publisher={Elsevier BV}, author={Nellenbach, K. and Guzzetta, N.A. and Brown, A.C.}, year={2018}, month={Nov}, pages={2159–2167} }
 @article{sproul_nandi_roosa_schreck_brown_2018, title={Biomimetic Microgels with Controllable Deformability Improve Healing Outcomes}, volume={2}, ISSN={2366-7478 2366-7478}, url={http://dx.doi.org/10.1002/adbi.201800042}, DOI={10.1002/adbi.201800042}, abstractNote={Abstract}, number={10}, journal={Advanced Biosystems}, publisher={Wiley}, author={Sproul, Erin P. and Nandi, Seema and Roosa, Colleen and Schreck, Luisa and Brown, Ashley C.}, year={2018}, month={Aug} }
 @article{welsch_brown_barker_lyon_2018, title={Enhancing clot properties through fibrin-specific self-cross-linked PEG side-chain microgels}, volume={166}, ISSN={["1873-4367"]}, DOI={10.1016/j.colsurfb.2018.03.003}, abstractNote={Excessive bleeding and resulting complications are a major cause of death in both trauma and surgical settings. Recently, there have been a number of investigations into the design of synthetic hemostatic agents with platelet-mimicking activity to effectively treat patients suffering from severe hemorrhage. We developed platelet-like particles from microgels composed of polymers carrying polyethylene glycol (PEG) side-chains and fibrin-targeting single domain variable fragment antibodies (PEG-PLPs). Comparable to natural platelets, PEG-PLPs were found to enhance the fibrin network formation in vitro through strong adhesion to the emerging fibrin clot and physical, non-covalent cross-linking of nascent fibrin fibers. Furthermore, the mechanical reinforcement of the fibrin mesh through the incorporation of particles into the network leads to a ∼three-fold decrease of the overall clot permeability as compared to control clots. However, transport of biomolecules through the fibrin clots, such as peptides and larger proteins is not hindered by the presence of PEG-PLPs and the altered microstructure. Compared to control clots with an elastic modulus of 460+/−260 Pa, PEG-PLP-reinforced fibrin clots exhibit higher degrees of stiffness as demonstrated by the significantly increased average Younǵs modulus of 1770 +/±720 Pa, as measured by AFM force spectroscopy. Furthermore, in vitro degradation studies with plasmin demonstrate that fibrin clots formed in presence of PEG-PLPs withstand hydrolysis for 24 h, indicating enhanced stabilization against exogenous fibrinolysis. The entire set of data suggests that the designed platelet-like particles have high potential for use as hemostatic agents in emergency medicine and surgical settings.}, journal={COLLOIDS AND SURFACES B-BIOINTERFACES}, author={Welsch, Nicole and Brown, Ashley C. and Barker, Thomas H. and Lyon, L. Andrew}, year={2018}, month={Jun}, pages={89–97} }
 @article{sproul_nandi_brown_2018, title={Fibrin biomaterials for tissue regeneration and repair}, ISBN={["978-0-08-100803-4"]}, ISSN={["2049-9485"]}, DOI={10.1016/b978-0-08-100803-4.00006-1}, abstractNote={Fibrin is an integral part of the clotting cascade and is formed by polymerization of the soluble plasma protein fibrinogen. Following the stimulation of the coagulation cascade, thrombin activates fibrinogen, which binds to adjacent fibrin(ogen) molecules resulting in the formation of an insoluble fibrin matrix. This fibrin network is the primary protein component in clots and subsequently provides a scaffold for infiltrating cells during tissue repair. Due to its role in hemostasis and tissue repair, fibrin has been used extensively as a tissue sealant. This chapter first provides an overview of the structure and function of fibrin(ogen) and details the role of fibrin-cell interactions in wound repair. The design and use of fibrin-based materials for promoting tissue repair is also discussed.}, journal={PEPTIDES AND PROTEINS AS BIOMATERIALS FOR TISSUE REGENERATION AND REPAIR}, author={Sproul, E. and Nandi, S. and Brown, A.}, year={2018}, pages={151–173} }
 @article{hardy_wang_iyer_mannino_sakurai_barker_chi_youn_wang_brown_et al._2018, title={Interdigitated microelectronic bandage augments hemostasis and clot formation at low applied voltage in vitro and in vivo}, volume={18}, ISSN={1473-0197 1473-0189}, url={http://dx.doi.org/10.1039/c8lc00573g}, DOI={10.1039/c8lc00573g}, abstractNote={An interdigitated microelectronic device that applies low voltage (<9 V) electrical field augments hemostasisin vitroandin vivo.}, number={19}, journal={Lab on a Chip}, publisher={Royal Society of Chemistry (RSC)}, author={Hardy, Elaissa T. and Wang, Yannan J. and Iyer, Sanathan and Mannino, Robert G. and Sakurai, Yumiko and Barker, Thomas H. and Chi, Taiyun and Youn, Yeojoon and Wang, Hua and Brown, Ashley C. and et al.}, year={2018}, pages={2985–2993} }
 @article{joshi_nandi_chester_brown_muller_2018, title={Study of Poly(<i>N</i>-isopropylacrylamide-<i>co</i>-acrylic acid) (pNIPAM) Microgel Particle Induced Deformations of Tissue-Mimicking Phantom by Ultrasound Stimulation}, volume={34}, ISSN={0743-7463 1520-5827}, url={http://dx.doi.org/10.1021/acs.langmuir.7b02801}, DOI={10.1021/acs.langmuir.7b02801}, abstractNote={Poly(N-isopropylacrylamide) (pNIPAm) microgels (microgels) are colloidal particles that have been used extensively for biomedical applications. Typically, these particles are synthesized in the presence of an exogenous cross-linker, such as N,N'-methylenebis(acrylamide) (BIS); however, recent studies have demonstrated that pNIPAm microgels can be synthesized in the absence of an exogenous cross-linker, resulting in the formation of ultralow cross-linked (ULC) particles, which are highly deformable. Microgel deformability has been linked in certain cases to enhanced bioactivity when ULC microgels are used for the creation of biomimetic particles. We hypothesized that ultrasound stimulation of microgels would enhance particle deformation and that the degree of enhancement would negatively correlate with the degree of particle cross-linking. Here, we demonstrate in tissue-mimicking phantoms that using ultrasound insonification causes deformations of ULC microgel particles. Furthermore, the amount of deformation depends on the ultrasound excitation frequency and amplitude and on the concentration of ULC microgel particles. We observed that the amplitude of deformation increases with increasing ULC microgel particle concentration up to 2.5 mg/100 mL, but concentrations higher than 2.5 mg/100 mL result in reduced amount of deformation. In addition, we observed that the amplitude of deformation was significantly higher at 1 MHz insonification frequency. We also report that increasing the degree of microgel cross-linking reduces the magnitude of the deformation and increases the optimal concentration required to achieve the largest amount of deformation. Stimulated ULC microgel particle deformation has numerous potential biomedical applications, including enhancement of localized drug delivery and biomimetic activity. These results demonstrate the potential of ultrasound stimulation for such applications.}, number={4}, journal={Langmuir}, publisher={American Chemical Society (ACS)}, author={Joshi, Aditya and Nandi, Seema and Chester, Daniel and Brown, Ashley C. and Muller, Marie}, year={2018}, month={Jan}, pages={1457–1465} }
 @article{mihalko_huang_sproul_cheng_brown_2018, title={Targeted Treatment of Ischemic and Fibrotic Complications of Myocardial Infarction Using a Dual-Delivery Microgel Therapeutic}, volume={12}, ISSN={1936-0851 1936-086X}, url={http://dx.doi.org/10.1021/ACSNANO.8B01977}, DOI={10.1021/ACSNANO.8B01977}, abstractNote={Myocardial infarction (MI), commonly known as a heart attack, affects millions of people worldwide and results in significant death and disabilities. A major cause of MI is fibrin-rich thrombus formation that occludes the coronary arteries, blocking blood flow to the heart and causing fibrin deposition. In treating MI, re-establishing blood flow is critical. However, ischemia reperfusion (I/R) injury itself can also occur and contributes to cardiac fibrosis. Fibrin-specific poly( N-isopropylacrylamide) nanogels (FSNs) comprised of a core-shell colloidal hydrogel architecture are utilized in this study to design a dual-delivery system that simultaneously addresses the need to (1) re-establish blood flow and (2) inhibit cardiac fibrosis following I/R injury. These therapeutic needs are met by controlling the release of a fibrinolytic protein, tissue plasminogen activator (tPA), and a small molecule cell contractility inhibitor (Y-27632). In vitro, tPA and Y-27632-loaded FSNs rapidly degrade fibrin and decrease cardiac cell stress fiber formation and connective tissue growth factor expression, which are both upregulated in cardiac fibrosis. In vivo, FSNs localize to fibrin in injured heart tissue and, when loaded with tPA and Y-27632, showed significant improvement in left ventricular ejection fraction 2 and 4 weeks post-I/R as well as significantly decreased infarct size, α-smooth muscle actin expression, and connective tissue growth factor expression 4 weeks post-I/R. Together, these data demonstrate the feasibility of this targeted therapeutic strategy to improve cardiac function following MI.}, number={8}, journal={ACS Nano}, publisher={American Chemical Society (ACS)}, author={Mihalko, Emily and Huang, Ke and Sproul, Erin and Cheng, Ke and Brown, Ashley C.}, year={2018}, month={Jul}, pages={7826–7837} }
 @article{tang_su_huang_dinh_wang_vandergriff_hensley_cores_allen_li_et al._2018, title={Targeted repair of heart injury by stem cells fused with platelet nanovesicles}, volume={2}, ISSN={2157-846X}, url={http://dx.doi.org/10.1038/s41551-017-0182-x}, DOI={10.1038/s41551-017-0182-x}, abstractNote={Stem cell transplantation, as used clinically, suffers from low retention and engraftment of the transplanted cells. Inspired by the ability of platelets to recruit stem cells to sites of injury on blood vessels, we hypothesized that platelets might enhance the vascular delivery of cardiac stem cells (CSCs) to sites of myocardial infarction injury. Here, we show that CSCs with platelet nanovesicles fused onto their surface membranes express platelet surface markers that are associated with platelet adhesion to injury sites. We also find that the modified CSCs selectively bind collagen-coated surfaces and endothelium-denuded rat aortas, and that in rat and porcine models of acute myocardial infarction the modified CSCs increase retention in the heart and reduce infarct size. Platelet-nanovesicle-fused CSCs thus possess the natural targeting and repairing ability of their parental cell types. This stem cell manipulation approach is fast, straightforward and safe, does not require genetic alteration of the cells, and should be generalizable to multiple cell types. The attachment of platelet nanovesicles to the surface of cardiac stem cells increases the retention of the cells delivered to the heart and reduces infarct size in rat and pig models of acute myocardial infarction.}, number={1}, journal={Nature Biomedical Engineering}, publisher={Springer Science and Business Media LLC}, author={Tang, Junnan and Su, Teng and Huang, Ke and Dinh, Phuong-Uyen and Wang, Zegen and Vandergriff, Adam and Hensley, Michael T. and Cores, Jhon and Allen, Tyler and Li, Taosheng and et al.}, year={2018}, month={Jan}, pages={17–26} }
 @article{chester_kathard_nortey_nellenbach_brown_2018, title={Viscoelastic properties of microgel thin films control fibroblast modes of migration and pro-fibrotic responses}, volume={185}, ISSN={0142-9612}, url={http://dx.doi.org/10.1016/j.biomaterials.2018.09.012}, DOI={10.1016/j.biomaterials.2018.09.012}, abstractNote={Cell behavior is influenced by the biophysical properties of their microenvironments, and the linear elastic properties of substrates strongly influences adhesion, migration, and differentiation responses. Because most biological tissues exhibit non-linear elastic properties, there is a growing interest in understanding how the viscous component of materials and tissues influences cell fate. Here we describe the use of microgel thin films with controllable non-linear elastic properties for investigating the role of material loss tangent on cell adhesion, migration, and myofibroblastic differentiation, which have implications in fibrotic responses. Fibroblast modes of migration are dictated by film loss tangent; high loss tangent induced ROCK-mediated amoeboid migration while low loss tangent induced Rac-mediated mesenchymal cell migration. Low loss tangent films were also associated with higher levels of myofibroblastic differentiation. These findings have implications in fibrosis and indicate that slight changes in tissue viscoelasticity following injury could contribute to early initiation of fibrotic related responses.}, journal={Biomaterials}, publisher={Elsevier BV}, author={Chester, Daniel and Kathard, Rahul and Nortey, Jeremy and Nellenbach, Kimberly and Brown, Ashley C.}, year={2018}, month={Dec}, pages={371–382} }
 @article{nandi_brown_2017, title={Characterizing Cell Migration Within Three-dimensional <em>In Vitro</em> Wound Environments}, volume={8}, ISSN={1940-087X}, url={http://dx.doi.org/10.3791/56099}, DOI={10.3791/56099}, abstractNote={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.}, number={126}, journal={Journal of Visualized Experiments}, publisher={MyJove Corporation}, author={Nandi, Seema and Brown, Ashley C.}, year={2017}, month={Aug} }
 @article{cao_nicosia_larouche_zhang_bachman_brown_holmgren_barker_2017, title={Detection of an Integrin-Binding Mechanoswitch within Fibronectin during Tissue Formation and Fibrosis}, volume={11}, ISSN={1936-0851 1936-086X}, url={http://dx.doi.org/10.1021/acsnano.7b02755}, DOI={10.1021/acsnano.7b02755}, abstractNote={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.}, number={7}, journal={ACS Nano}, publisher={American Chemical Society (ACS)}, author={Cao, Lizhi and Nicosia, John and Larouche, Jacqueline and Zhang, Yuanyuan and Bachman, Haylee and Brown, Ashley C. and Holmgren, Lars and Barker, Thomas H.}, year={2017}, month={Jul}, pages={7110–7117} }
 @article{mihalko_brown_2017, title={Material Strategies for Modulating Epithelial to Mesenchymal Transitions}, volume={4}, ISSN={2373-9878 2373-9878}, url={http://dx.doi.org/10.1021/acsbiomaterials.6b00751}, DOI={10.1021/acsbiomaterials.6b00751}, abstractNote={Epithelial to mesenchymal transitions (EMT) involve the phenotypic change of epithelial cells into fibroblast-like cells. This process is accompanied by the loss of cell-cell contacts, increased extracellular matrix (ECM) production, stress fiber alignment, and an increase in cell mobility. While essential for development and wound repair, EMT has also been recognized as a contributing factor to fibrotic diseases and cancer. Both chemical and mechanical cues, such as tumor necrosis factor alpha, NF-κB, Wnt, Notch, interleukin-8, metalloproteinase-3, ECM proteins, and ECM stiffness can determine the degree and duration of EMT events. Additionally, transforming growth factor beta is a primary driver of EMT and, interestingly, can be activated through cell-mediated mechanoactivation. In this review, we highlight recent findings demonstrating the contribution of mechanical stimuli, such as tissue and material stiffness, in driving EMT. We then highlight material strategies for controlling EMT events. Finally, we discuss drivers of the similar process of endothelial to mesenchymal transition (EndoMT) and corresponding material strategies for controlling EndoMT.}, number={4}, journal={ACS Biomaterials Science & Engineering}, publisher={American Chemical Society (ACS)}, author={Mihalko, Emily P. and Brown, Ashley C.}, year={2017}, month={Apr}, pages={1149–1161} }
 @article{nellenbach_brown_2017, title={Peptide Mimetic Drugs for Modulating Thrombosis and Hemostasis}, volume={78}, ISSN={0272-4391 1098-2299}, url={http://dx.doi.org/10.1002/ddr.21407}, DOI={10.1002/ddr.21407}, abstractNote={ABSTRACT}, number={6}, journal={Drug Development Research}, publisher={Wiley}, author={Nellenbach, Kimberly and Brown, Ashley C.}, year={2017}, month={Aug}, pages={236–244} }
 @article{chester_brown_2017, title={The role of biophysical properties of provisional matrix proteins in wound repair}, volume={60-61}, ISSN={0945-053X}, url={http://dx.doi.org/10.1016/j.matbio.2016.08.004}, DOI={10.1016/j.matbio.2016.08.004}, abstractNote={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.}, journal={Matrix Biology}, publisher={Elsevier BV}, author={Chester, Daniel and Brown, Ashley C.}, year={2017}, month={Jul}, pages={124–140} }
 @article{brown_hannan_timmins_fernandez_barker_guzzetta_2016, title={Fibrin Network Changes in Neonates after Cardiopulmonary Bypass}, volume={124}, ISSN={0003-3022}, url={http://dx.doi.org/10.1097/ALN.0000000000001058}, DOI={10.1097/aln.0000000000001058}, abstractNote={Abstract}, number={5}, journal={Anesthesiology}, publisher={Ovid Technologies (Wolters Kluwer Health)}, author={Brown, Ashley C. and Hannan, Riley H. and Timmins, Lucas H. and Fernandez, Janet D. and Barker, Thomas H. and Guzzetta, Nina A.}, year={2016}, month={May}, pages={1021–1031} }
 @article{nandi_brown_2016, title={Platelet-mimetic strategies for modulating the wound environment and inflammatory responses}, volume={241}, ISSN={1535-3702 1535-3699}, url={http://dx.doi.org/10.1177/1535370216647126}, DOI={10.1177/1535370216647126}, abstractNote={ Platelets closely interface with the immune system to fight pathogens, target wound sites, and regulate tissue repair. Natural platelet levels within the body can be depleted for a variety of reasons, including excessive bleeding following traumatic injury, or diseases such as cancer and bacterial or viral infections. Platelet transfusions are commonly used to improve platelet count and hemostatic function in these cases, but transfusions can be complicated by the contamination risks and short storage life of donated platelets. Lyophilized platelets that can be freeze-dried and stored for longer periods of time and synthetic platelet-mimetic technologies that can enhance or replace the functions of natural platelets, while minimizing adverse immune responses have been explored as alternatives to transfusion. Synthetic platelets typically comprise nanoparticles surface-decorated with peptides or ligands to recreate specific biological characteristics of platelets, including targeting of wound and disease sites and facilitating platelet aggregation. Recent efforts in synthetic platelet design have additionally focused on matching platelet shape and mechanics to recreate the marginalization and clot contraction capabilities of natural platelets. The ability to specifically tune the properties of synthetic platelet-mimetic materials has shown utility in a variety of applications including hemostasis, drug delivery, and targeted delivery of cancer therapeutics. }, number={10}, journal={Experimental Biology and Medicine}, publisher={Frontiers Media SA}, author={Nandi, Seema and Brown, Ashley C}, year={2016}, month={May}, pages={1138–1148} }
 @article{myers_qiu_fay_tennenbaum_chester_cuadrado_sakurai_baek_tran_ciciliano_et al._2016, title={Single-platelet nanomechanics measured by high-throughput cytometry}, volume={16}, ISSN={1476-1122 1476-4660}, url={http://dx.doi.org/10.1038/nmat4772}, DOI={10.1038/nmat4772}, abstractNote={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.}, number={2}, journal={Nature Materials}, publisher={Springer Science and Business Media LLC}, author={Myers, David R. and Qiu, Yongzhi and Fay, Meredith E. and Tennenbaum, Michael and Chester, Daniel and Cuadrado, Jonas and Sakurai, Yumiko and Baek, Jong and Tran, Reginald and Ciciliano, Jordan C. and et al.}, year={2016}, month={Oct}, pages={230–235} }
 @article{karumbaiah_enam_brown_saxena_betancur_barker_bellamkonda_2015, title={Chondroitin Sulfate Glycosaminoglycan Hydrogels Create Endogenous Niches for Neural Stem Cells}, volume={26}, ISSN={["1043-1802"]}, DOI={10.1021/acs.bioconjchem.5b00397}, abstractNote={Neural stem cells (NSCs) possess great potential for neural tissue repair after traumatic injuries to the central nervous system (CNS). However, poor survival and self-renewal of NSCs after injury severely limits its therapeutic potential. Sulfated chondroitin sulfate glycosaminoglycans (CS-GAGs) linked to CS proteoglycans (CSPGs) in the brain extracellular matrix (ECM) have the ability to bind and potentiate trophic factor efficacy, and promote NSC self-renewal in vivo. In this study, we investigated the potential of CS-GAG hydrogels composed of monosulfated CS-4 (CS-A), CS-6 (CS-C), and disulfated CS-4,6 (CS-E) CS-GAGs as NSC carriers, and their ability to create endogenous niches by enriching specific trophic factors to support NSC self-renewal. We demonstrate that CS-GAG hydrogel scaffolds showed minimal swelling and degradation over a period of 15 days in vitro, absorbing only 6.5 ± 0.019% of their initial weight, and showing no significant loss of mass during this period. Trophic factors FGF-2, BDNF, and IL10 bound with high affinity to CS-GAGs, and were significantly (p < 0.05) enriched in CS-GAG hydrogels when compared to unsulfated hyaluronic acid (HA) hydrogels. Dissociated rat subventricular zone (SVZ) NSCs when encapsulated in CS-GAG hydrogels demonstrated ∼88.5 ± 6.1% cell viability in vitro. Finally, rat neurospheres in CS-GAG hydrogels conditioned with the mitogen FGF-2 demonstrated significantly (p < 0.05) higher self-renewal when compared to neurospheres cultured in unconditioned hydrogels. Taken together, these findings demonstrate the ability of CS-GAG based hydrogels to regulate NSC self-renewal, and facilitate growth factor enrichment locally.}, number={12}, journal={BIOCONJUGATE CHEMISTRY}, author={Karumbaiah, Lohitash and Enam, Syed Faaiz and Brown, Ashley C. and Saxena, Tarun and Betancur, Martha I. and Barker, Thomas H. and Bellamkonda, Ravi V.}, year={2015}, month={Dec}, pages={2336–2349} }
 @article{brown_dysart_clarke_stabenfeldt_barker_2015, title={Integrin α3β1 Binding to Fibronectin Is Dependent on the Ninth Type III Repeat}, volume={290}, ISSN={0021-9258}, url={http://dx.doi.org/10.1074/jbc.M115.656702}, DOI={10.1074/jbc.m115.656702}, abstractNote={Background: The fibronectin (Fn) ninth type III repeat can modulate integrin binding and resulting cell spreading. Results: Mutations within the Fn integrin binding domains affect integrin α3β1 binding. Conclusion: Integrin α3β1-fibronectin binding depends on the presence and spacing of the RGD and synergy sites within Fn. Significance: α3β1-fibronectin binding may modulate epithelial cell wound healing responses. Fibronectin (Fn) is a promiscuous ligand for numerous cell adhesion receptors or integrins. The vast majority of Fn-integrin interactions are mediated through the Fn Arg-Gly-Asp (RGD) motif located within the tenth type III repeat. In the case of integrins αIIbβ3 and α5β1, the integrin binds RGD and the synergy site (PHSRN) located within the adjacent ninth type III repeat. Prior work has shown that these synergy-dependent integrins are exquisitely sensitive to perturbations in the Fn integrin binding domain conformation. Our own prior studies of epithelial cell responses to recombinant fragments of the Fn integrin binding domain led us to hypothesize that integrin α3β1 binding may also be modulated by the synergy site. To explore this hypothesis, we created a variety of recombinant variants of the Fn integrin binding domain: (i) a previously reported (Leu → Pro) stabilizing mutant (FnIII9′10), (ii) an Arg to Ala synergy site mutation (FnIII9R→A10), (iii) a two-Gly (FnIII92G10) insertion, and (iv) a four-Gly (FNIII94G10) insertion in the interdomain linker region and used surface plasmon resonance to determine binding kinetics of integrin α3β1 to the Fn fragments. Integrin α3β1 had the highest affinity for FnIII9′10 and FnIII92G10. Mutation within the synergy site decreased integrin α3β1 binding 17-fold, and the four-Gly insertion decreased binding 39-fold compared with FnIII9′10. Cell attachment studies demonstrate that α3β1-mediated epithelial cell binding is greater on FnIII9′10 compared with the other fragments. These studies suggest that the presence and spacing of the RGD and synergy sites modulate integrin α3β1 binding to Fn.}, number={42}, journal={Journal of Biological Chemistry}, publisher={Elsevier BV}, author={Brown, Ashley C. and Dysart, Marilyn M. and Clarke, Kimberly C. and Stabenfeldt, Sarah E. and Barker, Thomas H.}, year={2015}, month={Oct}, pages={25534–25547} }
 @article{brown_baker_douglas_keating_alvarez-elizondo_botvinick_guthold_barker_2015, title={Molecular interference of fibrin's divalent polymerization mechanism enables modulation of multiscale material properties}, volume={49}, ISSN={0142-9612}, url={http://dx.doi.org/10.1016/J.BIOMATERIALS.2015.01.010}, DOI={10.1016/J.BIOMATERIALS.2015.01.010}, abstractNote={Protein based polymers provide an exciting and complex landscape for tunable natural biomaterials through modulation of molecular level interactions. Here we demonstrate the ability to modify protein polymer structural and mechanical properties at multiple length scales by molecular 'interference' of fibrin's native polymerization mechanism. We have previously reported that engagement of fibrin's polymerization 'hole b', also known as 'b-pockets', through PEGylated complementary 'knob B' mimics can increase fibrin network porosity but also, somewhat paradoxically, increase network stiffness. Here, we explore the possible mechanistic underpinning of this phenomenon through characterization of the effects of knob B-fibrin interaction at multiple length scales from molecular to bulk polymer. Despite its weak monovalent binding affinity for fibrin, addition of both knob B and PEGylated knob B at concentrations near the binding coefficient, Kd, increased fibrin network porosity, consistent with the reported role of knob B-hole b interactions in promoting lateral growth of fibrin fibers. Addition of PEGylated knob B decreases the extensibility of single fibrin fibers at concentrations near its Kd but increases extensibility of fibers at concentrations above its Kd. The data suggest this bimodal behavior is due to the individual contributions knob B, which decreases fiber extensibility, and PEG, which increase fiber extensibility. Taken together with laser trap-based microrheological and bulk rheological analyses of fibrin polymers, our data strongly suggests that hole b engagement increases in single fiber stiffness that translates to higher storage moduli of fibrin polymers despite their increased porosity. These data point to possible strategies for tuning fibrin polymer mechanical properties through modulation of single fiber mechanics.}, journal={Biomaterials}, publisher={Elsevier BV}, author={Brown, Ashley C. and Baker, Stephen R. and Douglas, Alison M. and Keating, Mark and Alvarez-Elizondo, Martha B. and Botvinick, Elliot L. and Guthold, Martin and Barker, Thomas H.}, year={2015}, month={May}, pages={27–36} }
 @article{bachman_brown_clarke_dhada_douglas_hansen_herman_hyatt_kodlekere_meng_et al._2015, title={Ultrasoft, highly deformable microgels}, volume={11}, ISSN={1744-683X 1744-6848}, url={http://dx.doi.org/10.1039/C5SM00047E}, DOI={10.1039/C5SM00047E}, abstractNote={PNIPAm microgels formed under crosslinker free conditions are soft and highly deformable.}, number={10}, journal={Soft Matter}, publisher={Royal Society of Chemistry (RSC)}, author={Bachman, Haylee and Brown, Ashley C. and Clarke, Kimberly C. and Dhada, Kabir S. and Douglas, Alison and Hansen, Caroline E. and Herman, Emily and Hyatt, John S. and Kodlekere, Purva and Meng, Zhiyong and et al.}, year={2015}, pages={2018–2028} }
 @article{kim_park_brown_lyon_2014, title={Direct observation of ligand-induced receptor dimerization with a bioresponsive hydrogel}, volume={4}, ISSN={2046-2069}, url={http://dx.doi.org/10.1039/C4RA13251C}, DOI={10.1039/C4RA13251C}, abstractNote={Microgel assay for real-time measurement of protein multimerization, assembly, and disassembly identifies physiologically important dimerization pathway.}, number={110}, journal={RSC Advances}, publisher={Royal Society of Chemistry (RSC)}, author={Kim, Jongseong and Park, Yongdoo and Brown, Ashley C. and Lyon, L. Andrew}, year={2014}, pages={65173–65175} }
 @article{baker_carson-brown_guthold_barker_2014, title={Fibrin Fibers: Blocking the B:B Knob-Pocket Interaction}, volume={106}, ISSN={0006-3495}, url={http://dx.doi.org/10.1016/J.BPJ.2013.11.3399}, DOI={10.1016/J.BPJ.2013.11.3399}, abstractNote={Fibrin clot formation has been studied to determine the mechanical properties of fibrin fibers modified by blocking the B-b knob-pocket interaction. Synthetic B-knob peptides AHRPYAAC or AHRPYAAC-Peg have been added to a fibrinogen solution to allow for binding to the b-pockets prior to clot formation. After fibrin clot formation, a combined atomic force microscopic (AFM)/optical microscopic technique was used to study the properties of individual fibrin fibers in buffer. Mechanical testing of fibers was done using the AFM to laterally stretch individual fibers suspended over 13.5μm wide groves in a transparent substrate. The optical microscope, located below the sample, was used to monitor the stretching process. We found that the density and lateral aggregation of fibers was hindered by blocking the b-pockets with the synthetic B-knobs.}, number={2}, journal={Biophysical Journal}, publisher={Elsevier BV}, author={Baker, Stephen and Carson-Brown, Ashley and Guthold, Martin and Barker, Thomas}, year={2014}, month={Jan}, pages={614a} }
 @article{brown_barker_2014, title={Fibrin-based biomaterials: Modulation of macroscopic properties through rational design at the molecular level}, volume={10}, ISSN={1742-7061}, url={http://dx.doi.org/10.1016/J.ACTBIO.2013.09.008}, DOI={10.1016/J.ACTBIO.2013.09.008}, abstractNote={Fibrinogen is one of the primary components of the coagulation cascade and rapidly forms an insoluble matrix following tissue injury. In addition to its important role in hemostasis, fibrin acts as a scaffold for tissue repair and provides important cues for directing cell phenotype following injury. Because of these properties and the ease of polymerization of the material, fibrin has been widely utilized as a biomaterial for over a century. Modifying the macroscopic properties of fibrin, such as elasticity and porosity, has been somewhat elusive until recently, yet with a molecular-level rational design approach it can now be somewhat easily modified through alterations of molecular interactions key to the protein's polymerization process. This review outlines the biochemistry of fibrin and discusses methods for modification of molecular interactions and their application to fibrin based biomaterials.}, number={4}, journal={Acta Biomaterialia}, publisher={Elsevier BV}, author={Brown, Ashley C. and Barker, Thomas H.}, year={2014}, month={Apr}, pages={1502–1514} }
 @article{bryksin_brown_baksh_finn_barker_2014, title={Learning from nature – Novel synthetic biology approaches for biomaterial design}, volume={10}, ISSN={1742-7061}, url={http://dx.doi.org/10.1016/J.ACTBIO.2014.01.019}, DOI={10.1016/J.ACTBIO.2014.01.019}, abstractNote={Many biomaterials constructed today are complex chemical structures that incorporate biologically active components derived from nature, but the field can still be said to be in its infancy. The need for materials that bring sophisticated properties of structure, dynamics and function to medical and non-medical applications will only grow. Increasing appreciation of the functionality of biological systems has caused biomaterials researchers to consider nature for design inspiration, and many examples exist of the use of biomolecular motifs. Yet evolution, nature's only engine for the creation of new designs, has been largely ignored by the biomaterials community. Molecular evolution is an emerging tool that enables one to apply nature's engineering principles to non-natural situations using variation and selection. The purpose of this review is to highlight the most recent advances in the use of molecular evolution in synthetic biology applications for biomaterial engineering, and to discuss some of the areas in which this approach may be successfully applied in the future.}, number={4}, journal={Acta Biomaterialia}, publisher={Elsevier BV}, author={Bryksin, Anton V. and Brown, Ashley C. and Baksh, Michael M. and Finn, M.G. and Barker, Thomas H.}, year={2014}, month={Apr}, pages={1761–1769} }
 @article{qiu_brown_myers_sakurai_mannino_tran_ahn_hardy_kee_kumar_et al._2014, title={Platelet mechanosensing of substrate stiffness during clot formation mediates adhesion, spreading, and activation}, volume={111}, ISSN={0027-8424 1091-6490}, url={http://dx.doi.org/10.1073/PNAS.1322917111}, DOI={10.1073/PNAS.1322917111}, abstractNote={Significance}, number={40}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Qiu, Yongzhi and Brown, Ashley C. and Myers, David R. and Sakurai, Yumiko and Mannino, Robert G. and Tran, Reginald and Ahn, Byungwook and Hardy, Elaissa T. and Kee, Matthew F. and Kumar, Sanjay and et al.}, year={2014}, month={Oct}, pages={14430–14435} }
 @article{brown_stabenfeldt_ahn_hannan_dhada_herman_stefanelli_guzzetta_alexeev_lam_et al._2014, title={Ultrasoft microgels displaying emergent platelet-like behaviours}, volume={13}, ISSN={1476-1122 1476-4660}, url={http://dx.doi.org/10.1038/NMAT4066}, DOI={10.1038/NMAT4066}, abstractNote={Deformable synthetic microgel particles bearing molecular-recognition motifs for fibrin fibres are shown to augment clotting in vitro and mimic in vivo clot contraction, thus recapitulating the functions of natural platelets. Efforts to create platelet-like structures for the augmentation of haemostasis have focused solely on recapitulating aspects of platelet adhesion1; more complex platelet behaviours such as clot contraction2 are assumed to be inaccessible to synthetic systems. Here, we report the creation of fully synthetic platelet-like particles (PLPs) that augment clotting in vitro under physiological flow conditions and achieve wound-triggered haemostasis and decreased bleeding times in vivo in a traumatic injury model. PLPs were synthesized by combining highly deformable microgel particles with molecular-recognition motifs identified through directed evolution. In vitro and in silico analyses demonstrate that PLPs actively collapse fibrin networks, an emergent behaviour that mimics in vivo clot contraction. Mechanistically, clot collapse is intimately linked to the unique deformability and affinity of PLPs for fibrin fibres, as evidenced by dissipative particle dynamics simulations. Our findings should inform the future design of a broader class of dynamic, biosynthetic composite materials.}, number={12}, journal={Nature Materials}, publisher={Springer Science and Business Media LLC}, author={Brown, Ashley C. and Stabenfeldt, Sarah E. and Ahn, Byungwook and Hannan, Riley T. and Dhada, Kabir S. and Herman, Emily S. and Stefanelli, Victoria and Guzzetta, Nina and Alexeev, Alexander and Lam, Wilbur A. and et al.}, year={2014}, month={Sep}, pages={1108–1114} }
 @article{clarke_douglas_brown_barker_lyon_2013, title={Colloid-matrix assemblies in regenerative medicine}, volume={18}, ISSN={1359-0294}, url={http://dx.doi.org/10.1016/J.COCIS.2013.07.004}, DOI={10.1016/J.COCIS.2013.07.004}, abstractNote={The development of tissue engineering scaffolds has focused on mimicking the natural biochemical and biophysical environment of the extracellular matrix (ECM). In this review, we describe a variety of strategies aimed at reproducing and also simplifying the ECM. Despite the progress that has been made, the degree of complexity that needs to be incorporated into these scaffolds is still not known. We begin by describing the ECM and its biological functions followed by outlining current efforts to engineer ECMs with both natural and synthetic polymers. We then focus on colloidal particles as potential artificial ECM components that could increase the complexity as modular building blocks. Drawing from examples from the literature we present the broad utility of colloids and describe how these applications could be useful in the development of ECM mimetic systems.}, number={5}, journal={Current Opinion in Colloid & Interface Science}, publisher={Elsevier BV}, author={Clarke, Kimberly C. and Douglas, Alison M. and Brown, Ashley C. and Barker, Thomas H. and Lyon, L. Andrew}, year={2013}, month={Oct}, pages={393–405} }
 @article{brown_fiore_sulchek_barker_2013, title={Physical and chemical microenvironmental cues orthogonally control the degree and duration of fibrosis-associated epithelial-to-mesenchymal transitions}, volume={229}, ISSN={0022-3417}, url={http://dx.doi.org/10.1002/path.4114}, DOI={10.1002/path.4114}, abstractNote={Abstract}, number={1}, journal={The Journal of Pathology}, publisher={Wiley}, author={Brown, Ashley C and Fiore, Vincent F and Sulchek, Todd A and Barker, Thomas H}, year={2013}, month={Jan}, pages={25–35} }
 @article{baker_carson brown_barker_guthold_2013, title={The Mechanical Properties of Modified Fibrin Fibers: Blocking the B-b Knob-Pocket Interaction}, volume={104}, ISSN={0006-3495}, url={http://dx.doi.org/10.1016/j.bpj.2012.11.2831}, DOI={10.1016/j.bpj.2012.11.2831}, abstractNote={Fibrin clot formation has been studied to determine the mechanical properties of fibrin fibers modified by blocking the B-b knob-pocket interaction. Synthetic B-knob peptides AHRPYAAC or AHRPYAAC-Peg have been added to a fibrinogen solution to allow for binding to the b-pockets prior to clot formation. After fibrin clot formation, a combined atomic force microscopic (AFM)/optical microscopic technique was used to study the properties of individual fibrin fibers in buffer. Mechanical testing of fibers was done using the AFM to laterally stretch individual fibers suspended over 13.5μm wide groves in a transparent substrate. The optical microscope, located below the sample, was used to monitor the stretching process. We found that the density and lateral aggregation of fibers was hindered by blocking the b-pockets with the synthetic B-knobs. Fibrin fibers modified with the synthetic peptide AHRPYAAC-Peg were found to stretch to 2.27 times their original length before rupturing compared to unmodified fibrin fibers which were found to stretch to 2.47 times their original length. From these results it is expected that synthetic B-knob concentration impacts the mechanical properties of modified fibrin fibers. The binding constants for AHRPYAAC were found to be 30.3 μM and 80.1 μM while the binding constants for AHRPYAAC-Peg were found to be 1.75 mM and 57.2 μM.}, number={2}, journal={Biophysical Journal}, publisher={Elsevier BV}, author={Baker, Stephen and Carson Brown, Ashley and Barker, Thomas and Guthold, Martin}, year={2013}, month={Jan}, pages={512a–513a} }
 @article{markowski_brown_barker_2012, title={Directing epithelial to mesenchymal transition through engineered microenvironments displaying orthogonal adhesive and mechanical cues}, volume={100A}, ISSN={1549-3296}, url={http://dx.doi.org/10.1002/jbm.a.34068}, DOI={10.1002/jbm.a.34068}, abstractNote={Abstract}, number={8}, journal={Journal of Biomedical Materials Research Part A}, publisher={Wiley}, author={Markowski, Marilyn C. and Brown, Ashley C. and Barker, Thomas H.}, year={2012}, month={Aug}, pages={2119–2127} }
 @article{brown_rowe_barker_2011, title={Guiding Epithelial Cell Phenotypes with Engineered Integrin-Specific Recombinant Fibronectin Fragments}, volume={17}, ISSN={1937-3341 1937-335X}, url={http://dx.doi.org/10.1089/ten.tea.2010.0199}, DOI={10.1089/ten.tea.2010.0199}, abstractNote={The extracellular matrix (ECM) provides important cues for directing cell phenotype. Cells interact with underlying ECM through cell-surface receptors known as integrins, which bind to specific sequences on their ligands. During tissue development, repair, and regeneration of epithelial tissues, cells must interact with an interstitial fibronectin (Fn)-rich matrix, which has been shown to direct a more migratory/repair phenotype, presumably through interaction with Fn's cell binding domain comprised of both synergy Pro-His-Ser-Arg-Asn (PHSRN) and Arg-Gly-Asp (RGD) sequences. We hypothesized that the Fn synergy site is critical to the regulation of epithelial cell phenotype by directing integrin specificity. Epithelial cells were cultured on Fn fragments displaying stabilized synergy and RGD (FnIII9'10), or RGD alone (FnIII10) and cell phenotype analyzed by cytoskeleton changes, epithelial cell-cell contacts, changes in gene expression of epithelial and mesenchymal markers, and wound healing assay. Data indicate that epithelial cells engage RGD only with αv integrins and display a significant shift toward a mesenchymal phenotype due, in part, to enhanced transforming growth factor-β activation and/or signaling compared with cells on the synergy containing FnIII9'10. These studies demonstrate the importance of synergy in regulating epithelial cell phenotype relevant to tissue engineering as well as the utility of engineered integrin-specific ECM fragments in guiding cell phenotype.}, number={1-2}, journal={Tissue Engineering Part A}, publisher={Mary Ann Liebert Inc}, author={Brown, Ashley C. and Rowe, Jessica A. and Barker, Thomas H.}, year={2011}, month={Jan}, pages={139–150} }
 @article{park_brown_difeo_barker_lu_2010, title={Continuously perfused, non-cross-contaminating microfluidic chamber array for studying cellular responses to orthogonal combinations of matrix and soluble signals}, volume={10}, ISSN={1473-0197 1473-0189}, url={http://dx.doi.org/10.1039/b919294h}, DOI={10.1039/b919294h}, abstractNote={We present a microfluidic cell culture array with unique versatility and parallelization for experimental trials requiring perfusion cultures. Specifically, we realize a rectangular chamber array in a PDMS device with three attributes: (i) continuous perfusion; (ii) flow paths that forbid cross-chamber contamination; and (iii) chamber shielding from direct perfusion to minimize shear-induced cell behaviour. These attributes are made possible by a bridge-and-underpass architecture, where flow streams travel vertically to pass over (or under) channels and on-chip valves. The array is also designed for considerable versatility, providing subarray, row, column, or single chamber addressing. It allows for incubation with adsorbed molecules, perfusion of differing media, seeding or extraction of cells, and assay staining. We use the device to characterize different phenotypes of alveolar epithelial type II (ATII) cells, particularly the extent of epithelial-to-mesenchymal transition (EMT), a highly suspected pathway in tissue regeneration and fibrosis. Cells are cultured on combinations of matrix proteins (fibronectin or laminin by row) and soluble signals (with or without transforming growth factor-beta1 by column) with two repeats per chip. Fluorescent assays are performed in the array to assess viability, cytoskeletal organization, and cell-cell junction formation. Assay and morphological data are used to tease-out effects of cues driving each phenotype, confirming this as an effective and versatile combinatorial screening platform.}, number={5}, journal={Lab Chip}, publisher={Royal Society of Chemistry (RSC)}, author={Park, Edward S. and Brown, Ashley C. and DiFeo, Michael A. and Barker, Thomas H. and Lu, Hang}, year={2010}, pages={571–580} }
 @article{carson_barker_2009, title={Emerging concepts in engineering extracellular matrix variants for directing cell phenotype}, volume={4}, ISSN={1746-0751 1746-076X}, url={http://dx.doi.org/10.2217/rme.09.30}, DOI={10.2217/rme.09.30}, abstractNote={Directing specific, complex cell behaviors, such as differentiation, in response to biomaterials for regenerative medicine applications is, at present, a mostly unrealized goal. To date, current technological advances have been inspired by the reductionist point of view, focused on developing simple and merely adequate environments that facilitate simple cellular adhesion. However, even if extracellular matrix (ECM)-derived peptides, such as Arg–Gly–Asp (RGD), have largely demonstrated their utility in supporting cell adhesion, their lack of biological specificity is simply not optimal for controlling more integrated processes, such as cell differentiation. These more complex cellular processes require specific integrin-signaling scaffolds and presumably synergistic integrin and growth factor-receptor signaling. This article will introduce some current efforts to engineer ECM variants that incorporate additional levels of complexity for directing greater integrin specificity and synergistic ECM growth factor signaling toward directing cell phenotype.}, number={4}, journal={Regenerative Medicine}, publisher={Informa UK Limited}, author={Carson, Ashley E and Barker, Thomas H}, year={2009}, month={Jul}, pages={593–600} }