@article{rathod_aw_huang_lu_doherty_whithworth_xi_roy-chaudhury_polacheck_2024, title={Donor-Derived Engineered Microvessels for Cardiovascular Risk Stratification of Patients with Kidney Failure}, ISSN={["1613-6829"]}, DOI={10.1002/smll.202307901}, abstractNote={Cardiovascular disease is the cause of death in ≈50% of hemodialysis patients. Accumulation of uremic solutes in systemic circulation is thought to be a key driver of the endothelial dysfunction that underlies elevated cardiovascular events. A challenge in understanding the mechanisms relating chronic kidney disease to cardiovascular disease is the lack of in vitro models that allow screening of the effects of the uremic environment on the endothelium. Here, a method is described for microfabrication of human blood vessels from donor cells and perfused with donor serum. The resulting donor-derived microvessels are used to quantify vascular permeability, a hallmark of endothelial dysfunction, in response to serum spiked with pathophysiological levels of indoxyl sulfate, and in response to serum from patients with chronic kidney disease and from uremic pigs. The uremic environment has pronounced effects on microvascular integrity as demonstrated by irregular cell-cell junctions and increased permeability in comparison to cell culture media and healthy serum. Moreover, the engineered microvessels demonstrate an increase in sensitivity compared to traditional 2D assays. Thus, the devices and the methods presented here have the potential to be utilized to risk stratify and to direct personalized treatments for patients with chronic kidney disease.}, journal={SMALL}, author={Rathod, Mitesh L. and Aw, Wen Yih and Huang, Stephanie and Lu, Jingming and Doherty, Elizabeth L. and Whithworth, Chloe P. and Xi, Gang and Roy-Chaudhury, Prabir and Polacheck, William J.}, year={2024}, month={Jan} }
 @article{aw_cho_wang_cooper_doherty_rocco_huang_kubik_whitworth_armstrong_et al._2023, title={Microphysiological model of PIK3CA-driven vascular malformations reveals a role of dysregulated Rac1 and mTORC1/2 in lesion formation}, volume={9}, ISSN={["2375-2548"]}, DOI={10.1126/sciadv.ade8939}, abstractNote={Somatic activating mutations of PIK3CA are associated with development of vascular malformations (VMs). Here, we describe a microfluidic model of PIK3CA-driven VMs consisting of human umbilical vein endothelial cells expressing PIK3CA activating mutations embedded in three-dimensional hydrogels. We observed enlarged, irregular vessel phenotypes and the formation of cyst-like structures consistent with clinical signatures and not previously observed in cell culture models. Pathologic morphologies occurred concomitant with up-regulation of Rac1/p21-activated kinase (PAK), mitogen-activated protein kinase cascades (MEK/ERK), and mammalian target of rapamycin (mTORC1/2) signaling networks. We observed differential effects between alpelisib, a PIK3CA inhibitor, and rapamycin, an mTORC1 inhibitor, in mitigating matrix degradation and network topology. While both were effective in preventing vessel enlargement, rapamycin failed to reduce MEK/ERK and mTORC2 activity and resulted in hyperbranching, while inhibiting PAK, MEK1/2, and mTORC1/2 mitigates abnormal growth and vascular dilation. Collectively, these findings demonstrate an in vitro platform for VMs and establish a role of dysregulated Rac1/PAK and mTORC1/2 signaling in PIK3CA-driven VMs.}, number={7}, journal={SCIENCE ADVANCES}, author={Aw, Wen Yih and Cho, Crescentia and Wang, Hao and Cooper, Anne Hope and Doherty, Elizabeth L. and Rocco, David and Huang, Stephanie A. and Kubik, Sarah and Whitworth, Chloe P. and Armstrong, Ryan and et al.}, year={2023}, month={Feb} }
 @article{lee_huang_aw_rathod_cho_ligler_polacheck_2022, title={Multilayer microfluidic platform for the study of luminal, transmural, and interstitial flow}, volume={14}, ISSN={["1758-5090"]}, DOI={10.1088/1758-5090/ac48e5}, abstractNote={Efficient delivery of oxygen and nutrients to tissues requires an intricate balance of blood, lymphatic, and interstitial fluid pressures (IFPs), and gradients in fluid pressure drive the flow of blood, lymph, and interstitial fluid through tissues. While specific fluid mechanical stimuli, such as wall shear stress, have been shown to modulate cellular signaling pathways along with gene and protein expression patterns, an understanding of the key signals imparted by flowing fluid and how these signals are integrated across multiple cells and cell types in native tissues is incomplete due to limitations with current assays. Here, we introduce a multi-layer microfluidic platform (MμLTI-Flow) that enables the culture of engineered blood and lymphatic microvessels and independent control of blood, lymphatic, and IFPs. Using optical microscopy methods to measure fluid velocity for applied input pressures, we demonstrate varying rates of interstitial fluid flow as a function of blood, lymphatic, and interstitial pressure, consistent with computational fluid dynamics (CFD) models. The resulting microfluidic and computational platforms will provide for analysis of key fluid mechanical parameters and cellular mechanisms that contribute to diseases in which fluid imbalances play a role in progression, including lymphedema and solid cancer.}, number={2}, journal={BIOFABRICATION}, author={Lee, Gi-hun and Huang, Stephanie A. and Aw, Wen Y. and Rathod, Mitesh L. and Cho, Crescentia and Ligler, Frances S. and Polacheck, William J.}, year={2022}, month={Apr} }
 @article{wang_kent_huang_jarman_shikanov_davidson_hiraki_lin_wall_matera_et al._2021, title={Direct comparison of angiogenesis in natural and synthetic biomaterials reveals that matrix porosity regulates endothelial cell invasion speed and sprout diameter}, volume={135}, ISSN={["1878-7568"]}, DOI={10.1016/j.actbio.2021.08.038}, abstractNote={Vascularization of large, diffusion-hindered biomaterial implants requires an understanding of how extracellular matrix (ECM) properties regulate angiogenesis. Sundry biomaterials assessed across many disparate angiogenesis assays have highlighted ECM determinants that influence this complex multicellular process. However, the abundance of material platforms, each with unique parameters to model endothelial cell (EC) sprouting presents additional challenges of interpretation and comparison between studies. In this work we directly compared the angiogenic potential of commonly utilized natural (collagen and fibrin) and synthetic dextran vinyl sulfone (DexVS) hydrogels in a multiplexed angiogenesis-on-a-chip platform. Modulating matrix density of collagen and fibrin hydrogels confirmed prior findings that increases in matrix density correspond to increased EC invasion as connected, multicellular sprouts, but with decreased invasion speeds. Angiogenesis in synthetic DexVS hydrogels, however, resulted in fewer multicellular sprouts. Characterizing hydrogel Young's modulus and permeability (a measure of matrix porosity), we identified matrix permeability to significantly correlate with EC invasion depth and sprout diameter. Although microporous collagen and fibrin hydrogels produced lumenized sprouts in vitro, they rapidly resorbed post-implantation into the murine epididymal fat pad. In contrast, DexVS hydrogels proved comparatively stable. To enhance angiogenesis within DexVS hydrogels, we incorporated sacrificial microgels to generate cell-scale pores throughout the hydrogel. Microporous DexVS hydrogels resulted in lumenized sprouts in vitro and enhanced cell invasion in vivo. Towards the design of vascularized biomaterials for long-term regenerative therapies, this work suggests that synthetic biomaterials offer improved size and shape control following implantation and that tuning matrix porosity may better support host angiogenesis. STATEMENT OF SIGNIFICANCE: Understanding how extracellular matrix properties govern angiogenesis will inform biomaterial design for engineering vascularized implantable grafts. Here, we utilized a multiplexed angiogenesis-on-a-chip platform to compare the angiogenic potential of natural (collagen and fibrin) and synthetic dextran vinyl sulfone (DexVS) hydrogels. Characterization of matrix properties and sprout morphometrics across these materials points to matrix porosity as a critical regulator of sprout invasion speed and diameter, supported by the observation that nanoporous DexVS hydrogels yielded endothelial cell sprouts that were not perfusable. To enhance angiogenesis into synthetic hydrogels, we incorporated sacrificial microgels to generate microporosity. We find that microporosity increased sprout diameter in vitro and cell invasion in vivo. This work establishes a composite materials approach to enhance the vascularization of synthetic hydrogels.}, journal={ACTA BIOMATERIALIA}, author={Wang, William Y. and Kent, Robert N., III and Huang, Stephanie A. and Jarman, Evan H. and Shikanov, Eve H. and Davidson, Christopher D. and Hiraki, Harrison L. and Lin, Daphne and Wall, Monica A. and Matera, Daniel L. and et al.}, year={2021}, month={Nov}, pages={260–273} }
 @misc{rickard_conrad_sorrin_ruhi_reader_huang_franco_scarcelli_polacheck_roque_et al._2021, title={Malignant Ascites in Ovarian Cancer: Cellular, Acellular, and Biophysical Determinants of Molecular Characteristics and Therapy Response}, volume={13}, ISSN={["2072-6694"]}, DOI={10.3390/cancers13174318}, abstractNote={Simple Summary Accumulation of excess fluid in the abdomen typically indicates abnormal function or disease, such as cancer, in the underlying tissues. This accumulation of fluid, or ascites, occurs more frequently in patients with advanced-stage ovarian cancer than any other type of cancer. The presence of ascites indicates the poorest outcomes for patients with advanced stage ovarian cancer, but little is known about the reasons for these dismal outcomes. This review discusses the current understanding of ascites, starting with an overview of ovarian cancer and ascites, followed by a description of the tools used to analyze the components of ascites and how these components modulate ovarian cancer biology. A perspective on the mechanical effects of ascites and the impact of mechanical stress on treatment resistance is provided. Lastly, treatment options for ascites and opportunities to develop new therapeutic strategies to improve outcomes are discussed. Abstract Ascites refers to the abnormal accumulation of fluid in the peritoneum resulting from an underlying pathology, such as metastatic cancer. Among all cancers, advanced-stage epithelial ovarian cancer is most frequently associated with the production of malignant ascites and is the leading cause of death from gynecologic malignancies. Despite decades of evidence showing that the accumulation of peritoneal fluid portends the poorest outcomes for cancer patients, the role of malignant ascites in promoting metastasis and therapy resistance remains poorly understood. This review summarizes the current understanding of malignant ascites, with a focus on ovarian cancer. The first section provides an overview of heterogeneity in ovarian cancer and the pathophysiology of malignant ascites. Next, analytical methods used to characterize the cellular and acellular components of malignant ascites, as well the role of these components in modulating cell biology, are discussed. The review then provides a perspective on the pressures and forces that tumors are subjected to in the presence of malignant ascites and the impact of physical stress on therapy resistance. Treatment options for malignant ascites, including surgical, pharmacological and photochemical interventions are then discussed to highlight challenges and opportunities at the interface of drug discovery, device development and physical sciences in oncology.}, number={17}, journal={CANCERS}, author={Rickard, Brittany P. and Conrad, Christina and Sorrin, Aaron J. and Ruhi, Mustafa Kemal and Reader, Jocelyn C. and Huang, Stephanie A. and Franco, Walfre and Scarcelli, Giuliano and Polacheck, William J. and Roque, Dana M. and et al.}, year={2021}, month={Sep} }
 @article{perez-rodriguez_huang_borau_manuel garcia-aznar_polacheck_2021, title={Microfluidic model of monocyte extravasation reveals the role of hemodynamics and subendothelial matrix mechanics in regulating endothelial integrity}, volume={15}, ISSN={["1932-1058"]}, DOI={10.1063/5.0061997}, abstractNote={Extravasation of circulating cells is an essential process that governs tissue inflammation and the body's response to pathogenic infection. To initiate anti-inflammatory and phagocytic functions within tissues, immune cells must cross the vascular endothelial barrier from the vessel lumen to the subluminal extracellular matrix. In this work, we present a microfluidic approach that enables the recreation of a three-dimensional, perfused endothelial vessel formed by human endothelial cells embedded within a collagen-rich matrix. Monocytes are introduced into the vessel perfusate, and we investigate the role of luminal flow and collagen concentration on extravasation. In vessels conditioned with the flow, increased monocyte adhesion to the vascular wall was observed, though fewer monocytes extravasated to the collagen hydrogel. Our results suggest that the lower rates of extravasation are due to the increased vessel integrity and reduced permeability of the endothelial monolayer. We further demonstrate that vascular permeability is a function of collagen hydrogel mass concentration, with increased collagen concentrations leading to elevated vascular permeability and increased extravasation. Collectively, our results demonstrate that extravasation of monocytes is highly regulated by the structural integrity of the endothelial monolayer. The microfluidic approach developed here allows for the dissection of the relative contributions of these cues to further understand the key governing processes that regulate circulating cell extravasation and inflammation.}, number={5}, journal={BIOMICROFLUIDICS}, author={Perez-Rodriguez, Sandra and Huang, Stephanie A. and Borau, Carlos and Manuel Garcia-Aznar, Jose and Polacheck, William J.}, year={2021}, month={Sep} }
 @misc{fleming_stafford_huang_hu_ferris_huang_2021, title={Myoelectric control of robotic lower limb prostheses: a review of electromyography interfaces, control paradigms, challenges and future directions}, volume={18}, ISSN={["1741-2552"]}, url={http://dx.doi.org/10.1088/1741-2552/ac1176}, DOI={10.1088/1741-2552/ac1176}, abstractNote={Objective. Advanced robotic lower limb prostheses are mainly controlled autonomously. Although the existing control can assist cyclic movements during locomotion of amputee users, the function of these modern devices is still limited due to the lack of neuromuscular control (i.e. control based on human efferent neural signals from the central nervous system to peripheral muscles for movement production). Neuromuscular control signals can be recorded from muscles, called electromyographic (EMG) or myoelectric signals. In fact, using EMG signals for robotic lower limb prostheses control has been an emerging research topic in the field for the past decade to address novel prosthesis functionality and adaptability to different environments and task contexts. The objective of this paper is to review robotic lower limb Prosthesis control via EMG signals recorded from residual muscles in individuals with lower limb amputations. Approach. We performed a literature review on surgical techniques for enhanced EMG interfaces, EMG sensors, decoding algorithms, and control paradigms for robotic lower limb prostheses. Main results. This review highlights the promise of EMG control for enabling new functionalities in robotic lower limb prostheses, as well as the existing challenges, knowledge gaps, and opportunities on this research topic from human motor control and clinical practice perspectives. Significance. This review may guide the future collaborations among researchers in neuromechanics, neural engineering, assistive technologies, and amputee clinics in order to build and translate true bionic lower limbs to individuals with lower limb amputations for improved motor function.}, number={4}, journal={JOURNAL OF NEURAL ENGINEERING}, publisher={IOP Publishing}, author={Fleming, Aaron and Stafford, Nicole and Huang, Stephanie and Hu, Xiaogang and Ferris, Daniel P. and Huang, He}, year={2021}, month={Aug} }
 @article{griffith_huang_cho_khare_rich_lee_ligler_diekman_polacheck_2020, title={Microfluidics for the study of mechanotransduction}, volume={53}, ISSN={["1361-6463"]}, DOI={10.1088/1361-6463/ab78d4}, abstractNote={Mechanical forces regulate a diverse set of biological processes at cellular, tissue, and organismal length scales. Investigating the cellular and molecular mechanisms that underlie the conversion of mechanical forces to biological responses is challenged by limitations of traditional animal models and in vitro cell culture, including poor control over applied force and highly artificial cell culture environments. Recent advances in fabrication methods and material processing have enabled the development of microfluidic platforms that provide precise control over the mechanical microenvironment of cultured cells. These devices and systems have proven to be powerful for uncovering and defining mechanisms of mechanotransduction. In this review, we first give an overview of the main mechanotransduction pathways that function at sites of cell adhesion, many of which have been investigated with microfluidics. We then discuss how distinct microfluidic fabrication methods can be harnessed to gain biological insight, with description of both monolithic and replica molding approaches. Finally, we present examples of how microfluidics can be used to apply both solid forces (substrate mechanics, strain, and compression) and fluid forces (luminal, interstitial) to cells. Throughout the review, we emphasize the advantages and disadvantages of different fabrication methods and applications of force in order to provide perspective to investigators looking to apply forces to cells in their own research.}, number={22}, journal={JOURNAL OF PHYSICS D-APPLIED PHYSICS}, author={Griffith, Christian M. and Huang, Stephanie A. and Cho, Crescentia and Khare, Tanmay M. and Rich, Matthew and Lee, Gi-hun and Ligler, Frances S. and Diekman, Brian O. and Polacheck, William J.}, year={2020}, month={May} }
 @article{fleming_huang_huang_2019, title={Proportional Myoelectric Control of a Virtual Inverted Pendulum Using Residual Antagonistic Muscles: Toward Voluntary Postural Control}, volume={27}, ISSN={["1558-0210"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85068905602&partnerID=MN8TOARS}, DOI={10.1109/TNSRE.2019.2922102}, abstractNote={This paper aims to investigate whether transtibial amputees are capable of coordinating the descending neural commands to antagonistic residual ankle muscles for performing dynamic tasks that require continuous, precise control. To achieve this goal, we developed a virtual inverted pendulum that was inherently unstable and mimicked human-like dynamics in a standing posture. Balancing this dynamic system requires continuous inputs, proportional to electromyography (EMG) magnitudes recorded from (residual) tibialis anterior (TA) and lateral gastrocnemius muscles (GAS), respectively. The six able-bodied and six transtibial amputees were recruited and asked to balance the inverted pendulum for ten 90-s trials. The results showed that the amputees were capable of controlling this unstable dynamic system with a proportional myoelectric control; however, they underperformed the able-bodied subjects, who maintained the pendulum closer to center ( ${p} = {0.041}$ ). Compared to the performance in the initial two trials, amputees improved the performance by significantly reducing the number of pendulum falls ( ${p} = {0.0329}$ ) and sway size ( ${p} ={0.048}$ ) in the final two trials. However, the amount of improvement varied across amputee subjects. Amputee subjects demonstrated different task adaptation strategies, including reduction of erroneous residual muscle contractions, development of an appropriate state-action (pendulum state-EMG activation) relationship for the task, and/or reduction of muscle control variability with the improved task performance efficiency (i.e., increased inactivity and sway minimization). The results suggest that after the training of transtibial amputees in coordinating antagonistic residual muscles in dynamic systems, it may be feasible to implement the proportional myoelectric control of the powered ankle prostheses in order to assist the postural control mechanisms, such as anticipatory and compensatory postural adjustments.}, number={7}, journal={IEEE TRANSACTIONS ON NEURAL SYSTEMS AND REHABILITATION ENGINEERING}, author={Fleming, Aaron and Huang, Stephanie and Huang, He}, year={2019}, month={Jul}, pages={1473–1482} }
 @article{huang_huang_2019, title={Voluntary Control of Residual Antagonistic Muscles in Transtibial Amputees: Reciprocal Activation, Coactivation, and Implications for Direct Neural Control of Powered Lower Limb Prostheses}, volume={27}, ISSN={["1558-0210"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85058152428&partnerID=MN8TOARS}, DOI={10.1109/TNSRE.2018.2885641}, abstractNote={Residual ankle muscles (i.e., previously antagonistic ankle muscles) of transtibial amputees are a potential source for continuous feedforward control of powered ankle prostheses using proportional myoelectric control. The ability for transtibial amputees to use their residual ankle muscles for two control input degrees of freedom (i.e., two independent myoelectric control input sources) for direct neural control depends on the ability for amputees to generate varying magnitudes of reciprocal activation and coactivation using their residual ankle muscles, which is not well understood. In this paper, we aimed to fill this knowledge gap. We asked 12 transtibial amputees to control the 2-D movement of a computer cursor using continuous proportional myoelectric control via their residual plantar flexor and residual dorsiflexor muscles to define their reachable 2-D control input space. The x–y position of the computer cursor was directly proportional to the independent continuous myoelectric control signals from the residual lateral gastrocnemius (x-axis) and the residual tibialis anterior (y-axis) where the limits of each axis were 0%–100% maximum voluntary activation of the corresponding residual muscle. Our results show that the reachable control input space varied widely across amputee subjects ranging from 38% to 81% of the maximum possible control input space. The cumulative time for the amputee subjects to saturate their reachable control input space ranged from 1.95 to 6.85 min. The amputee subjects used different residual muscle activation patterns and coordination strategies to expand their reachable control input space depending on their ability to perform coactivation and reciprocal activation using their residual plantar flexor and dorsiflexor muscles. The future development of powered lower limb prostheses using direct continuous proportional myoelectric control via residual muscles (e.g., for direct voluntary control of prosthesis joint impedance) should consider how an amputee user’s immediately accessible residual muscle activation patterns and reachable 2-D control input space may affect their learning and performance.}, number={1}, journal={IEEE TRANSACTIONS ON NEURAL SYSTEMS AND REHABILITATION ENGINEERING}, author={Huang, Stephanie and Huang, He}, year={2019}, month={Jan}, pages={85–95} }
 @article{huang_huang_2018, title={Voluntary Control of Residual Antagonistic Muscles in Transtibial Amputees: Feedforward Ballistic Contractions and Implications for Direct Neural Control of Powered Lower Limb Prostheses}, volume={26}, ISSN={["1558-0210"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85042875741&partnerID=MN8TOARS}, DOI={10.1109/tnsre.2018.2811544}, abstractNote={Discrete, rapid (i.e., ballistic like) muscle activation patterns have been observed in ankle muscles (i.e., plantar flexors and dorsiflexors) of able-bodied individuals during voluntary posture control. This observation motivated us to investigate whether transtibial amputees are capable of generating such a ballistic-like activation pattern accurately using their residual ankle muscles in order to assess whether the volitional postural control of a powered ankle prosthesis using proportional myoelectric control via residual muscles could be feasible. In this paper, we asked ten transtibial amputees to generate ballistic-like activation patterns using their residual lateral gastrocnemius and residual tibialis anterior to control a computer cursor via proportional myoelectric control to hit targets positioned at 20% and 40% of maximum voluntary contraction of the corresponding residual muscle. During practice conditions, we asked amputees to hit a single target repeatedly. During testing conditions, we asked amputees to hit a random sequence of targets. We compared movement time to target and end-point accuracy. We also examined motor recruitment synchronization via time-frequency representations of residual muscle activation. The result showed that median end-point error ranged from −0.6% to 1% maximum voluntary contraction across subjects during practice, which was significantly lower compared to testing ( $p < 0.001$ ). Average movement time for all amputees was 242 ms during practice and 272 ms during testing. Motor recruitment synchronization varied across subjects, and amputees with the highest synchronization achieved the fastest movement times. End-point accuracy was independent of movement time. Results suggest that it is feasible for transtibial amputees to generate ballistic control signals using their residual muscles. Future work on volitional control of powered power ankle prostheses might consider anticipatory postural control based on ballistic-like residual muscle activation patterns and direct continuous proportional myoelectric control.}, number={4}, journal={IEEE TRANSACTIONS ON NEURAL SYSTEMS AND REHABILITATION ENGINEERING}, author={Huang, Stephanie and Huang, He}, year={2018}, month={Apr}, pages={894–903} }
 @article{wen_si_gao_huang_huang_2017, title={A new powered lower limb prosthesis control framework based on adaptive dynamic programming}, volume={28}, number={9}, journal={IEEE Transactions on Neural Networks and Learning Systems}, author={Wen, Y. and Si, J. and Gao, X. and Huang, S. and Huang, H.}, year={2017}, pages={2215–2220} }