Marvin J Slepian

Interests

Research

Innovation Science and Invention;Inventive Knowledge Flow;Intravascular Stents;Intravascular Biodegradable Polymer-based Support and Drug Delivery Systems - Polymeric Endoluminal Paving and Sealing;Cell Biology of Restenosis and Vascular Wound Healing;Intravascular Ultrasound Imaging;Smooth muscle cell integrin - matrix interactions; Integrin Biology – role in cell locomotion;Estrogen and Smooth Muscle Cell Migration and Integrin Expression;Myocardial angiogenesis and alternative revascularization means;Mechanical Circulatory Support – TAH/VAD, Mechanical & Biomaterial Issues;Oral-Body Inflammatory Connection – Periodontal Disease and CAD;Flexible/Stretchable Bioelectronics;Microfluidics and Medical Diagnostics;Microchip Medical Diagnostics;Grape Polyphenolics, Inflammation and CAD;Bioglass Biomaterials;Nanotextured Biomaterials/Surface Endothelialization;Mathematical Modeling/Enhanced CFD of Mechanical Circulatory Support; Systems for Improved Thromboresistance;Biodegradable/Transient electronic systems;Wearable Health Systems;Microfluidic Point-of-Care Systems;Big Data Tools for Health Care;Microbiome and Its Impact on CV Diz and Chronic Disease;Piezoelectric Biomaterials;Soft Robotics;Virtual Realty Systems; Supercomputing and Big data in HealthcareLaw and Medical Device Development

Teaching

Innovation, Translation and Entrepreneurship;Medical Device Development;Science and Technology Administration;Thrombosis; Biomaterial Science;Mechanical Circulatory Support and Heart failure;Interventional Cardiology;Medicine;Cardiology;Law and Medical Device Development

Courses

Scholarly Contributions

Chapters

• Giovinco, N. A., Slepian, M. J., Armstrong, D. G., Mahmoud, A. Z., Giovinco, N. A., Slepian, M. J., Armstrong, D. G., & Mahmoud, A. Z. (2015). Tissue Repair and Wound Healing: A Trip Back to the Future. In Technological Advances in Surgery, Trauma, and Critical Care(pp 563-573). New York: Springer. doi:10.1007/978-1-4939-2671-8
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  Latifi R, Rhee P, and Gruessner R (eds)
• Rankin, T., Slepian, M. J., & Armstrong, D. G. (2015). Augmented Reality in Surgery. In Technological Advances in Surgery, Trauma, and Critical Care(pp 59-72). New York: Springer. doi:10.1007/978-1-4939-2671-8
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  Latifi R, Rhee P, and Gruessner R (eds)
• Rankin, T., Slepian, M. J., Armstrong, D. G., Rankin, T., Slepian, M. J., & Armstrong, D. G. (2015). Augmented Reality in Surgery. In Technological Advances in Surgery, Trauma, and Critical Care. Media, Pennsylvania: Springer Science.
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  Latifi R, Rhee P, and Gruessner R, eds.

Journals/Publications

• Slepian, M. J., Ammann, K. R., Ding, J., Gilman, V., & Corbett, S. (2023). Sodium Bicarbonate Alters Protein Stability and Blood Coagulability in a Simulated Impella Purge Gap Model. Artificial Organs. doi:10.1111/aor.14497
• Reza, S., Bianchi, M., Kovarovic, B., Anam, S., Slepian, M. J., Hamdan, A., Haj-Ali, R., & Bluestein, D. (2022). A computational framework for post-TAVR cardiac conduction abnormality (CCA) risk assessment in patient-specific anatomy. Artificial organs.
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  Cardiac conduction abnormality (CCA)- one of the major persistent complications associated with transcatheter aortic valve replacement (TAVR) may lead to permanent pacemaker implantation. Localized stresses exerted by the device frame on the membranous septum (MS) which lies between the aortic annulus and the bundle of His, may disturb the cardiac conduction and cause the resultant CCA. We hypothesize that the area-weighted average maximum principal logarithmic strain (AMPLS) in the MS region can predict the risk of CCA following TAVR.
• Slepian, M. J., Kovarovic, B., Helbock, R., Baylous, K., Rotman, O. M., & Bluestein, D. (2022). Visions of TAVR Future: Development and Optimization of a Second Generation Novel Polymeric TAVR. Journal of Biomechanical Engineering, 144(6). doi:10.1115/1.4054149
• Slepian, M. J., Reza, S., Bianchi, M., Kovarovic, B., Anam, S., Hamdan, A., Haj‐Ali, R., & Bluestein, D. (2022). A computational framework for post‐TAVR cardiac conduction abnormality (CCA) risk assessment in patient‐specific anatomy. Artificial Organs, 46(7), 1305-1317. doi:10.1111/aor.14189
• Slepian, M. J., Roka-Moiia, Y., Cleveland, E., Lewis, S., & Italiano, J. E. (2022). Shear Stress Promotes Platelet Surface Desialylation, Platelet Count Drop, and Microvesiculation: Do Platelets Need to be Sugar-Coated?. Blood, 140(Supplement 1), 5518-5519. doi:10.1182/blood-2022-159140
• Slepian, M. J., Roka-Moiia, Y., Walawalkar, V., Liu, Y., Italiano, J. E., & Taylor, R. E. (2022). DNA Origami–Platelet Adducts: Nanoconstruct Binding without Platelet Activation. Bioconjugate Chemistry, 33(7), 1295-1310. doi:10.1021/acs.bioconjchem.2c00197
• Ammann, K. R., & Slepian, M. J. (2021). Vascular endothelial and smooth muscle cell galvanotactic response and differential migratory behavior. Experimental cell research, 399(1), 112447.
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  Chronic disease or injury of the vasculature impairs the functionality of vascular wall cells particularly in their ability to migrate and repair vascular surfaces. Under pathologic conditions, vascular endothelial cells (ECs) lose their non-thrombogenic properties and decrease their motility. Alternatively, vascular smooth muscle cells (SMCs) may increase motility and proliferation, leading to blood vessel luminal invasion. Current therapies to prevent subsequent blood vessel occlusion commonly mechanically injure vascular cells leading to endothelial denudation and smooth muscle cell luminal migration. Due to this dichotomous migratory behavior, a need exists for modulating vascular cell growth and migration in a more targeted manner. Here, we examine the efficacy of utilizing small direct current electric fields to influence vascular cell-specific migration ("galvanotaxis"). We designed, fabricated, and implemented an in vitro chamber for tracking vascular cell migration direction, distance, and displacement under galvanotactic influence of varying magnitude. Our results indicate that vascular ECs and SMCs have differing responses to galvanotaxis; ECs exhibit a positive correlation of anodal migration while SMCs exhibit minimal change in directional migration in relation to the electric field direction. SMCs exhibit less motility response (i.e. distance traveled in 4 h) compared to ECs, but SMCs show a significantly higher motility at low electric potentials (80 mV/cm). With further investigation and translation, galvanotaxis may be an effective solution for modulation of vascular cell-specific migration, leading to enhanced endothelialization, with coordinate reduced smooth muscle in-migration.
• Bozzi, S., Roka-Moiia, Y., Mencarini, T., Vercellino, F., Epifani, I., Ammann, K. R., Consolo, F., Slepian, M. J., & Redaelli, A. (2021). Characterization of the competing role of surface-contact and shear stress on platelet activation in the setting of blood contacting devices. The International journal of artificial organs, 44(12), 1013-1020.
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  Supraphysiological shear stress and surface-contact are recognized as driving mechanisms of platelet activation (PA) in blood contacting devices (BCDs). However, the competing role of these mechanisms in triggering thrombogenic events is poorly understood. Here, we characterized the dynamics of PA in response to the combined effect of shear stress and material exposure. Human platelets were stimulated with different levels of shear stress (500, 750, 1000 dynes/cm) over a range of exposure times (10, 20, and 30 min) within capillary tubes made of various polymeric materials. Polyethylene (PE), polytetrafluoroethylene (PTFE), ethylene tetrafluoroethylene (ETFE), and polyether ether ketone (PEEK), used for BCDs fabrication, were investigated as compared to glass and thromboresistant Sigma™-coated glass. PA was quantified using the Platelet Activity State assay. Our results indicate that mechanical stimulation and polymer surface-contact both significantly contribute to PA. Notably, the contribution of the mechanical stimulus ranges between +36% and +43%, while that associated with polymer surface-contact ranges from +48% to +59%, depending on the exposure time. In more detail, our results indicate that: (i) PA increases with increasing shear stress magnitude; (ii) PA has a non-linear, time-dependent relationship to exposure time; (iii) PA is largely influenced by biomaterials, with PE and PEEK having respectively the lowest and highest prothrombotic potential; (iv) the effects of polymer surface-contact and shear stress are not correlated and can be studied separately. Our results suggest the importance of incorporating the evaluation of platelet activation driven by the combined effect of shear stress and polymer surface-contact for the comprehensive assessment, and eventually minimization, of BCDs thrombogenic potential.
• Cheng, K., Martin, L. F., Slepian, M. J., Patwardhan, A. M., & Ibrahim, M. M. (2021). Mechanisms and Pathways of Pain Photobiomodulation: A Narrative Review. The journal of pain, 22(7), 763-777.
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  A growing body of evidence supports the modulation of pain by light exposure. As such, phototherapy is being increasingly utilized for the management of a variety of pain conditions. The modes of delivery, and hence applications of phototherapy, vary by wavelength, intensity, and route of exposure. As such, differing mechanisms of action exist depending upon those parameters. Cutaneous application of red light (660 nm) has been shown to reduce pain in neuropathies and complex regional pain syndrome-I, whereas visual application of the same wavelength of red light has been reported to exacerbate migraine headache in patients and lead to the development of functional pain in animal models. Interestingly visual exposure to green light can result in reduction in pain in variety of pain conditions such as migraine and fibromyalgia. Cutaneous application typically requires exposure on the order of minutes, whereas visual application requires exposure on the order of hours. Both routes of exposure elicit changes centrally in the brainstem and spinal cord, and peripherally in the dorsal root ganglia and nociceptors. The mechanisms of photobiomodulation of pain presented in this review provide a foundation in furtherance of exploration of the utility of phototherapy as a tool in the management of pain. PERSPECTIVE: This review synopsizes the pathways and mechanisms through which light modulates pain and the therapeutic utility of different colors and exposure modalities of light on pain. Recent advances in photobiomodulation provide a foundation for understanding this novel treatment for pain on which future translational and clinical studies can build upon.
• Chiu, W. C., Slepian, M. J., & Bluestein, D. (2021). Thrombus formation patterns in the HeartMate II ventricular assist device: clinical observations can be predicted by numerical simulations. ASAIO journal (American Society for Artificial Internal Organs : 1992), 60(2), 237-40.
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  Postimplant device thrombosis remains a life-threatening complication and limitation of continuous-flow ventricular assist devices (VADs). Using advanced computational fluid dynamic (CFD) simulations, we successfully depicted various flow patterns, recirculation zones, and stagnant platelet trajectories which promote thrombus formation and observed that they matched actual thrombus formation patterns observed in Thoratec HeartMate II VADs explanted from patients with pump thrombosis. Previously, these small eddies could not be captured by either digital particle image velocimetry or CFD due to insufficient resolution. Our study successfully demonstrated the potential capability of advanced CFD to be adopted for device optimization, leading to enhanced safety and efficacy of VADs for long-term destination therapy.
• Deshpande, S. R., Slepian, M. J., & Alsoufi, B. (2021). HeartWare HVAD Market Withdrawal and Impact on the Pediatric Field. ASAIO journal (American Society for Artificial Internal Organs : 1992), 67(8), 825-826.
• Jacobs, J. P., Stammers, A. H., Louis, J. S., Hayanga, J. W., Firstenberg, M. S., Mongero, L. B., Tesdahl, E. A., Rajagopal, K., Cheema, F. H., Patel, K., Esseghir, F., Coley, T., Sestokas, A. K., Slepian, M. J., & Badhwar, V. (2021). Multi-institutional Analysis of 100 Consecutive Patients with COVID-19 and Severe Pulmonary Compromise Treated with Extracorporeal Membrane Oxygenation: Outcomes and Trends Over Time. ASAIO journal (American Society for Artificial Internal Organs : 1992), 67(5), 496-502.
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  The role of extracorporeal membrane oxygenation (ECMO) in the management of severely ill patients with coronavirus disease 2019 (COVID-19) continues to evolve. The purpose of this study is to review a multi-institutional clinical experience in 100 consecutive patients, at 20 hospitals, with confirmed COVID-19 supported with ECMO. This analysis includes our first 100 patients with complete data who had confirmed COVID-19 and were supported with ECMO. The first patient in the cohort was placed on ECMO on March 17, 2020. Differences by the mortality group were assessed using χ2 tests for categorical variables and Kruskal-Wallis rank-sum tests and Welch's analysis of variance for continuous variables. The median time on ECMO was 12.0 days (IQR = 8-22 days). All 100 patients have since been separated from ECMO: 50 patients survived and 50 patients died. The rate of survival with veno-venous ECMO was 49 of 96 patients (51%), whereas that with veno-arterial ECMO was 1 of 4 patients (25%). Of 50 survivors, 49 have been discharged from the hospital and 1 remains hospitalized at the ECMO-providing hospital. Survivors were generally younger, with a lower median age (47 versus 56.5 years, p = 0.014). In the 50 surviving patients, adjunctive therapies while on ECMO included intravenous steroids (26), anti-interleukin-6 receptor blockers (26), convalescent plasma (22), remdesivir (21), hydroxychloroquine (20), and prostaglandin (15). Extracorporeal membrane oxygenation may facilitate salvage and survival of selected critically ill patients with COVID-19. Survivors tend to be younger. Substantial variation exists in the drug treatment of COVID-19, but ECMO offers a reasonable rescue strategy.
• Jacobs, J. P., Stammers, A. H., St Louis, J. D., Hayanga, J. W., Firstenberg, M. S., Mongero, L. B., Tesdahl, E. A., Rajagopal, K., Cheema, F. H., Patel, K., Coley, T., Sestokas, A. K., Slepian, M. J., & Badhwar, V. (2021). Multi-institutional Analysis of 200 COVID-19 Patients Treated With Extracorporeal Membrane Oxygenation: Outcomes and Trends. The Annals of thoracic surgery.
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  The role of extracorporeal membrane oxygenation (ECMO) in the management of patients with COVID-19 continues to evolve. The purpose of this analysis is to review our multi-institutional clinical experience involving 200 consecutive patients at 29 hospitals with confirmed COVID-19 supported with ECMO.
• Kapp, M. E., Fogo, A. B., Roufouse, C., Najafian, B., Radhakrishnan, J., Mohan, S., Miller, S. E., D'Agati, V. D., Silberzweig, J., Barbar, T., Gopalan, T., Srivatana, V., Mokrzycki, M. H., Benstein, J. A., Ng, Y. H., Lentine, K. L., Aggarwal, V., Perl, J., Salenger, P., , Koyner, J. L., et al. (2021). Renal Considerations in COVID-19: Biology, Pathology, and Pathophysiology. ASAIO journal (American Society for Artificial Internal Organs : 1992), 67(10), 1087-1096.
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  Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has emerged into a worldwide pandemic of epic proportion. Beyond pulmonary involvement in coronavirus disease 2019 (COVID-19), a significant subset of patients experiences acute kidney injury. Patients who die from severe disease most notably show diffuse acute tubular injury on postmortem examination with a possible contribution of focal macro- and microvascular thrombi. Renal biopsies in patients with proteinuria and hematuria have demonstrated a glomerular dominant pattern of injury, most notably a collapsing glomerulopathy reminiscent of findings seen in human immunodeficiency virus (HIV) in individuals with apolipoprotein L-1 (APOL1) risk allele variants. Although various mechanisms have been proposed for the pathogenesis of acute kidney injury in SARS-CoV-2 infection, direct renal cell infection has not been definitively demonstrated and our understanding of the spectrum of renal involvement remains incomplete. Herein we discuss the biology, pathology, and pathogenesis of SARS-CoV-2 infection and associated renal involvement. We discuss the molecular biology, risk factors, and pathophysiology of renal injury associated with SARS-CoV-2 infection. We highlight the characteristics of specific renal pathologies based on native kidney biopsy and autopsy. Additionally, a brief discussion on ancillary studies and challenges in the diagnosis of SARS-CoV-2 is presented.
• Lopez-Pier, M. A., Koppinger, M. P., Harris, P. R., Cannon, D. K., Skaria, R. S., Hurwitz, B. L., Watts, G., Aras, S., Slepian, M. J., & Konhilas, J. P. (2021). An adaptable and non-invasive method for tracking Bifidobacterium animalis subspecies lactis 420 in the mouse gut. Journal of microbiological methods, 189, 106302.
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  Probiotic strains from the Bifidobacterium or Lactobacillus genera improve health outcomes in models of metabolic and cardiovascular disease. Yet, underlying mechanisms governing these improved health outcomes are rooted in the interaction of gut microbiota, intestinal interface, and probiotic strain. Central to defining the underlying mechanisms governing these improved health outcomes is the development of adaptable and non-invasive tools to study probiotic localization and colonization within the host gut microbiome. The objective of this study was to test labeling and tracking efficacy of Bifidobacterium animalis subspecies lactis 420 (B420) using a common clinical imaging agent, indocyanine green (ICG). ICG was an effective in situ labeling agent visualized in either intact mouse or excised gastrointestinal (GI) tract at different time intervals. Quantitative PCR was used to validate ICG visualization of B420, which also demonstrated that B420 transit time matched normal murine GI motility (~8 hours). Contrary to previous thoughts, B420 did not colonize any region of the GI tract whether following a single bolus or daily administration for up to 10 days. We conclude that ICG may provide a useful tool to visualize and track probiotic species such as B420 without implementing complex molecular and genetic tools. Proof-of-concept studies indicate that B420 did not colonize and establish residency align the murine GI tract.
• Mencarini, T., Roka-Moiia, Y., Bozzi, S., Redaelli, A., & Slepian, M. J. (2021). Electrical impedance vs. light transmission aggregometry: Testing platelet reactivity to antiplatelet drugs using the MICELI POC impedance aggregometer as compared to a commercial predecessor. Thrombosis research, 204, 66-75.
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  Patients' responses to antiplatelet therapy significantly vary, with individuals showing high residual platelet reactivity associated with thrombosis. To personalize thrombosis management, platelet function testing has been suggested as a promising tool able to monitor the antithrombotic effect of antiplatelet agents in real-time. We have prototyped the MICELI, a miniature and easy-to-use electrical impedance aggregometer (EIA), measuring platelet aggregation in whole blood. Here, we tested the capability of the MICELI aggregometer to quantify platelet reactivity on antiplatelet agents, as compared with conventional light-transmission aggregometry (LTA).
• Palomares, D., Ammann, K. R., Saldana Perez, J. J., Gomez, A., Barreda, A., Russell-Cheung, A., Martin, A., Tran, P. L., Hossainy, S., Slepian, R. C., Hossainy, S. F., & Slepian, M. J. (2021). Patterned Electrospinning: A Method of Generating Defined Fibrous Constructs Influencing Cell Adhesion and Retention. ACS applied bio materials, 4(5), 4084-4093.
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  A critical component of tissue engineering is the ability to functionally replace native tissue stroma. Electrospinning is a technique capable of forming fibrous constructs with a high surface area for increased cell-material interaction and enhanced biocompatibility. However, physical and biological properties of electrospun scaffolds are limited by design controllability on a macroscale. We developed a methodology for generating electrospun scaffolds with defined patterns and topographic features to influence physical properties and biological interactions. Five unique design electrospinning target collectors were fabricated to allow for generation of defined polymeric scaffold patterns including lines, sinusoids, squares, zigzags, and solid. Poly(lactic--glycolic) acid was electrospun under identical conditions utilizing these varied targets, and constructs generated were examined as to their physical configuration, mechanical and chemical properties, and their ability to foster vascular smooth muscle cell adhesion and retention at 24 h. Modifying collector designs led to significant differences in fiber target coverage ranging from 300 mm for solid (100% of the target area) to 217.8 mm for lines (72.6% of the target area). Measured fiber excess, residual open area, and contact angle (hydrophobicity) followed the same trend as fiber target coverage with respect to the collector pattern: lines > sinusoids > squares > zigzags > solid. Similarly, the line design allowed for the greatest cell adhesion and retention (258 ± 31 cells), whereas solid exhibited the lowest (150 ± 15 cells); < 0.05. There was a strong direct correlation of cell adhesion to construct residual open area ( = 0.94), normalized fiber excess ( = 0.99), and fiber grammage ( = 0.72), with an inverse relationship to fiber target coverage ( = 0.94). Our results demonstrate the ability to utilize patterned collectors for modifying macroscopic and microscopic electrospun scaffold features, which directly impact cell adhesion and retention, offering translational utility for designing specific tissue constructs.
• Rahman, F., Meyer, R., Kriak, J., Goldblatt, S., & Slepian, M. J. (2021). Big Data Analytics + Virtual Clinical Semantic Network (vCSN): An Approach to Addressing the Increasing Clinical Nuances and Organ Involvement of COVID-19. ASAIO journal (American Society for Artificial Internal Organs : 1992), 67(1), 18-24.
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  The coronavirus disease 2019 (COVID-19) pandemic has revealed deep gaps in our understanding of the clinical nuances of this extremely infectious viral pathogen. In order for public health, care delivery systems, clinicians, and other stakeholders to be better prepared for the next wave of SARS-CoV-2 infections, which, at this point, seems inevitable, we need to better understand this disease-not only from a clinical diagnosis and treatment perspective-but also from a forecasting, planning, and advanced preparedness point of view. To predict the onset and outcomes of a next wave, we first need to understand the pathologic mechanisms and features of COVID-19 from the point of view of the intricacies of clinical presentation, to the nuances of response to therapy. Here, we present a novel approach to model COVID-19, utilizing patient data from related diseases, combining clinical understanding with artificial intelligence modeling. Our process will serve as a methodology for analysis of the data being collected in the ASAIO database and other data sources worldwide.
• Roka-Moiia, Y., Ammann, K. R., Miller-Gutierrez, S., Sweedo, A., Palomares, D., Italiano, J., Sheriff, J., Bluestein, D., & Slepian, M. J. (2021). Shear-mediated platelet activation in the free flow II: Evolving mechanobiological mechanisms reveal an identifiable signature of activation and a bi-directional platelet dyscrasia with thrombotic and bleeding features. Journal of biomechanics, 123, 110415.
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  Shear-mediated platelet activation (SMPA) in the "free flow" is the net result of a range of cell mechanobiological mechanisms. Previously, we outlined three main groups of mechanisms including: 1) mechano-destruction - i.e. additive platelet (membrane) damage; 2) mechano-activation - i.e. activation of shear-sensitive ion channels and pores; and 3) mechano-transduction - i.e. "outside-in" signaling via a range of transducers. Here, we report on recent advances since our original report which describes additional features of SMPA. A clear "signature" of SMPA has been defined, allowing differentiation from biochemically-mediated activation. Notably, SMPA is characterized by mitochondrial dysfunction, platelet membrane eversion, externalization of anionic phospholipids, and increased thrombin generation on the platelet surface. However, SMPA does not lead to integrin αIIbβ3 activation or P-selectin exposure due to platelet degranulation, as is commonly observed in biochemical activation. Rather, downregulation of GPIb, αIIbβ3, and P-selectin surface expression is evident. Furthermore, SMPA is accompanied by a decrease in overall platelet size coupled with a concomitant, progressive increase in microparticle generation. Shear-ejected microparticles are highly enriched in GPIb and αIIbβ3. These observations indicate the enhanced diffusion, migration, or otherwise dispersion of platelet adhesion receptors to membrane zones, which are ultimately shed as receptor-rich PDMPs. The pathophysiological consequence of this progressive shear accumulation phenomenon is an associated dyscrasia of remaining platelets - being both reduced in size and less activatable via biochemical means - a tendency to favor bleeding, while concomitantly shed microparticles are highly prothrombotic and increase the tendency for thrombosis in both local and systemic milieu. These mechanisms and observations offer direct clinical utility in allowing measurement and guidance of the net balance of platelet driven events in patients with implanted cardiovascular therapeutic devices.
• Roka-Moiia, Y., Li, M., Ivich, A., Muslmani, S., Kern, K. B., & Slepian, M. J. (2021). Impella 5.5 Versus Centrimag: A Head-to-Head Comparison of Device Hemocompatibility. ASAIO journal (American Society for Artificial Internal Organs : 1992), 66(10), 1142-1151.
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  Despite growing use of mechanical circulatory support, limitations remain related to hemocompatibility. Here, we performed a head-to-head comparison of the hemocompatibility of a centrifugal cardiac assist system-the Centrimag, with that of the latest generation of an intravascular microaxial system-the Impella 5.5. Specifically, hemolysis, platelet activation, microparticle (MP) generation, and von Willebrand factor (vWF) degradation were evaluated for both devices. Freshly obtained porcine blood was recirculated within device propelled mock loops for 4 hours, and alteration of the hemocompatibility parameters was monitored over time. We found that the Impella 5.5 and Centrimag exhibited low levels of hemolysis, as indicated by minor increase in plasma free hemoglobin. Both devices did not induce platelet degranulation, as no alteration of β-thromboglobulin and P-selectin in plasma occurred, rather minor downregulation of platelet surface P-selectin was detected. Furthermore, blood exposure to shear stress via both Centrimag and Impella 5.5 resulted in a minor decrease of platelet count with associated ejection of procoagulant MPs, and a decrease of vWF functional activity (but not plasma level of vWF-antigen). Greater MP generation was observed with the Centrimag relative to the Impella 5.5. Thus, the Impella 5.5 despite having a lower profile and higher impeller rotational speed demonstrated good and equivalent hemocompatibility, in comparison with the predicate Centrimag, with the advantage of lower generation of MPs.
• Roka-Moiia, Y., Miller-Gutierrez, S., Palomares, D. E., Italiano, J. E., Sheriff, J., Bluestein, D., & Slepian, M. J. (2021). Platelet Dysfunction During Mechanical Circulatory Support: Elevated Shear Stress Promotes Downregulation of αβ and GPIb via Microparticle Shedding Decreasing Platelet Aggregability. Arteriosclerosis, thrombosis, and vascular biology, 41(4), 1319-1336.
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  [Figure: see text].
• Slepian, M. J., Ammann, K. R., Hossainy, S. F., & Hossainy, S. (2021). Hemocompatibility of polymers for use in vascular endoluminal implants. Journal of Applied Polymer Science, 138(43), 51277. doi:10.1002/app.51277
• Slepian, M. J., Ammann, K. R., Palomares, D., Saldana Perez, J. J., Gomez, A., Barreda, A., Russell-Cheung, A., Martin, A., Tran, P. L., Hossainy, S., Slepian, R. C., & Hossainy, S. F. (2021). Patterned Electrospinning: A Method of Generating Defined Fibrous Constructs Influencing Cell Adhesion and Retention. ACS Applied Bio Materials, 4(5), 4084-4093. doi:10.1021/acsabm.0c01311
• Slepian, M. J., Italiano, J., Bluestein, D., Sheriff, J., & Roka-Moiia, Y. (2021). Evolving perspectives on mechanical circulatory support biocompatibility and interfaces. Annals of cardiothoracic surgery, 10(3), 396-398.
• Slepian, M. J., Li, M., Chen, Y., Howard, J., Thomas, S., & Barth, E. J. (2021). Design, Modeling, and Experimental Characterization of A Valveless Pulsatile Flow Mechanical Circulatory Support Device. Journal of Medical Devices, 15(2). doi:10.1115/1.4049560
• Slepian, M. J., Yu, T. Z., Tchantchaleishvili, V., & Bonde, P. N. (2021). Highlights from the 66th Annual Meeting of the American Society for Artificial Internal Organs in Washington, DC. Artificial Organs, 45(10), 1250-1256. doi:10.1111/aor.14048
• Sweedo, A., Wise, L. M., Roka-Moiia, Y., Arce, F. T., Saavedra, S. S., Sheriff, J., Bluestein, D., Slepian, M. J., & Purdy, J. G. (2021). Shear-Mediated Platelet Activation is Accompanied by Unique Alterations in Platelet Release of Lipids. Cellular and molecular bioengineering, 14(6), 597-612.
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  Platelet activation by mechanical means such as shear stress exposure, is a vital driver of thrombotic risk in implantable blood-contacting devices used in the treatment of heart failure. Lipids are essential in platelets activation and have been studied following biochemical activation. However, little is known regarding lipid alterations occurring with mechanical shear-mediated platelet activation.
• Yu, T. Z., Tchantchaleishvili, V., Bonde, P. N., & Slepian, M. J. (2021). Highlights from the 66th Annual Meeting of the American Society for Artificial Internal Organs in Washington, DC. Artificial organs, 45(10), 1250-1256.
• Zhang, P., Sheriff, J., Einav, S., Slepian, M. J., Deng, Y., & Bluestein, D. (2021). A predictive multiscale model for simulating flow-induced platelet activation: Correlating in silico results with in vitro results. Journal of biomechanics, 117, 110275.
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  Flow-induced platelet activation prompts complex filopodial formation. Continuum methods fail to capture such molecular-scale mechanisms. A multiscale numerical model was developed to simulate this activation process, where a Dissipative Particle Dynamics (DPD) model of viscous blood flow is interfaced with a Coarse Grained Molecular Dynamics (CGMD) platelet model. Embedded in DPD blood flow, the macroscopic dynamic stresses are interactively transferred to the CGMD model, inducing intra-platelet associated events. The platelets activate by a biomechanical transductive linkage chain and dynamically change their shape in response. The models are fully coupled via a hybrid-potential interface and multiple time-stepping (MTS) schemes for handling the disparity between the spatiotemporal scales. Cumulative hemodynamic stresses that may lead to platelet activation are mapped on the surface membrane and simultaneously transmitted to the cytoplasm and cytoskeleton. Upon activation, the flowing platelets lose their quiescent discoid shape and evolve by forming filopodia. The model predictions were validated by a set of in vitro experiments, Platelets were exposed to various combinations of shear stresses and durations in our programmable hemodynamic shearing device (HSD). Their shape change was measured at multiple time points using scanning electron microscopy (SEM). The CGMD model parameters were fine-tuned by interrogating a parameter space established in these experiments. Segmentation of the SEM imaging streams was conducted by a deep machine learning system. This model can be further employed to simulate shear mediated platelet activation thrombosis initiation and to study the effects of modulating platelet properties to enhance their shear resistance via mechanotransduction pathways.
• Ammann, K. R., Ahamed, T., Sweedo, A. L., Ghaffari, R., Weiner, Y. E., Slepian, R. C., Jo, H., & Slepian, M. J. (2020). Human motion component and envelope characterization via wireless wearable sensors. BMC biomedical engineering, 2, 3.
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  The characterization of limb biomechanics has broad implications for analyzing and managing motion in aging, sports, and disease. Motion capture videography and on-body wearable sensors are powerful tools for characterizing linear and angular motions of the body, though are often cumbersome, limited in detection, and largely non-portable. Here we examine the feasibility of utilizing an advanced wearable sensor, fabricated with stretchable electronics, to characterize linear and angular movements of the human arm for clinical feedback. A wearable skin-adhesive patch with embedded accelerometer and gyroscope (BioStampRC, MC10 Inc.) was applied to the volar surface of the forearm of healthy volunteers. Arms were extended/flexed for the range of motion of three different regimes: 1) horizontal adduction/abduction 2) flexion/extension 3) vertical abduction. Data were streamed and recorded revealing the signal "pattern" of movement in three separate axes. Additional signal processing and filtering afforded the ability to visualize these motions in each plane of the body; and the 3-dimensional motion envelope of the arm.
• Beltrán, S. M., Slepian, M. J., & Taylor, R. E. (2020). Extending the Capabilities of Molecular Force Sensors via DNA Nanotechnology. Critical reviews in biomedical engineering, 48(1), 1-16.
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  At the nanoscale, pushing, pulling, and shearing forces drive biochemical processes in development and remodeling as well as in wound healing and disease progression. Research in the field of mechanobiology investigates not only how these loads affect biochemical signaling pathways but also how signaling pathways respond to local loading by triggering mechanical changes such as regional stiffening of a tissue. This feedback between mechanical and biochemical signaling is increasingly recognized as fundamental in embryonic development, tissue morphogenesis, cell signaling, and disease pathogenesis. Historically, the interdisciplinary field of mechanobiology has been driven by the development of technologies for measuring and manipulating cellular and molecular forces, with each new tool enabling vast new lines of inquiry. In this review, we discuss recent advances in the manufacturing and capabilities of molecular-scale force and strain sensors. We also demonstrate how DNA nanotechnology has been critical to the enhancement of existing techniques and to the development of unique capabilities for future mechanosensor assembly. DNA is a responsive and programmable building material for sensor fabrication. It enables the systematic interrogation of molecular biomechanics with forces at the 1- to 200-pN scale that are needed to elucidate the fundamental means by which cells and proteins transduce mechanical signals.
• Boraschi, A., Bozzi, S., Thamsen, B., Granegger, M., Wiegmann, L., Pappalardo, F., Slepian, M. J., Kurtcuoglu, V., Redaelli, A., De Zélicourt, D., & Consolo, F. (2020). Thrombotic Risk of Rotor Speed Modulation Regimes of Contemporary Centrifugal Continuous-flow Left Ventricular Assist Devices. ASAIO journal (American Society for Artificial Internal Organs : 1992).
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  Contemporary centrifugal continuous-flow left ventricular assist devices (LVADs) incorporate dynamic speed modulation algorithms. Hemocompatibility of these periodic unsteady pump operating conditions has been only partially explored. We evaluated whether speed modulation induces flow alterations associated with detrimental prothrombotic effects. For this aim, we evaluated the thrombogenic profile of the HeartWare ventricular assist device (HVAD) Lavare Cycle (LC) and HeartMate3 (HM3) artificial pulse (AP) via comprehensive numerical evaluation of (i) pump washout, (ii) stagnation zones, (iii) shear stress regimens, and (iv) modeling of platelet activation status via the platelet activity state (PAS) model. Data were compared between different simulated operating scenarios, including: (i) constant rotational speed and pump pressure head, used as reference; (ii) unsteady pump pressure head as induced by cardiac pulsatility; and (iii) unsteady rotor speed modulation of the LC (HVAD) and AP (HM3). Our results show that pump washout did not improve across the different simulated scenarios in neither the HVAD nor the HM3. The LC reduced but did not eliminate flow stagnation (-57%) and did not impact metrics of HVAD platelet activation (median PAS: +0.4%). The AP reduced HM3 flow stagnation by up to 91% but increased prothrombotic shear stress and simulated platelet activation (median PAS: +124%). Our study advances understanding of the pathogenesis of LVAD thrombosis, suggesting mechanistic implications of rotor speed modulation. Our data provide rationale criteria for the future design optimization of next generation LVADs to further reduce hemocompatibility-related adverse events.
• Findley, J., Woods, A., Robertson, C., & Slepian, M. (2020). Keeping the Patient at the Center of Machine Learning in Healthcare. The American journal of bioethics : AJOB, 20(11), 54-56.
• Jacobs, J. P., Stammers, A. H., St Louis, J., Hayanga, J. W., Firstenberg, M. S., Mongero, L. B., Tesdahl, E. A., Rajagopal, K., Cheema, F. H., Coley, T., Badhwar, V., Sestokas, A. K., & Slepian, M. J. (2020). Extracorporeal Membrane Oxygenation in the Treatment of Severe Pulmonary and Cardiac Compromise in Coronavirus Disease 2019: Experience with 32 Patients. ASAIO journal (American Society for Artificial Internal Organs : 1992), 66(7), 722-730.
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  As coronavirus disease 2019 (COVID-19) cases surge worldwide, an urgent need exists to enhance our understanding of the role of extracorporeal membrane oxygenation (ECMO) in the management of severely ill patients with COVID-19 who develop acute respiratory and cardiac compromise refractory to conventional therapy. The purpose of this manuscript is to review our initial clinical experience in 32 patients with confirmed COVID-19 treated with ECMO. A multi-institutional registry and database was created and utilized to assess all patients who were supported with ECMO provided by SpecialtyCare. Data captured included patient characteristics, pre-COVID-19 risk factors and comorbidities, confirmation of COVID-19 diagnosis, features of ECMO support, specific medications utilized to treat COVID-19, and short-term outcomes through hospital discharge. This analysis includes all of our patients with COVID-19 supported with ECMO, with an analytic window starting March 17, 2020, when our first COVID-19 patient was placed on ECMO, and ending April 9, 2020. During the 24 days of this study, 32 consecutive patients with COVID-19 were placed on ECMO at nine different hospitals. As of the time of analysis, 17 remain on ECMO, 10 died before or shortly after decannulation, and five are alive and extubated after removal from ECMO, with one of these five discharged from the hospital. Adjunctive medication in the surviving patients while on ECMO was as follows: four of five survivors received intravenous steroids, three of five survivors received antiviral medications (Remdesivir), two of five survivors were treated with anti-interleukin-6-receptor monoclonal antibodies (Tocilizumab or Sarilumab), and one of five survivors received hydroxychloroquine. Analysis of these 32 COVID-19 patients with severe pulmonary compromise supported with ECMO suggests that ECMO may play a useful role in salvaging select critically ill patients with COVID-19. Additional patient experience and associated clinical and laboratory data must be obtained to further define the optimal role of ECMO in patients with COVID-19 and acute respiratory distress syndrome (ARDS). These initial data may provide useful information to help define the best strategies to care for these challenging patients and may also provide a framework for much-needed future research about the use of ECMO to treat patients with COVID-19.
• Kovarovic, B. J., Rotman, O. M., Parikh, P., Slepian, M. J., & Bluestein, D. (2020). Patient-specific in vitro testing for evaluating TAVR clinical performance- a complementary approach to current ISO standard testing. Artificial organs.
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  Following in vitro tests established for surgical prosthetic heart valves, transcatheter aortic valves (TAV) are similarly tested in idealized geometries- excluding effects that may hamper TAVR performance in situ. Testing in vitro in pulse duplicator systems that incorporated patient specific replicas would enhance the testing veracity by bringing it closer to the clinical scenario. To that end we compare TAV hemodynamic performance tested in idealized geometries according to the ISO standard (baseline performance) to that obtained by testing the TAVs following deployment in patient-specific replicas. Balloon-expandable (n=2) and self-expandable (n=3) TAVs were tested in an idealized geometry in mock-circulation system (following ISO 5840-3 guidelines) and compared to measurements in a dedicated mock-circulation system adapted for the five patient-specific replicas. Patient-specific deployments resulted in a decline in performance as compared to the baseline idealized testing, as well as a variation in performance that depended on the design features of each device that was further correlated with the radial expansion and eccentricity of the deployed TAV stent (obtained with CT-scans of the deployed valves). By excluding deployment effects in irregular geometries, the current idealized ISO testing is limited to characterize baseline device performance. Utilizing patient-specific anatomic contours provides performance indicators under more stringent conditions likely encountered in vivo. It has the potential to enhance testing and development complementary to the ISO standard, for improved TAV safety and effectiveness.
• Rajagopal, K., Keller, S. P., Akkanti, B., Bime, C., Loyalka, P., Cheema, F. H., Zwischenberger, J. B., El Banayosy, A., Pappalardo, F., Slaughter, M. S., & Slepian, M. J. (2020). Advanced Pulmonary and Cardiac Support of COVID-19 Patients: Emerging Recommendations From ASAIO-A "Living Working Document". ASAIO journal (American Society for Artificial Internal Organs : 1992), 66(6), 588-598.
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  The severe acute respiratory syndrome (SARS)-CoV-2 is an emerging viral pathogen responsible for the global coronavirus disease 2019 (COVID)-19 pandemic resulting in significant human morbidity and mortality. Based on preliminary clinical reports, hypoxic respiratory failure complicated by acute respiratory distress syndrome is the leading cause of death. Further, septic shock, late-onset cardiac dysfunction, and multiorgan system failure are also described as contributors to overall mortality. Although extracorporeal membrane oxygenation and other modalities of mechanical cardiopulmonary support are increasingly being utilized in the treatment of respiratory and circulatory failure refractory to conventional management, their role and efficacy as support modalities in the present pandemic are unclear. We review the rapidly changing epidemiology, pathophysiology, emerging therapy, and clinical outcomes of COVID-19; and based on these data and previous experience with artificial cardiopulmonary support strategies, particularly in the setting of infectious diseases, provide consensus recommendations from ASAIO. Of note, this is a "living document," which will be updated periodically, as additional information and understanding emerges.
• Rajagopal, K., Keller, S. P., Akkanti, B., Bime, C., Loyalka, P., Cheema, F. H., Zwischenberger, J. B., El Banayosy, A., Pappalardo, F., Slaughter, M. S., & Slepian, M. J. (2020). Advanced Pulmonary and Cardiac Support of COVID-19 Patients: Emerging Recommendations From ASAIOa Living Working Document. Circulation. Heart failure, 13(5), e007175.
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  The severe acute respiratory syndrome-CoV-2 is an emerging viral pathogen responsible for the global coronavirus disease 2019 pandemic resulting in significant human morbidity and mortality. Based on preliminary clinical reports, hypoxic respiratory failure complicated by acute respiratory distress syndrome is the leading cause of death. Further, septic shock, late-onset cardiac dysfunction, and multiorgan system failure are also described as contributors to overall mortality. Although extracorporeal membrane oxygenation and other modalities of mechanical cardiopulmonary support are increasingly being utilized in the treatment of respiratory and circulatory failure refractory to conventional management, their role and efficacy as support modalities in the present pandemic are unclear. We review the rapidly changing epidemiology, pathophysiology, emerging therapy, and clinical outcomes of coronavirus disease 2019; and based on these data and previous experience with artificial cardiopulmonary support strategies, particularly in the setting of infectious diseases, provide consensus recommendations from American Society for Artificial Internal Organs. Of note, this is a living document, which will be updated periodically, as additional information and understanding emerges.
• Roka-Moiia, Y., Bozzi, S., Ferrari, C., Mantica, G., Dimasi, A., Rasponi, M., Santoleri, A., Scavone, M., Consolo, F., Cattaneo, M., Slepian, M. J., & Redaelli, A. (2020). The MICELI (MICrofluidic, ELectrical, Impedance): Prototyping a Point-of-Care Impedance Platelet Aggregometer. International journal of molecular sciences, 21(4).
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  As key cellular elements of hemostasis, platelets represent a primary target for thrombosis and bleeding management. Currently, therapeutic manipulations of platelet function (antithrombotic drugs) and count (platelet transfusion) are performed with limited or no real-time monitoring of the desired outcome at the point-of-care. To address the need, we have designed and fabricated an easy-to-use, accurate, and portable impedance aggregometer called "MICELI" (MICrofluidic, ELectrical, Impedance). It improves on current platelet aggregation technology by decreasing footprint, assay complexity, and time to obtain results. The current study aimed to optimize the MICELI protocol; validate sensitivity to aggregation agonists and key blood parameters, i.e., platelet count and hematocrit; and verify the MICELI operational performance as compared to commercial impedance aggregometry. We demonstrated that the MICELI aggregometer could detect platelet aggregation in 250 μL of whole blood or platelet-rich plasma, stimulated by ADP, TRAP-6, collagen, epinephrine, and calcium ionophore. Using hirudin as blood anticoagulant allowed higher aggregation values. Aggregation values obtained by the MICELI strongly correlated with platelet count and were not affected by hematocrit. The operational performance comparison of the MICELI and the Multiplate Analyzer demonstrated strong correlation and similar interdonor distribution of aggregation values obtained between these devices. With the proven reliability of the data obtained by the MICELI aggregometer, it can be further translated into a point-of-care diagnostic device aimed at monitoring platelet function in order to guide pharmacological hemostasis management and platelet transfusions.
• Roka-Moiia, Y., Walk, R., Palomares, D. E., Ammann, K. R., Dimasi, A., Italiano, J. E., Sheriff, J., Bluestein, D., & Slepian, M. J. (2020). Platelet Activation via Shear Stress Exposure Induces a Differing Pattern of Biomarkers of Activation versus Biochemical Agonists. Thrombosis and haemostasis, 120(5), 776-792.
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   Implantable cardiovascular therapeutic devices, while hemodynamically effective, remain limited by thrombosis. A driver of device-associated thrombosis is shear-mediated platelet activation (SMPA). Underlying mechanisms of SMPA, as well as useful biomarkers able to detect and discriminate mechanical versus biochemical platelet activation, are poorly defined. We hypothesized that SMPA induces a differing pattern of biomarkers compared with biochemical agonists.
• Slepian, M. J., Li, M., & Barth, E. J. (2020). Bond Graph Modeling of Mechanical Circulatory Support Device—Cardiovascular System Interactions. Journal of Biomechanical Engineering, 142(8). doi:10.1115/1.4045812
• Slepian, M. J., Li, M., Walk, R., Roka‐Moiia, Y., Sheriff, J., Bluestein, D., & Barth, E. J. (2020). Circulatory loop design and components introduce artifacts impacting in vitro evaluation of ventricular assist device thrombogenicity: A call for caution. Artificial Organs, 44(6). doi:10.1111/aor.13626
• Slepian, M. J., Slaughter, M. S., Bime, C., Keller, S. P., Rajagopal, K., Akkanti, B., Loyalka, P., Cheema, F. H., Zwischenberger, J. B., El Banayosy, A., & Pappalardo, F. (2020). Advanced Pulmonary and Cardiac Support of COVID-19 Patients: Emerging Recommendations From ASAIO — a Living Working Document. Circulation: Heart Failure, 13(5). doi:10.1161/circheartfailure.120.007175
• Ammann, K. R., DeCook, K. J., Li, M., & Slepian, M. J. (2019). Migration versus Proliferation as Contributor to In Vitro Wound Healing of Vascular Endothelial and Smooth Muscle Cells. Experimental cell research.
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  Wound closure, as a result of collective cell growth, is an essential biological response to injury. In the field of vascular biology, the response of vascular smooth muscle cells (SMCs) and endothelial cells (ECs) to injury and substrate surface is important in therapeutic clinical treatment interventions such as angioplasty and atherectomy. Specifically, the mechanism by which cells close wounds (i.e. proliferation versus migration) in response to injury stimuli is of interest to better modulate recurrent vascular stenosis, prevent thrombus formation, occlusion, and life-threatening cardiovascular events. Here, we examine growth extent and temporal sequence of events following wound or gap introduction to a confluent monolayer of vascular SMCs or ECs. Significant differences in the preferred mechanisms of these cells to close wounds or gaps were observed; after 48hours, 73% of SMC wound closure was observed to be due to proliferation, while 75% of EC wound closure resulted from migration. These mechanisms were further modulated via addition or removal of extracellular matrix substrate and injury, with ECs more responsive to substrate composition and less to injury, in comparison to SMCs. Our results indicate that ECs and SMCs heal wounds differently, and that the time and mode of injury and associated substrate surface all impact this response.
• Ammann, K. R., Li, M., Hossainy, S., & Slepian, M. J. (2019). The Influence of Polymer Processing Methods on Polymer Film Physical Properties and Vascular Cell Responsiveness. ACS applied bio materials, 2(8), 3234-3244.
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  Implantable vascular devices typically interface with blood and vascular tissues. Physical properties of device materials and coatings, independent of chemical composition, can significantly influence cell responses and implant success. Here, we analyzed the effect of various polymer processing regimes, using a single implant polymer - poly(ε-caprolactone) (PCL), on vascular endothelial cell (EC), smooth muscle cell (SMC), and platelet response. PCL films were formed by varying three parameters: 1) formation method - solvent casting, melt pressing or spin coating; 2) molecular weight - 50 or 100 kDa; and 3) solvent type - dichloromethane (DCM) or tetrahydrofuran (THF). We quantified the relationship of polymer processing choice to surface roughness, wettability, and bulk stiffness; and to EC adhesion, SMC adhesion, and platelet activity state (PAS). Multiple regression analysis identified which processing method signficantly impacted (F-ratio>p-value; p
• Apostoli, A., Bianchi, V., Bono, N., Dimasi, A., Ammann, K. R., Moiia, Y. R., Montisci, A., Sheriff, J., Bluestein, D., Fiore, G. B., Pappalardo, F., Candiani, G., Redaelli, A., Slepian, M. J., & Consolo, F. (2019). Prothrombotic activity of cytokine-activated endothelial cells and shear-activated platelets in the setting of ventricular assist device support. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation, 38(6), 658-667.
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  We systematically analyzed the synergistic effect of: (i) cytokine-mediated inflammatory activation of endothelial cells (ECs) with and (ii) shear-mediated platelet activation (SMPA) as a potential contributory mechanism to intraventricular thrombus formation in the setting of left ventricular assist device (LVAD) support.
• Ardila, D. C., Liou, J. J., Maestas, D., Slepian, M. J., Badowski, M., Wagner, W. R., Harris, D., & Vande Geest, J. P. (2019). Surface Modification of Electrospun Scaffolds for Endothelialization of Tissue-Engineered Vascular Grafts Using Human Cord Blood-Derived Endothelial Cells. Journal of clinical medicine, 8(2).
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  Tissue engineering has gained attention as an alternative approach for developing small diameter tissue-engineered vascular grafts intended for bypass surgery, as an option to treat coronary heart disease. To promote the formation of a healthy endothelial cell monolayer in the lumen of the graft, polycaprolactone/gelatin/fibrinogen scaffolds were developed, and the surface was modified using thermoforming and coating with collagen IV and fibronectin. Human cord blood-derived endothelial cells (hCB-ECs) were seeded onto the scaffolds and the important characteristics of a healthy endothelial cell layer were evaluated under static conditions using human umbilical vein endothelial cells as a control. We found that polycaprolactone/gelatin/fibrinogen scaffolds that were thermoformed and coated are the most suitable for endothelial cell growth. hCB-ECs can proliferate, produce endothelial nitric oxide synthase, respond to interleukin 1 beta, and reduce platelet deposition.
• Chiu, W. C., Tran, P. L., Khalpey, Z., Lee, E., Woo, Y. R., Slepian, M. J., & Bluestein, D. (2019). Device Thrombogenicity Emulation: An In Silico Predictor of In Vitro and In Vivo Ventricular Assist Device Thrombogenicity. Scientific reports, 9(1), 2946.
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  Ventricular assist devices (VAD), a mainstay of therapy for advanced and end-stage heart failure, remain plagued by device thrombogenicity. Combining advanced in silico and in vitro methods, Device Thrombogenicity Emulation (DTE) is a device design approach for enhancing VAD thromboresistance. Here we tested DTE efficacy in experimental VAD designs. DTE incorporates iterative design modifications with advanced CFD to compute the propensity of large populations of platelets to activate by flow-induced stresses (statistically representing the VAD 'Thrombogenic Footprint'). The DTE approach was applied to a VAD (MIN) design with a favorable thromboresistance profile and compared against a design (MAX) that generated an intentionally poor thromboresistance profile. DTE predictions were confirmed by testing physical prototypes in vitro by measuring VAD thrombogenicity using the modified prothrombinase assay. Chronic in vivo studies in VAD implanted calves, revealed MIN calf surviving well with low platelet activation, whereas the MAX animal sustained thromboembolic strokes. DTE predictions were confirmed, correlating with in vitro and in vivo thrombogenicity, supporting utility in guiding device development, potentially reducing the need for animal studies.
• Dean, Z. S., Jamilpour, N., Slepian, M. J., & Wong, P. K. (2019). Decreasing Wound Edge Stress Enhances Leader Cell Formation during Collective Smooth Muscle Cell Migration. ACS biomaterials science & engineering, 5(8), 3864-3875.
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  Collective cell migration is vital to tissue remodeling in wound repair, development, and cancer invasion. Nevertheless, studies on collective cell migration have largely focused on epithelial growth and repair mechanisms and have only recently expanded to explore coordinated metastatic cancer and smooth muscle cell behaviors. The regulatory mechanisms of smooth muscle cell collective migration, such as leader-follower organization and mechanosensitivity, remain poorly understood. In this study, we demonstrate the involvement of leader cells during collective smooth muscle cell migration using dynamic cell tracking and single cell gene expression analysis. Engineered wound models, including ingrowth, outgrowth, and straight edge geometries, along with traction force microscopy and finite element stress mapping reveal that smooth muscle leader cells are enhanced at the wound edge when the intercellular tension near the cell wound boundary is reduced. Pharmacological perturbation further supports the notion that mechanical force negatively regulates the formation of leader cells. The mechanical regulation of collective smooth muscle cell migration via the formation of leader cells may lead to novel treatment strategies for pathogenic smooth muscle cell conditions in the future.
• Garlant, J. A., Ammann, K. R., & Slepian, M. J. (2019). Stretchable Electronic Wearable Motion Sensors Delineate Signatures of Human Motion Tasks. ASAIO journal (American Society for Artificial Internal Organs : 1992), 64(3), 351-359.
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  Digital tracking of human motion offers the potential to monitor a wide range of activities detecting normal versus abnormal performance of tasks. We examined the ability of a wearable, conformal sensor system, fabricated from stretchable electronics with contained accelerometers and gyroscopes, to specifically detect, monitor, and define motion signals and "signatures," associated with tasks of daily living activities. The sensor system was affixed to the dominant hand of healthy volunteers (n = 4) who then completed four tasks. For all tasks examined, motion data could be captured, monitored continuously, uploaded to the digital cloud, and stored for further analysis. Acceleration and gyroscope data were collected in the x-, y-, and z-axes, yielding unique patterns of component motion signals for each task studied. Upon analysis, low-frequency (
• Kern, K. B., Colberg, T. P., Wunder, C., Newton, C., & Slepian, M. J. (2019). A local neighborhood volunteer network improves response times for simulated cardiac arrest. Resuscitation, 144, 131-136.
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  Each minute is crucial in the treatment of out-of-hospital cardiac arrest (CA). Immediate chest compressions and early defibrillation are keys to good outcomes. We hypothesized that a coordinated effort of alerting trained local neighborhood volunteers (vols) simultaneously with 911 activation of professional EMS providers would result in substantial decreases in call-to-arrival times, leading to earlier CPR and defibrillation.
• Li, M., Slepian, M. J., & Barth, E. J. (2019). Bond Graph Modeling of Mechanical Circulatory Support (MCS) - Cardiovascular System Interactions. Journal of biomechanical engineering.
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  Though mechanical circulatory support (MCS) devices, such as ventricular assist devices (VAD) and total artificial hearts (TAH), provide heart failure patients with bridges to heart transplantation or are alternatives to transplantation, device performance and corresponding control strategies are often difficult to evaluate. Difficulties arise due to the complex interaction of multiple domains - i.e. biological, hydraulic, hemodynamics, electromechanical, system dynamics, and controls. In an attempt to organize, integrate and clarify these interactions, a technique often used in hydraulic pump design and robotics, called bond graph modeling, is applied to describe the performance and functionality of MCS devices and the interaction between the cardiovascular system and the MCS devices. To illustrate the advantages of this tool, a bond graph model was developed for the systemic circulation interacting with the left side of a basic TAH, adopting the fundamental structure of either a hydraulic mechanism (i.e. AbioCor/Carmat) or a pneumatic mechanism (i.e. SynCardia), combined with a systemic circulation loop. The model captures the dynamics of the membrane, the hydraulic source or pneumatic source, and the systemic circulation. The values of multiple variables were tuned and the corresponding effects were plotted. It was shown that this bond graph methodology faithfully captures the interaction of an MCS device with the CV system. This multi-disciplinary cross-pollination of an analytical tool from the field of dynamic systems may provide important insight to further aid and improve the design and control of future MCS systems.
• Li, M., Walk, R., Roka-Moiia, Y., Sheriff, J., Bluestein, D., Barth, E. J., & Slepian, M. J. (2019). Circulatory Loop Design and Components Introduce Artifacts Impacting In-Vitro Evaluation of Ventricular Assist Device Thrombogenicity: A Call for Caution. Artificial organs.
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  Mechanical circulatory support (MCS) devices continue to be hampered by thrombotic adverse events, a consequence of device-imparted supraphysiologic shear stresses, leading to shear-mediated platelet activation (SMPA). In advancing MCS devices from design to clinical use, in-vitro circulatory loops containing the device under development and testing are utilized as a means of assessing device thrombogenicity. Physical characteristics of these test circulatory loops may too contribute to inadvertent platelet activation through imparted shear stress, adding inadvertent error in evaluating MCS device thrombogenicity. While investigators normally control for the effect of a loop, inadvertent addition of what are considered innocuous connectors may impact test results. Here we tested the effect of common, additive components of in-vitro circulatory test loops, i.e. connectors and loop geometry, as to their additive contribution to shear stress via both in-silico and in-vitro models. A series of test circulatory loops containing a ventricular assist device (VAD) with differing constituent components, were established in-silico including: loops with 0 ~ 5 Luer connectors, a loop with a T-connector creating 90° angulation, and a loop with 90° angulation. Computational fluid dynamics (CFD) simulations were performed using a Ƙ-ω shear stress transport (SST) turbulence model to platelet activation index based on a power law model. VAD-operated loops replicating in-silico designs were assembled in-vitro and gel-filtered human platelets were recirculated within (1 h) and SMPA was determined. Results: CFD simulations demonstrated high shear being introduced at non-smooth regions such as edge-connector boundaries, tubing, and at Luer holes. Noticeable peaks' shifts of sss distributions towards high shear-region existed with increasing loop complexity. Platelet activation also increased with increasing shear exposure time, being statistically higher when platelets were exposed to connector-employed loop designs. The extent of platelet activation in-vitro could be successfully predicted by CFD simulations. Loops employing additional components (non-physiologically flow pattern connectors) resulted in higher platelet activation index. Loops with more components (5-connector loop and 90° T-connector) showed 63% and 128% higher platelet activation levels, respectively, versus those with fewer (0-connector (p=0.023) and a 90° heat-bend loop (p=0.0041). Our results underscore the importance of careful consideration of all component elements, and suggest the need for standardization, in designing in-vitro circulatory loops for MCS device evaluation to avoid inadvertent additive SMPA during device evaluation, confounding overall results. Specifically, we caution on the use and inadvertent introduction of additional connectors, ports and other shear-generating elements which introduce artifact, clouding primary device evaluation via introduction of additive SMPA.
• Rotman, O. M., Kovarovic, B., Bianchi, M., Slepian, M. J., & Bluestein, D. (2019). In Vitro Durability and Stability Testing of a Novel Polymeric Transcatheter Aortic Valve. ASAIO journal (American Society for Artificial Internal Organs : 1992).
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  Transcatheter aortic valve replacement (TAVR) has emerged as an effective therapy for the unmet clinical need of inoperable patients with severe aortic stenosis (AS). Current clinically used tissue TAVR valves suffer from limited durability that hampers TAVR's rapid expansion to younger, lower risk patients. Polymeric TAVR valves optimized for hemodynamic performance, hemocompatibility, extended durability, and resistance to calcific degeneration offer a viable solution to this challenge. We present extensive in vitro durability and stability testing of a novel polymeric TAVR valve (PolyNova valve) using 1) accelerated wear testing (AWT, ISO 5840); 2) calcification susceptibility (in the AWT)-compared with clinically used tissue valves; and 3) extended crimping stability (valves crimped to 16 Fr for 8 days). Hydrodynamic testing was performed every 50M cycles. The valves were also evaluated visually for structural integrity and by scanning electron microscopy for evaluation of surface damage in the micro-scale. Calcium and phosphorus deposition was evaluated using micro-computed tomography (μCT) and inductive coupled plasma spectroscopy. The valves passed 400M cycles in the AWT without failure. The effective orifice area kept stable at 1.8 cm with a desired gradual decrease in transvalvular pressure gradient and regurgitation (10.4 mm Hg and 6.9%, respectively). Calcium and phosphorus deposition was significantly lower in the polymeric valve: down by a factor of 85 and 16, respectively-as compared to a tissue valve. Following the extended crimping testing, no tears nor surface damage were evident. The results of this study demonstrate the potential of a polymeric TAVR valve to be a viable alternative to tissue-based TAVR valves.
• Rotman, O. M., Kovarovic, B., Chiu, W. C., Bianchi, M., Marom, G., Slepian, M. J., & Bluestein, D. (2019). Novel Polymeric Valve for Transcatheter Aortic Valve Replacement Applications: In Vitro Hemodynamic Study. Annals of biomedical engineering, 47(1), 113-125.
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  Transcatheter aortic valve replacement (TAVR) is a minimally-invasive approach for treating severe aortic stenosis. All clinically-used TAVR valves to date utilize chemically-fixed xenograft as the leaflet material. Inherent limitation of the tissue (e.g., calcific degeneration) motivates the search for alternative leaflet material. Here we introduce a novel polymeric TAVR valve that was designed to address the limitations of tissue-valves. In this study, we experimentally evaluated the hemodynamic performance of the valve and compared its performance to clinically-used valves: a gold standard surgical tissue valve, and a TAVR valve. Our comparative testing protocols included: (i) baseline hydrodynamics (ISO:5840-3), (ii) complementary patient-specific hydrodynamics in a dedicated system, and (iii) thrombogenicity. The patient-specific testing system facilitated comparing TAVR valves performance under more realistic conditions. Baseline hydrodynamics results at CO 4-7 L/min showed superior effective orifice area (EOA) for the polymer valve, most-notably as compared to the reference TAVR valve. Regurgitation fraction was higher in the polymeric valve, but within the ISO minimum requirements. Thrombogenicity trends followed the EOA results with the polymeric valve being the least thrombogenic, and clinical TAVR being the most. Hemodynamic-wise, the results strongly indicate that our polymeric TAVR valve can outperform tissue valves.
• Slepian, M. J., Ammann, K. R., Li, M., & Hossainy, S. (2019). The Influence of Polymer Processing Methods on Polymer Film Physical Properties and Vascular Cell Responsiveness. ACS Applied Bio Materials, 2(8), 3234-3244. doi:10.1021/acsabm.9b00175
• Watts, G. S., Thornton, J. E., Youens-Clark, K., Ponsero, A. J., Slepian, M. J., Menashi, E., Hu, C., Deng, W., Armstrong, D. G., Reed, S., Cranmer, L. D., & Hurwitz, B. L. (2019). Identification and quantitation of clinically relevant microbes in patient samples: Comparison of three k-mer based classifiers for speed, accuracy, and sensitivity. PLoS computational biology, 15(11), e1006863.
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  Infections are a serious health concern worldwide, particularly in vulnerable populations such as the immunocompromised, elderly, and young. Advances in metagenomic sequencing availability, speed, and decreased cost offer the opportunity to supplement or even replace culture-based identification of pathogens with DNA sequence-based diagnostics. Adopting metagenomic analysis for clinical use requires that all aspects of the workflow are optimized and tested, including data analysis and computational time and resources. We tested the accuracy, sensitivity, and resource requirements of three top metagenomic taxonomic classifiers that use fast k-mer based algorithms: Centrifuge, CLARK, and KrakenUniq. Binary mixtures of bacteria showed all three reliably identified organisms down to 1% relative abundance, while only the relative abundance estimates of Centrifuge and CLARK were accurate. All three classifiers identified the organisms present in their default databases from a mock bacterial community of 20 organisms, but only Centrifuge had no false positives. In addition, Centrifuge required far less computational resources and time for analysis. Centrifuge analysis of metagenomes obtained from samples of VAP, infected DFUs, and FN showed Centrifuge identified pathogenic bacteria and one virus that were corroborated by culture or a clinical PCR assay. Importantly, in both diabetic foot ulcer patients, metagenomic sequencing identified pathogens 4-6 weeks before culture. Finally, we show that Centrifuge results were minimally affected by elimination of time-consuming read quality control and host screening steps.
• Consolo, F., Pozzi, L., Sferrazza, G., Della Valle, P., D'Angelo, A., Slepian, M. J., & Pappalardo, F. (2018). Which Antiplatelet Therapy in Patients With Left Ventricular Assist Device and Aspirin Allergy?. The Annals of thoracic surgery, 105(2), e47-e49.
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  In patients with left ventricular assist device support and aspirin allergy, the choice of effective antiplatelet strategy remains a challenge. We compared the antithrombotic effect of clopidogrel vs ticagrelor in an LVAD patient with aspirin allergy by using a modified protocol of the thrombin generation test, accounting selectively for the platelet contribution on thrombin generation. Our results demonstrate enhanced antithrombotic efficacy offered by ticagrelor. Consistent with experimental results, the patient has passed more than 300 days without thromboembolic complications. This study provides additional mechanistic rationale supporting clinical evidence and opens the perspective to identify individual poor responsiveness to drugs by specifically evaluating drug-mediated platelet function.
• Consolo, F., Sferrazza, G., Motolone, G., Pieri, M., De Bonis, M., Zangrillo, A., Redaelli, A., Slepian, M. J., & Pappalardo, F. (2018). Shear-Mediated Platelet Activation Enhances Thrombotic Complications in Patients With LVAD and Is Reversed After Heart Transplantation. ASAIO journal (American Society for Artificial Internal Organs : 1992).
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  We present a time-series analysis of shear-mediated platelet activation (SMPA) in a patient supported by a left ventricular assist device (LVAD) who developed recurrent thromboembolic events over the course of support. The patient showed marked alterations of SMPA as quantified via the platelet activity state (PAS) assay. At the time of a first pump thrombosis, PAS was equal to 16.2 ± 2.1%, indicating a significant level of SMPA. A moderate decrease of PAS was observed 30 days after pump exchange (PAS = 9.5 ± 1.0%). A sudden PAS increase was recorded after 60 days (PAS = 60.5 ± 4.3%), and an ischemic stroke with hemorrhagic transformation was subsequently diagnosed at 120 days after pump exchange (PAS = 86.9 ± 7.5%); high PAS values did not recover over time likely because of sustained platelet activation from the inflammatory milieu caused by a driveline infection occurred at 240 days of support (PAS = 84.4 ± 7.3%). Platelet activity state values were completely reversed after heart transplantation (PAS = 0.6 ± 0.1%), demonstrating resolution of SMPA. This study provides further insight into our understanding of the pathogenesis of LVAD thrombosis, addressing SMPA as a relevant key factor associated with thrombotic complications. With the PAS assay, we have identified a reliable biomarker to promote tailored pharmacological therapy for the prevention of thromboembolic events in patients with LVADs.
• Dimasi, A., Roka-Moiia, Y., Consolo, F., Rasponi, M., Fiore, G. B., Slepian, M. J., & Redaelli, A. (2018). Microfluidic flow-based platforms for induction and analysis of dynamic shear-mediated platelet activation-Initial validation versus the standardized hemodynamic shearing device. Biomicrofluidics, 12(4), 042208.
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  A microfluidic flow-based platform (μFP), able to stimulate platelets via exposure of shear stress patterns pertinent to cardiovascular devices and prostheses, was compared to the Hemodynamic Shearing Device (HSD)-a state-of-the-art bench-top system for exposure of platelets to defined levels and patterns of shear. Platelets were exposed to time-varying shear stress patterns in the two systems; in detail, platelets were recirculated in the μFP or stimulated in the HSD to replicate comparable exposure time. Shear-mediated platelet activation was evaluated via (i) the platelet activity state assay, allowing the measurement of platelet-mediated thrombin generation and associated prothrombotic tendencies, (ii) scanning electron microscopy to evaluate morphological changes of sheared platelets, and (iii) flow cytometry for the determination of platelet phosphatidylserine exposure as a marker of shear activation. The results revealed good matching and comparability between the two systems, with similar trends of platelet activation, formation of microaggregates, and analogous trends of activation marker exposure for both the HSD and microfluidic-stimulated samples. These findings support future translation of the microfluidic platform as a Point-of-Care facsimile system for the diagnosis of thrombotic risk in patients implanted with cardiovascular devices.
• Ghosh, R., Marom, G., Rotman, O., Slepian, M. J., Prabhakar, S., Horner, M., & Bluestein, D. (2018). Comparative Fluid-Structure Interaction Analysis of Polymeric Transcatheter and Surgical Aortic Valves' Hemodynamics and Structural Mechanics. Journal of biomechanical engineering.
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  Transcatheter aortic valve replacement (TAVR) has emerged as an effective alternative to conventional surgical aortic valve replacement (SAVR) in high-risk elderly patients with calcified aortic valve disease. All currently FDA-approved TAVR devices use tissue valves that were adapted to but not specifically designed for TAVR use. Emerging clinical evidence indicates that these valves may get damaged during crimping and deployment- leading to valvular calcification, thrombotic complications, and limited durability. This impedes the expected expansion of TAVR to lower-risk and younger patients. Viable polymeric valves have the potential to overcome such limitations. We have developed a polymeric SAVR valve, which was optimized to reduce leaflet stresses and offer a thromboresistance profile similar to that of a tissue valve. This study compares the polymeric SAVR valve's hemodynamic performance and mechanical stresses to a new version of the valve- specifically designed for TAVR. Fluid-structure interaction (FSI) models were utilized and the valves' hemodynamics, flexural stresses, strains, orifice area, and wall shear stresses were compared. The TAVR valve had 42% larger opening area and 27% higher flow rate versus the SAVR valve, while wall shear stress distribution and mechanical stress magnitudes were of the same order, demonstrating the enhanced performance of the TAVR valve prototype. The TAVR valve FSI simulation and Vivitro pulse duplicator experiments were compared in terms of the leaflets' kinematics and the effective orifice area. The numerical methodology presented can be further used as a predictive tool for valve design optimization for enhanced hemodynamics and durability.
• Kern, K. B., Slepian, M. J., Colberg, T. P., Wunder, C. "., & Newton, C. (2018). Abstract 29: A Neighborhood Local Volunteer Response Network Improves Response Time for Cardiac Arrest. Circulation, 138(Suppl_2). doi:10.1161/circ.138.suppl_2.29
• Khalpey, Z., Slepian, M., Malo, J., Mosier, J., Rao, P., Dotson, V., Mogan, C., Smith, R., & Keller, R. (2018). Peripheral VA-ECMO with direct biventricular decompression for refractory cardiogenic shock. Perfusion, 33(6), 493-495. doi:10.1177/0267659118761558
• Ma, Y., Choi, J., Hourlier-Fargette, A., Xue, Y., Chung, H. U., Lee, J. Y., Wang, X., Xie, Z., Kang, D., Wang, H., Han, S., Kang, S. K., Kang, Y., Yu, X., Slepian, M. J., Raj, M. S., Model, J. B., Feng, X., Ghaffari, R., , Rogers, J. A., et al. (2018). Relation between blood pressure and pulse wave velocity for human arteries. Proceedings of the National Academy of Sciences of the United States of America, 115(44), 11144-11149.
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  Continuous monitoring of blood pressure, an essential measure of health status, typically requires complex, costly, and invasive techniques that can expose patients to risks of complications. Continuous, cuffless, and noninvasive blood pressure monitoring methods that correlate measured pulse wave velocity (PWV) to the blood pressure via the Moens-Korteweg (MK) and Hughes Equations, offer promising alternatives. The MK Equation, however, involves two assumptions that do not hold for human arteries, and the Hughes Equation is empirical, without any theoretical basis. The results presented here establish a relation between the blood pressure and PWV that does not rely on the Hughes Equation nor on the assumptions used in the MK Equation. This relation degenerates to the MK Equation under extremely low blood pressures, and it accurately captures the results of in vitro experiments using artificial blood vessels at comparatively high pressures. For human arteries, which are well characterized by the Fung hyperelastic model, a simple formula between and PWV is established within the range of human blood pressures. This formula is validated by literature data as well as by experiments on human subjects, with applicability in the determination of blood pressure from PWV in continuous, cuffless, and noninvasive blood pressure monitoring systems.
• Marom, G., Eswaran, S. K., Rapoza, R. J., Hossainy, S. F., Slepian, M. J., & Bluestein, D. (2018). Design Effect of Metallic (Durable) and Polymeric (Resorbable) Stents on Blood Flow and Platelet Activation. Artificial organs, 42(12), 1148-1156.
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  Bioresorbable vascular scaffolds (BVS) provide transient vessel support for occluded coronary arteries while resorbing over time, potentially allowing vessel restoration approximating the native, healthy state. Clinical trials indicate that the Absorb BVS (Abbott Vascular, Santa Clara, CA) performance was similar to that of the Xience metallic drug-eluting stent (DES), with low long-term complications rates. However, when under-deployed in very small vessels (diameter
• Mikail, P., Crosby, J. R., Slepian, M. J., Smith, R., & Khalpey, Z. (2018). LVAD Pulsatility Assesses Cardiac Contractility: In Vitro Model Utilizing the Total Artificial Heart and Mock Circulation. ASAIO journal (American Society for Artificial Internal Organs : 1992).
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  There is a need for a consistent, reproducible, and cost-effective method of determining cardiac recovery in patients who receive emerging novel therapeutics for advanced and end-stage heart failure (HF). With the increasing use of ventricular assist devices (VADs) in end-stage HF, objective device diagnostics are available for analysis. Pulsatility, one of the accessible diagnostic measures, is a variable gage of the differential between peak systolic and minimum diastolic flow during a single cardiac cycle. Following implantation of the VAD, HeartWare's HVAD records pulsatility regularly. Thus, we hypothesize that this measurement relates to the contractility of the heart and could be utilized as a metric for determining patient response to various therapeutics. In this study, therefore, we develop a translatable and effective predictive model characterizing pulsatility to determine HF status and potential HF recovery using the SynCardia Total Artificial Heart (TAH) in conjunction with a Donovan Mock Circulation System to create a simulation platform for the collection of pulsatility data. We set the simulation platform to patient conditions ranging from critical heart failure to a normal operating condition through the variation preload, afterload, and left ventricular (LV) pumping force or TAH "contractility." By manipulating these variables, pulsatility was found to accurately indicate significant (p < 0.05) improvements in LV contractility at every recorded afterload and preload, suggesting that it is a valuable parameter for the assessment of cardiac recovery in patients.
• Rao, P., Mosier, J., Malo, J., Dotson, V., Mogan, C., Smith, R., Keller, R., Slepian, M., & Khalpey, Z. (2018). Peripheral VA-ECMO with direct biventricular decompression for refractory cardiogenic shock. PERFUSION-UK, 33(6), 493-495.
• Rao, P., Mosier, J., Malo, J., Dotson, V., Mogan, C., Smith, R., Keller, R., Slepian, M., & Khalpey, Z. (2018). Peripheral VA-ECMO with direct biventricular decompression for refractory cardiogenic shock. Perfusion, 33(6), 493-495.
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  Cardiogenic shock and cardiac arrest are life-threatening emergencies that result in high mortality rates. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) via peripheral cannulation is an option for patients who do not respond to conventional therapies. Left ventricular (LV) distention is a major limitation with peripheral VA-ECMO and is thought to contribute to poor recovery and the inability to wean off VA-ECMO. We report on a novel technique that combines peripheral VA-ECMO with off-pump insertion of a trans-apical LV venting cannula and a right ventricular decompression cannula.
• Roka-Moiia, Y., Palomares, D. E., Sheriff, J., Bluestein, D., & Slepian, M. J. (2018). MCS Shear-Medicated Platelet Activation Does not Cause Integrin GPIIbIIIa Activation, Rather Shedding and Microparticle Generation. JOURNAL OF HEART AND LUNG TRANSPLANTATION, 37(4), S162-S162.
• Selmi, M., Chiu, W. C., Chivukula, V. K., Melisurgo, G., Beckman, J. A., Mahr, C., Aliseda, A., Votta, E., Redaelli, A., Slepian, M. J., Bluestein, D., Pappalardo, F., & Consolo, F. (2018). Blood damage in Left Ventricular Assist Devices: Pump thrombosis or system thrombosis?. The International journal of artificial organs, 391398818806162.
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  Despite significant technical advancements in the design and manufacture of Left Ventricular Assist Devices, post-implant thrombotic and thromboembolic complications continue to affect long-term outcomes. Previous efforts, aimed at optimizing pump design as a means of reducing supraphysiologic shear stresses generated within the pump and associated prothrombotic shear-mediated platelet injury, have only partially altered the device hemocompatibility.
• Sheriff, J., Tran, P. L., Valerio, L., Hutchinson, M., Bluestein, D., & Slepian, M. J. (2018). Ticagrelor but not Aspirin Limits Shear-Mediated Platelet Activation. JOURNAL OF HEART AND LUNG TRANSPLANTATION, 37(4), S161-S161.
• Slepian, M. J. (2018). Routine clinical anti-platelet agents have limited efficacy in modulating hypershear-mediated platelet activation associated with mechanical circulatory support. Thrombosis Research, 163, 162-181. doi:doi.org/10.1016/j.thromres.2017.12.001
• Slepian, M. J., Aliseda, A., Mahr, C., Beckman, J. A., Selmi, M., Chiu, W., Chivukula, V. K., Melisurgo, G., Votta, E., Redaelli, A., Bluestein, D., Pappalardo, F., & Consolo, F. (2018). Blood damage in Left Ventricular Assist Devices: Pump thrombosis or system thrombosis?. The International Journal of Artificial Organs, 42(3), 113-124. doi:10.1177/0391398818806162
• Slepian, M. J., Ghosh, R. P., Marom, G., Rotman, O. M., Prabhakar, S., Horner, M., & Bluestein, D. (2018). Comparative Fluid–Structure Interaction Analysis of Polymeric Transcatheter and Surgical Aortic Valves' Hemodynamics and Structural Mechanics. Journal of Biomechanical Engineering, 140(12). doi:10.1115/1.4040600
• Slepian, M. J., Marom, G., Eswaran, S. K., Rapoza, R. J., Hossainy, S. F., & Bluestein, D. (2018). Design Effect of Metallic (Durable) and Polymeric (Resorbable) Stents on Blood Flow and Platelet Activation: Stent Design Effect on Rheologic Thrombogenicity. Artificial Organs, 42(12), 1148-1156. doi:10.1111/aor.13276
• Valerio, L., Sheriff, J., Tran, P. L., Brengle, W., Redaelli, A., Fiore, G. B., Pappalardo, F., Bluestein, D., & Slepian, M. J. (2018). Routine clinical anti-platelet agents have limited efficacy in modulating hypershear-mediated platelet activation associated with mechanical circulatory support. Thrombosis research, 163, 162-171.
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  Continuous flow ventricular assist devices (cfVADs) continue to be limited by thrombotic complications associated with disruptive flow patterns and supraphysiologic shear stresses. Patients are prescribed complex antiplatelet therapies, which do not fully prevent recurrent thromboembolic events. This is partially due to limited data on antiplatelet efficacy under cfVAD-associated shear conditions.
• Armstrong, D. G., Slepian, M. J., Joseph, B., & Boghossian, J. A. (2017). Remote Ischemic Conditioning. Journal of the American Podiatric Medical Association, 107(4), 313-317. doi:10.7547/15-172
• Attaran, R. R., Habibzadeh, M. R., Baweja, G., & Slepian, M. J. (2017). Quadricuspid aortic valve with ascending aortic aneurysm: report of a case and discussion of embryological mechanisms. Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology, 18(1), 49-52.
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  Congenital quadricuspid aortic valves (QAVs) are rare phenomena. They are often associated with aortic insufficiency and significant morbidity. A QAV with an associated ascending aortic aneurysm is extremely rare, and these conditions might have a shared embryonic etiology. We describe the case of a patient with a QAV associated with aortic aneurysm. Pertinent literature on the QAV is reviewed, and embryological factors that may contribute to its pathogenesis are discussed.
• Boghossian, J. A., Joseph, B., Slepian, M. J., & Armstrong, D. G. (2017). Remote Ischemic ConditioningPromising Potential in Wound Repair in Diabetes?. Journal of the American Podiatric Medical Association, 107(4), 313-317.
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  Remote ischemic conditioning involves the use of a blood pressure cuff or similar device to induce brief (3-5 min) episodes of limb ischemia. This, in turn, seems to activate a group of distress signals that has shown the potential ability to improve healing of the heart muscle and other organ systems. Until recently, this has not been tested in people with diabetic foot ulcers. The purpose of this review was to provide background on remote ischemic conditioning and recent data to potentially support its use as an adjunct to healing diabetic foot ulcers and other types of tissue loss. We believe that this inexpensive therapy has the potential to be deployed and incorporated into a variety of other therapies to prime patients for healing and to reduce morbidity in patients with this common, complex, and costly complication.
• Consolo, F., Pozzi, L., Motolone, G., Sferrazza, G., Pieri, M., Della, V. P., Zangrillo, A., Slepian, M. J., D'Angelo, A., & Pappalardo, E. (2017). Does Aspirin Effectively Inhibit Platelet Activation During Left Ventricular Assist Device Support?. JOURNAL OF HEART AND LUNG TRANSPLANTATION, 36(4), S444-S444.
• Consolo, F., Sferrazza, G., Motolone, G., Contri, R., Valerio, L., Lembo, R., Pozzi, L., Della Valle, P., De Bonis, M., Zangrillo, A., Fiore, G. B., Redaelli, A., Slepian, M. J., & Pappalardo, F. (2017). Platelet activation is a preoperative risk factor for the development of thromboembolic complications in patients with continuous-flow left ventricular assist device. European journal of heart failure.
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  To correlate the dynamics of platelet activation with the development of thromboembolic events in patients with continuous-flow left ventricular assist device (cf-LVAD).
• Consolo, F., Sheriff, J., Gorla, S., Magri, N., Bluestein, D., Pappalardo, F., Slepian, M. J., Fiore, G. B., & Redaelli, A. (2017). High Frequency Components of Hemodynamic Shear Stress Profiles are a Major Determinant of Shear-Mediated Platelet Activation in Therapeutic Blood Recirculating Devices. Scientific reports, 7(1), 4994.
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  We systematically analyzed the relative contributions of frequency component elements of hemodynamic shear stress waveforms encountered in cardiovascular blood recirculating devices as to overall platelet activation over time. We demonstrated that high frequency oscillations are the major determinants for priming, triggering and yielding activated "prothrombotic behavior" for stimulated platelets, even if the imparted shear stress has low magnitude and brief exposure time. Conversely, the low frequency components of the stress signal, with limited oscillations over time, did not induce significant activation, despite being of high magnitude and/or exposure time. In vitro data were compared with numerical predictions computed according to a recently proposed numerical model of shear-mediated platelet activation. The numerical model effectively resolved the correlation between platelet activation and the various frequency components examined. However, numerical predictions exhibited a different activation trend compared to experimental results for different time points of a stress activation sequence. With this study we provide a more fundamental understanding for the mechanobiological responsiveness of circulating platelets to the hemodynamic environment of cardiovascular devices, and the importance of these environments in mediating life-threatening thromboembolic complications associated with shear-mediated platelet activation. Experimental data will guide further optimization of the thromboresistance of cardiovascular implantable therapeutic devices.
• Danilo, C. A., Constantopoulos, E., McKee, L. A., Chen, H., Regan, J. A., Lipovka, Y., Lahtinen, S., Stenman, L. K., Nguyen, T. V., Doyle, K. P., Slepian, M. J., Khalpey, Z. I., & Konhilas, J. P. (2017). Bifidobacterium animalis subsp. lactis 420 mitigates the pathological impact of myocardial infarction in the mouse. Beneficial microbes, 8(2), 257-269.
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  There is a growing appreciation that our microbial environment in the gut plays a critical role in the maintenance of health and the pathogenesis of disease. Probiotic, beneficial gut microbes, administration can directly attenuate cardiac injury and post-myocardial infarction (MI) remodelling, yet the mechanisms of cardioprotection are unknown. We hypothesised that administration of Bifidobacterium animalis subsp. lactis 420 (B420), a probiotic with known anti-inflammatory properties, to mice will mitigate the pathological impact of MI, and that anti-inflammatory T regulatory (Treg) immune cells are necessary to impart protection against MI as a result of B420 administration. Wild-type male mice were administered B420, saline or Lactobacillus salivarius 33 (Ls-33) by gavage daily for 14 or 35 days, and underwent ischemia/reperfusion (I/R). Pretreatment with B420 for 10 or 28 days attenuated cardiac injury from I/R and reduced levels of inflammatory markers. Depletion of Treg cells by administration of anti-CD25 monoclonal antibodies eliminated B420-mediated cardio-protection. Further cytokine analysis revealed a shift from a pro-inflammatory to an anti-inflammatory environment in the probiotic treated post-MI hearts compared to controls. To summarise, B420 administration mitigates the pathological impact of MI. Next, we show that Treg immune cells are necessary to mediate B420-mediated protection against MI. Finally, we identify putative cellular, epigenetic and/or post-translational mechanisms of B420-mediated protection against MI.
• Dimasi, A., Rasponi, M., Consolo, F., Fiore, G. B., Bluestein, D., Slepian, M. J., & Redaelli, A. (2017). Microfludic platforms for the evaluation of anti-platelet agent efficacy under hyper-shear conditions associated with ventricular assist devices. Medical engineering & physics, 48, 31-38.
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  Thrombus formation is a major adverse event affecting patients implanted with ventricular assist devices (VADs). Despite anti-thrombotic drug administration, thrombotic events remain frequent within the first year post-implantation. Platelet activation (PA) is an essential process underling thrombotic adverse events in VAD systems. Indeed, abnormal shear forces, correlating with specific flow trajectories of VADs, are strong agonists mediating PA. To date, the ability to determine efficacy of anti-platelet (AP) agents under shear stress conditions is limited. Here, we present a novel microfluidic platform designed to replicate shear stress patterns of a clinical VAD, and use it to compare the efficacy of two AP agents in vitro. Gel-filtered platelets were incubated with i) acetylsalicylic acid (ASA) and ii) ticagrelor, at two different concentrations (ASA: 125 and 250 µM; ticagrelor: 250 and 500 nM) and were circulated in the VAD-emulating microfluidic platform using a peristaltic pump. GFP was collected after 4 and 52 repetitions of exposure to the VAD shear pattern and tested for shear-mediated PA. ASA significantly inhibited PA only at 2-fold higher concentration (250 µM) than therapeutic dose (125 µM). The effect of ticagrelor was not dependent on drug concentration, and did not show significant inhibition with respect to untreated control. This study demonstrates the potential use of microfluidic platforms as means of testing platelet responsiveness and AP drug efficacy under complex and realistic VAD-like shear stress conditions.
• Dimasi, A., Rasponi, M., Consolo, F., Redaelli, A., & Slepian, M. (2017). Platelet Membrane-Related Morphologic Alterations: An Early Marker of Supra-Physiologic Shear-Mediated Platelet Activation Associated with VADs. JOURNAL OF HEART AND LUNG TRANSPLANTATION, 36(4), S11-S12.
• Hurwitz, B., Cranmer, L., Slepian, M., Watts, G., Youens‐Clark, K., Wolk, D., Oshiro, M., Metzger, G., & Dhingra, D. (2017). 16S rRNA gene sequencing on a benchtop sequencer: accuracy for identification of clinically important bacteria. Journal of Applied Microbiology, 123(6), 1584-1596. doi:10.1111/jam.13590
• Khalpey, Z., Slepian, M., Nguyen, T., Lipovka, Y., Chen, H., Danilo, C., Constantopoulos, E., McKee, L., Regan, J., Lahtinen, S., Stenman, L., Doyle, K., & Konhilas, J. (2017). Bifidobacterium animalis subsp. lactis 420 mitigates the pathological impact of myocardial infarction in the mouse. Beneficial Microbes, 8(2), 257-269. doi:10.3920/bm2016.0119
• Liu, Y., Ammann, K. R., Rogers, J. A., & Slepian, M. J. (2017). Mechano-Acoustic Detection of Dysfunction in Continuous Flow VADs Utilizing Stretchable Electronic Systems. JOURNAL OF HEART AND LUNG TRANSPLANTATION, 36(4), S13-S13.
• Movahed, M. R., Kern, K., Thai, H., Ebrahimi, R., Friedman, M., & Slepian, M. (2017). Coronary artery bifurcation lesions: a review and update on classification and interventional techniques. Cardiovascular revascularization medicine : including molecular interventions, 9(4), 263-8.
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  Coronary artery bifurcation lesions pose a particular challenge in the field of interventional cardiology. Coronary bifurcation interventions are associated with higher rate of short- and long-term complications. There are many coronary artery bifurcation lesion classifications published in the literature. The goal of this article is to update and review current schemes of coronary artery bifurcation lesion classifications and interventional techniques.
• Saeed, O., Rangasamy, S., Luke, A., Patel, S. P., Sims, D. B., Shin, J., Gil, M. R., Slepian, M. J., Billett, H. H., Goldstein, D. J., & Jorde, U. P. (2017). Sildenafil Reduces Risk of Ischemic Stroke and Pump Thrombosis with Ongoing Low Level Hemolysis During Heart Mate II Support. JOURNAL OF HEART AND LUNG TRANSPLANTATION, 36(4), S111-S112.
• Saeed, O., Rangasamy, S., Luke, A., Patel, S. R., Shin, J., Sims, D. B., Gil, M. R., Goldstein, D. J., Slepian, M. J., Billett, H. H., & Jorde, U. (2017). Hemolysis and Von Willebrand Factor Levels During Continuous Flow Left Ventricular Assist Device Support. JOURNAL OF HEART AND LUNG TRANSPLANTATION, 36(4), S247-S247.
• Saeed, O., Rangasamy, S., Selevany, I., Madan, S., Fertel, J., Eisenberg, R., Aljoudi, M., Patel, S. R., Shin, J., Sims, D. B., Reyes Gil, M., Goldstein, D. J., Slepian, M. J., Billett, H. H., & Jorde, U. P. (2017). Sildenafil Is Associated With Reduced Device Thrombosis and Ischemic Stroke Despite Low-Level Hemolysis on Heart Mate II Support. Circulation. Heart failure, 10(11).
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  Persistent low-level hemolysis (LLH) during continuous-flow mechanical circulatory support is associated with subsequent thrombosis. Free hemoglobin from ongoing hemolysis scavenges nitric oxide (NO) to create an NO deficiency which can augment platelet function leading to a prothrombotic state. The phosphodiesterase-5 inhibitor, sildenafil, potentiates NO signaling to inhibit platelet function. Accordingly, we investigated the association of sildenafil administration and thrombotic events in patients with LLH during Heart Mate II support.
• Shir, S., Harhash, A. A., & Slepian, M. (2017). Oxidized LDL Exposure Enhances Baseline Platelet Activation and Amplifies Shear-mediated Activation. CIRCULATION, 136.
• Slepian, M. J. (2017). Welcome to “24 +1 = 25” the Quarter Century Anniversary Meeting of Our Society: Evolving to the International Society for Mechanical Circulatory Support: WELCOME LETTER. Artificial Organs, 41(10), 888-889. doi:10.1111/aor.13043
• Slepian, M. J. (2017). Welcome to "24 +1 = 25" the Quarter Century Anniversary Meeting of Our Society: Evolving to the International Society for Mechanical Circulatory Support. Artificial organs, 41(10), 888-889.
• Slepian, M. J., Consolo, F., Sferrazza, G., Motolone, G., Contri, R., Valerio, L., Lembo, R., Pozzi, L., Della Valle, P., De Bonis, M., Zangrillo, A., Fiore, G. B., Redaelli, A., & Pappalardo, F. (2017). Platelet activation is a preoperative risk factor for the development of thromboembolic complications in patients with continuous-flow left ventricular assist device: Platelet activation and thrombosis in continuous-flow LVAD. European Journal of Heart Failure, 20(4), 792-800. doi:10.1002/ejhf.1113
• Slepian, M. J., Sheriff, J., Hutchinson, M., Tran, P., Bajaj, N., Garcia, J. G., Scott Saavedra, S., & Bluestein, D. (2017). Shear-mediated platelet activation in the free flow: Perspectives on the emerging spectrum of cell mechanobiological mechanisms mediating cardiovascular implant thrombosis. Journal of biomechanics, 50, 20-25.
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  Shear-mediated platelet activation (SMPA) is central in thrombosis of implantable cardiovascular therapeutic devices. Despite the morbidity and mortality associated with thrombosis of these devices, our understanding of mechanisms operative in SMPA, particularly in free flowing blood, remains limited. Herein we present and discuss a range of emerging mechanisms for consideration for "free flow" activation under supraphysiologic shear. Further definition and manipulation of these mechanisms will afford opportunities for novel pharmacologic and mechanical strategies to limit SMPA and enhance overall implant device safety.
• Valerio, L., Tran, P. L., Hutchinson, M., Consolo, F., Redaelli, A., & Slepian, M. (2017). Anti-Platelet Drug Efficacy In Vitro Under VAD-Like Shear Stress Conditions. JOURNAL OF HEART AND LUNG TRANSPLANTATION, 36(4), S255-S255.
• Watts, G. S., Youens-Clark, K., Slepian, M. J., Wolk, D. M., Oshiro, M. M., Metzger, G. S., Dhingra, D., Cranmer, L. D., & Hurwitz, B. L. (2017). 16S rRNA gene sequencing on a benchtop sequencer: accuracy for identification of clinically important bacteria. JOURNAL OF APPLIED MICROBIOLOGY, 123(6), 1584-1596.
• Watts, G. S., Youens-Clark, K., Slepian, M. J., Wolk, D. M., Oshiro, M. M., Metzger, G. S., Dhingra, D., Cranmer, L. D., & Hurwitz, B. L. (2017). 16S rRNA gene sequencing on a benchtop sequencer: accuracy for identification of clinically important bacteria. Journal of applied microbiology, 123(6), 1584-1596.
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  Test the choice of 16S rRNA gene amplicon and data analysis method on the accuracy of identification of clinically important bacteria utilizing a benchtop sequencer.
• Xu, W., Yang, H., Zeng, W., Houghton, T., Wang, X. u., Murthy, R., Kim, H., Lin, Y., Mignolet, M., Duan, H., Yu, H., Slepian, M., & Jiang, H. (2017). Food-Based Edible and Nutritive Electronics. ADVANCED MATERIALS TECHNOLOGIES, 2(11).
• Zhang, P., Zhang, L. i., Slepian, M. J., Deng, Y., & Bluestein, D. (2017). A multiscale biomechanical model of platelets: Correlating with in-vitro results. Journal of Biomechanics, 50, 26--33.
• Zhang, P., Zhang, L., Slepian, M. J., Deng, Y., & Bluestein, D. (2017). A multiscale biomechanical model of platelets: Correlating with in-vitro results. Journal of biomechanics, 50, 26-33.
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  Using dissipative particle dynamics (DPD) combined with coarse grained molecular dynamics (CGMD) approaches, we developed a multiscale deformable platelet model to accurately describe the molecular-scale intra-platelet constituents and biomechanical properties of platelets in blood flow. Our model includes the platelet bilayer membrane, cytoplasm and an elaborate elastic cytoskeleton. Correlating numerical simulations with published in-vitro experiments, we validated the biorheology of the cytoplasm, the elastic response of membrane to external stresses, and the stiffness of the cytoskeleton actin filaments, resulting in an accurate representation of the molecular-level biomechanical microstructures of platelets. This enabled us to study the mechanotransduction process of the hemodynamic stresses acting onto the platelet membrane and transmitted to these intracellular constituents. The platelets constituents continuously deform in response to the flow induced stresses. To the best of our knowledge, this is the first molecular-scale platelet model that can be used to accurately predict platelets activation mechanism leading to thrombus formation in prosthetic cardiovascular devices and in vascular disease processes. This model can be further employed to study the effects of novel therapeutic approaches of modulating platelet properties to enhance their shear resistance via mechanotransduction pathways.
• Bianchi, M., Marom, G., Ghosh, R. P., Fernandez, H. A., Taylor, J. R., Slepian, M. J., & Bluestein, D. (2016). Effect of Balloon-Expandable Transcatheter Aortic Valve Replacement Positioning: A Patient-Specific Numerical Model. Artificial organs, 40(12), E292-E304.
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  Transcatheter aortic valve replacement (TAVR) has emerged as a life-saving and effective alternative to surgical valve replacement in high-risk, elderly patients with severe calcific aortic stenosis. Despite its early promise, certain limitations and adverse events, such as suboptimal placement and valve migration, have been reported. In the present study, it was aimed to evaluate the effect of various TAVR deployment locations on the procedural outcome by assessing the risk for valve migration. The deployment of a balloon-expandable Edwards SAPIEN valve was simulated via finite element analysis in a patient-specific calcified aortic root, which was reconstructed from CT scans of a retrospective case of valve migration. The deployment location was parametrized in three configurations and the anchorage was quantitatively assessed based on the contact between the stent and the native valve during the deployment and recoil phases. The proximal deployment led to lower contact area between the native leaflets and the stent which poses higher risk for valve migration. The distal and midway positions resulted in comparable outcomes, with the former providing a slightly better anchorage. The approach presented might be used as a predictive tool for procedural planning in order to prevent prosthesis migration and achieve better clinical outcomes.
• Bime, C., Zhou, T., Wang, T., Slepian, M. J., Garcia, J. G., & Hecker, L. (2016). Reactive oxygen species-associated molecular signature predicts survival in patients with sepsis. Pulmonary circulation, 6(2), 196-201.
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  Sepsis-related multiple organ dysfunction syndrome is a leading cause of death in intensive care units. There is overwhelming evidence that oxidative stress plays a significant role in the pathogenesis of sepsis-associated multiple organ failure; however, reactive oxygen species (ROS)-associated biomarkers and/or diagnostics that define mortality or predict survival in sepsis are lacking. Lung or peripheral blood gene expression analysis has gained increasing recognition as a potential prognostic and/or diagnostic tool. The objective of this study was to identify ROS-associated biomarkers predictive of survival in patients with sepsis. In-silico analyses of expression profiles allowed the identification of a 21-gene ROS-associated molecular signature that predicts survival in sepsis patients. Importantly, this signature performed well in a validation cohort consisting of sepsis patients aggregated from distinct patient populations recruited from different sites. Our signature outperforms randomly generated signatures of the same signature gene size. Our findings further validate the critical role of ROSs in the pathogenesis of sepsis and provide a novel gene signature that predicts survival in sepsis patients. These results also highlight the utility of peripheral blood molecular signatures as biomarkers for predicting mortality risk in patients with sepsis, which could facilitate the development of personalized therapies.
• Chiu, W. C., Alemu, Y., McLarty, A. J., Einav, S., Slepian, M. J., & Bluestein, D. (2016). Ventricular Assist Device Implantation Configurations Impact Overall Mechanical Circulatory Support System Thrombogenic Potential. ASAIO journal (American Society for Artificial Internal Organs : 1992).
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  Ventricular assist devices (VAD) became in recent years the standard of care therapy for advanced heart failure with hemodynamic compromise. With the steadily growing population of device recipients, various post-implant complications have been reported, mostly associated with the hyper-shear generated by VADs that enhance their thrombogenicity by activating platelets. While VAD design optimization can significantly improve its thromboresistance, the implanted VAD need to be evaluated as part of a system. Several clinical studies indicated that variability in implantation configurations may contribute to the overall system thrombogenicity. Numerical simulations were conducted in the HeartAssist 5 (HA5) and HeartMate II (HMII) VADs in the following implantation configurations: (i) Inflow cannula angles - 115° and 140° (HA5); (ii) three VAD circumferential orientations: 0°, 30° and 60° (HA5 and HMII); and (iii) 60° and 90° outflow graft anastomotic angles (AA) with respect to the ascending aorta (HA5). The stress accumulation of the platelets was calculated along flow trajectories and collapsed into a probability density function (PDF), representing the "thrombogenic footprint" (TF) of each configuration- a proxy to its thrombogenic potential (TP). The 140° HA5 cannula generated lower TP independent of the circumferential orientation of the VAD. 60° orientation generated the lowest TP for the HA5 versus 0° for the HMII. An AA of 60° resulted in lower TP for HA5. These results demonstrate that optimizing the implantation configuration reduces the overall system TP. Thromboresistance can be enhanced by combining VAD design optimization with the surgical implantation configurations for achieving better clinical outcomes of implanted VADs.
• Consolo, F., Dimasi, A., Rasponi, M., Valerio, L., Pappalardo, F., Bluestein, D., Slepian, M. J., Fiore, G. B., & Redaelli, A. (2016). Microfluidic approaches for the assessment of blood cell trauma: a focus on thrombotic risk in mechanical circulatory support devices. The International journal of artificial organs, 0.
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  Mechanical circulatory support devices (MCSDs) are emerging as a valuable therapeutic option for the management of end-stage heart failure. However, although recipients are routinely administered with anti-thrombotic (AT) drugs, thrombosis persists as a severe post-implant complication. Conventional clinical assays and coagulation markers demonstrate partial ability in preventing the onset of thrombosis. Through years, different laboratory techniques have been proposed as potential tools for the evaluation of platelets' hemostatic response in MCSD recipients. Most rely on platelet aggregation tests; they are performed in static or low shear conditions, neglecting the prominent contribution of MCSD shear-induced mechanical load in enhancing platelet activation (PA). On the other hand, those tests able to account for shear-induced PA have limited possibility of effective clinical translation.
• Copeland, J., Copeland, H., Nolan, P., Gustafson, M., Slepian, M., & Smith, R. (2016). Results with an anticoagulation protocol in 99 SynCardia total artificial heart recipients. ASAIO journal (American Society for Artificial Internal Organs : 1992), 59(3), 216-20.
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  For 15 years, we employed a consistent anticoagulation protocol in 99 consecutive SynCardia Systems total artificial heart (TAH) recipients. Thromboelastography and platelet aggregation studies were used for evaluating and modulating therapy with dipyridamole, pentoxiphylline, aspirin, and heparin. Partial thromboplastin times, international normalized ratios, and platelet counts were also followed. After the second post-implant day in patients who were free of endo-device infection (97 patients), the embolic stroke incidence was 0.08 per patient year. This included 23.6 patient years of device support. There were no spontaneous hemorrhagic strokes. Two patients had endo-device infections and both had strokes. Postimplantation bleeding was seen in 20% of patients. All but two of these were within the first postoperative week. In all, 4% of patients had gastrointestinal bleeding. We did not observe heparin-induced thrombocytopenia in any patient. We conclude that stroke rates on TAH support have been low, and recommend this protocol.
• Crosby, J. R., DeCook, K. J., Tran, P. L., Betterton, E., Smith, R. G., Larson, D. F., Khalpey, Z. I., Burkhoff, D., & Slepian, M. J. (2016). A Physical Heart Failure Simulation System Utilizing the Total Artificial Heart and Modified Donovan Mock Circulation. Artificial organs.
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  With the growth and diversity of mechanical circulatory support (MCS) systems entering clinical use, a need exists for a robust mock circulation system capable of reliably emulating and reproducing physiologic as well as pathophysiologic states for use in MCS training and inter-device comparison. We report on the development of such a platform utilizing the SynCardia Total Artificial Heart and a modified Donovan Mock Circulation System, capable of being driven at normal and reduced output. With this platform, clinically relevant heart failure hemodynamics could be reliably reproduced as evidenced by elevated left atrial pressure (+112%), reduced aortic flow (-12.6%), blunted Starling-like behavior, and increased afterload sensitivity when compared with normal function. Similarly, pressure-volume relationships demonstrated enhanced sensitivity to afterload and decreased Starling-like behavior in the heart failure model. Lastly, the platform was configured to allow the easy addition of a left ventricular assist device (HeartMate II at 9600 RPM), which upon insertion resulted in improvement of hemodynamics. The present configuration has the potential to serve as a viable system for training and research, aimed at fostering safe and effective MCS device use.
• Crosby, J. R., DeCook, K. J., Tran, P. L., Smith, R. G., Larson, D. F., Khalpey, Z. I., Burkhoff, D., & Slepian, M. J. (2016). Physiological characterization of the SynCardia total artificial heart in a mock circulation system. ASAIO journal (American Society for Artificial Internal Organs : 1992), 61(3), 274-81.
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  The SynCardia total artificial heart (TAH) has emerged as an effective, life-saving biventricular replacement system for a wide variety of patients with end-stage heart failure. Although the clinical performance of the TAH is established, modern physiological characterization, in terms of elastance behavior and pressure-volume (PV) characterization has not been defined. Herein, we examine the TAH in terms of elastance using a nonejecting left ventricle, and then characterize the PV relation of the TAH by varying preload and afterload parameters using a Donovan Mock Circulatory System. We demonstrate that the TAH does not operate with time-varying elastance, differing from the human heart. Furthermore, we show that the TAH has a PV relation behavior that also differs from that of the human heart. The TAH does exhibit Starling-like behavior, with output increasing via preload-dependent mechanisms, without reliance on an alteration of inotropic state within the operating window of the TAH. Within our testing range, the TAH is insensitive to variations in afterload; however, this insensitivity has a limit, the limit being the maximum driving pressure of the pneumatic driver. Understanding the physiology of the TAH affords insight into the functional parameters that govern artificial heart behavior providing perspective on differences compared with the human heart.
• El Banayosy, A., Kizner, L., Arusoglu, L., Morshuis, M., Brehm, C., Koerfer, R., Schuermann, C., Smith, R. G., Copeland, J. G., & Slepian, M. J. (2016). Home discharge and out-of-hospital follow-up of total artificial heart patients supported by a portable driver system. ASAIO journal (American Society for Artificial Internal Organs : 1992), 60(2), 148-53.
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  To enhance ambulation and facilitate hospital discharge of total artificial heart (TAH)-supported patients, we adapted a mobile ventricular assistance device (VAD) driver (Excor) for TAH use and report on the performance of Excor-driven TAH patients discharged home. Ten patients stabilized on a TAH, driven by the CSS ("Circulatory Support System"), were progressively switched over to the Excor in hospital over 14 days as a pilot, with daily hemodynamics and laboratory parameters measured. Twenty-two stable TAH patients were subsequently placed on the Excor, trained, and discharged home. Clinical and hemodynamic parameters were followed. All pilot study patients were clinically stable on the Excor, with no decrease in TAH output noted (6.3 + 0.3 L/min [day 1] vs. 5.8 + 0.2 L/min [day 14], p = 0.174), with a trend suggesting improvement of both hepatic and renal function. Twenty-two TAH patients were subsequently successfully discharged home on the portable driver and were supported out of hospital for up to 598 days (range, 2-598; mean = 179 ± 140 days), remaining ambulatory, New York Heart Association (NYHA) class I or II, and free of readmission for 88.5% of the time of support. TAH patients may be effectively and safely supported by a mobile drive system. As such, the utility of the TAH may be extended to support patients beyond the hospital, at home, with overall ambulatory freedom.
• Hecker, L., Slepian, M. J., Wang, T., Zhou, T., Bime, C., & Garcia, J. G. (2016). Reactive Oxygen Species–Associated Molecular Signature Predicts Survival in Patients with Sepsis. Pulmonary Circulation, 6(2), 196-201. doi:10.1086/685547
• Herskowitz, A., Tamura, F., Ueda, K., Neumann, D. A., Slepian, M., Rose, N. R., Beschorner, W. E., Baumgartner, W. A., Reitz, B. R., & Sell, K. W. (2016). Induction of donor major histocompatibility complex antigens in coronary arterial vessels: mechanism of arterial vasculitis in rat allografts treated with cyclosporine. The Journal of heart transplantation, 8(1), 11-9.
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  Recently, a potentially lethal pattern of vascular rejection has been described in heart transplant patients treated with cyclosporine. The purpose of this study was to identify potential immune mechanisms responsible for the development of coronary vascular injury associated with acute rejection. Our hypothesis was that changes in histocompatibility (MHC) expression induced by immunosuppressive therapy with cyclosporine plays an important role in directing an immune response to the arterial bed. With the ACI to Lewis allograft model, we compared the histology and immunohistology of both unmodified allograft rejection at days 2, 3, and 4 after transplantation, and allograft rejection modified by pretreatment with cyclosporine. Both models exhibit histologic evidence of early rejection before extensive myocyte necrosis is seen. Unmodified early rejection develops rapidly and is associated with dense MHC class I antigen expression on both myocytes and venous endothelium. Cyclosporine-modified rejection develops more slowly and is characterized by an arterial vasculitis. This modified pattern of rejection is associated with increased myocardial expression of MHC class II antigens with the arterial bed preferentially expressing increased MHC antigens. It is interesting to speculate that in the setting of a slower developing rejection process, the preferential expression of MHC antigens within the arterial bed produces a delayed-type hypersensitivity response directed toward either the endothelium and/or adjacent MHC class II expressing myocytes. A prolonged periarterial and intraluminal inflammatory reaction may then produce a true vasculitis, which may be detrimental to the survival of the graft.
• Khalpey, Z., Bin Riaz, I., Marsh, K. M., Ansari, M. Z., Bilal, J., Cooper, A., Paidy, S., Schmitto, J. D., Smith, R., Friedman, M., Slepian, M. J., & Poston, R. (2016). Robotic Left Ventricular Assist Device Implantation Using Left Thoracotomy Approach in Patients with Previous Sternotomies. ASAIO journal (American Society for Artificial Internal Organs : 1992), 61(6), e44-6.
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  Left ventricular assist devices (LVADs) are commonly used as either a bridge-to-transplant or a destination therapy. The traditional approach for LVAD implantation is via median sternotomy, but many candidates for this procedure have a history of failed cardiac surgeries and previous sternotomy. Redo sternotomy increases the risk of heart surgery, particularly in the setting of advanced heart failure. Robotics facilitates a less invasive approach to LVAD implantation that circumvents some of the morbidity associated with a redo sternotomy. We compared the outcomes of all patients at our institution who underwent LVAD implantation via either a traditional sternotomy or using robotic assistance. The robotic cohort showed reduced resource utilization including length of hospital stay and use of blood products. As the appropriate candidates become elucidated, robotic assistance may improve the safety and cost-effectiveness of reoperative LVAD surgery.
• Khalpey, Z., Kazui, T., Ferng, A. S., Connell, A., Tran, P. L., Meyer, M., Rawashdeh, B., Smith, R. G., Sweitzer, N. K., Friedman, M., Lick, S., Slepian, M. J., & Copeland, J. G. (2016). First North American 50cc Total Artificial Heart Experience: Conversion from a 70cc Total Artificial Heart. ASAIO journal (American Society for Artificial Internal Organs : 1992).
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  The 70cc Total Artificial Heart (TAH) has been utilized as bridge to transplant (BTT) for biventricular failure. However the utilization of 70cc TAH has been limited to large patients for the low output from the pulmonary as well as systemic vein compression after chest closure. Therefore the 50cc TAH was developed by SynCardia (Tucson, AZ, USA) to accommodate smaller chest cavity. We report the first TAH exchange from a 70cc to 50cc due to a fit difficulty. The patient failed to be closed with a 70cc TAH, although the patient met the conventional 70cc TAH fit criteria. We successfully closed the chest with a 50cc TAH.
• Khalpey, Z., Sydow, N., Paidy, S., Slepian, M. J., Friedman, M., Cooper, A., Marsh, K. M., Schmitto, J. D., & Poston, R. (2016). Robotic-assisted implantation of ventricular assist device after sternectomy and pectoralis muscle flap. ASAIO journal (American Society for Artificial Internal Organs : 1992), 60(6), 742-3.
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  Left ventricular assist devices are increasingly important in the management of advanced heart failure. Most patients who benefit from these devices have had some prior cardiac surgery, making implantation of higher risk. This is especially true in patients who have had prior pectoralis flap reconstruction after sternectomy for mediastinitis. We outline the course of such a patient, in whom the use of robotic assistance allowed for a less invasive device implantation approach with preservation of the flap for transplantation.
• Koh, A., Kang, D., Xue, Y., Lee, S., Pielak, R. M., Kim, J., Hwang, T., Min, S., Banks, A., Bastien, P., Manco, M. C., Wang, L., Ammann, K. R., Jang, K. I., Won, P., Han, S., Ghaffari, R., Paik, U., Slepian, M. J., , Balooch, G., et al. (2016). A soft, wearable microfluidic device for the capture, storage, and colorimetric sensing of sweat. Science translational medicine, 8(366), 366ra165.
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  Capabilities in health monitoring enabled by capture and quantitative chemical analysis of sweat could complement, or potentially obviate the need for, approaches based on sporadic assessment of blood samples. Established sweat monitoring technologies use simple fabric swatches and are limited to basic analysis in controlled laboratory or hospital settings. We present a collection of materials and device designs for soft, flexible, and stretchable microfluidic systems, including embodiments that integrate wireless communication electronics, which can intimately and robustly bond to the surface of the skin without chemical and mechanical irritation. This integration defines access points for a small set of sweat glands such that perspiration spontaneously initiates routing of sweat through a microfluidic network and set of reservoirs. Embedded chemical analyses respond in colorimetric fashion to markers such as chloride and hydronium ions, glucose, and lactate. Wireless interfaces to digital image capture hardware serve as a means for quantitation. Human studies demonstrated the functionality of this microfluidic device during fitness cycling in a controlled environment and during long-distance bicycle racing in arid, outdoor conditions. The results include quantitative values for sweat rate, total sweat loss, pH, and concentration of chloride and lactate.
• Leung, S. L., Lu, Y., Bluestein, D., & Slepian, M. J. (2016). Dielectrophoresis-Mediated Electrodeformation as a Means of Determining Individual Platelet Stiffness. Annals of biomedical engineering, 44(4), 903-13.
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  Platelets, essential for hemostasis, are easily activated via biochemical and mechanical stimuli. Cell stiffness is a vital parameter modulating the mechano-transduction of exogenous mechanical stimuli. While methods exist to measure cell stiffness, no ready method exists for measuring platelet stiffness that is both minimally-contacting, imparting minimal exogenous force and non-activating. We developed a minimal-contact methodology capable of trapping and measuring the stiffness of individual platelets utilizing dielectrophoresis (DEP)-mediated electrodeformation. Parametric studies demonstrate a non-uniform electric field in the MHz frequency range (0.2-20 MHz) is required for generating effective DEP forces on platelets, suspended in isotonic buffer with conductivity ~100-200 μS/cm. A nano-Newton DEP force (0.125-4.5 nN) was demonstrated to be essential for platelet electrodeformation, which could be generated with an electric field with strength of 1.5-9 V/μm. Young's moduli of platelets were calculated using a Maxwell stress tensor model and stress-deformation relationship. Platelet stiffness was determined to be in the range of 3.5 ± 1.4 and 8.5 ± 1.5 kPa for resting and 0.4% paraformaldehyde-treated cells, respectively. The developed methodology fills a gap in approaches of measuring individual platelet stiffness, free of inadvertent platelet activation, which will facilitate further studies of mechanisms involved in mechanically-mediated platelet activation.
• Liu, Y., Norton, J. J., Qazi, R., Zou, Z., Ammann, K. R., Liu, H., Yan, L., Tran, P. L., Jang, K. I., Lee, J. W., Zhang, D., Kilian, K. A., Jung, S. H., Bretl, T., Xiao, J., Slepian, M. J., Huang, Y., Jeong, J. W., & Rogers, J. A. (2016). Epidermal mechano-acoustic sensing electronics for cardiovascular diagnostics and human-machine interfaces. Science advances, 2(11), e1601185.
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  Physiological mechano-acoustic signals, often with frequencies and intensities that are beyond those associated with the audible range, provide information of great clinical utility. Stethoscopes and digital accelerometers in conventional packages can capture some relevant data, but neither is suitable for use in a continuous, wearable mode, and both have shortcomings associated with mechanical transduction of signals through the skin. We report a soft, conformal class of device configured specifically for mechano-acoustic recording from the skin, capable of being used on nearly any part of the body, in forms that maximize detectable signals and allow for multimodal operation, such as electrophysiological recording. Experimental and computational studies highlight the key roles of low effective modulus and low areal mass density for effective operation in this type of measurement mode on the skin. Demonstrations involving seismocardiography and heart murmur detection in a series of cardiac patients illustrate utility in advanced clinical diagnostics. Monitoring of pump thrombosis in ventricular assist devices provides an example in characterization of mechanical implants. Speech recognition and human-machine interfaces represent additional demonstrated applications. These and other possibilities suggest broad-ranging uses for soft, skin-integrated digital technologies that can capture human body acoustics.
• Pappalardo, J., Pappalardo, J., Luu, C., Luu, C., Larson, E., Larson, E., Rankin, T. M., Rankin, T. M., Slepian, M. J., Slepian, M. J., Armstrong, D. G., & Armstrong, D. G. (2016). Plantar Fat Grafting and Tendon Balancing for the Diabetic Foot Ulcer in Remission. Plastic and Reconstructive Surgery Global Open, 4(7), e810. doi:(PRS-GO), 4:e810,
• Pappalardo, J., Pappalardo, J., Pappalardo, J., Luu, C., Luu, C., Luu, C., Larson, E., Larson, E., Larson, E., Rankin, T. M., Rankin, T. M., Rankin, T. M., Slepian, M. J., Slepian, M. J., Slepian, M. J., Armstrong, D. G., Armstrong, D. G., & Armstrong, D. G. (2016). Plantar Fat Grafting and Tendon Balancing for the Diabetic Foot Ulcer in Remission. Plastic Reconstructive Surgery Global Open, 4(7), e810.
• Rahman, F., Slepian, M., & Mitra, A. (2016). A Novel Big-Data Processing Framwork for Healthcare Applications Big-Data-Healthcare-in-a-Box. 2016 IEEE INTERNATIONAL CONFERENCE ON BIG DATA (BIG DATA), 3548-3555.
• Slepian, M. J., Consolo, F., Dimasi, A., Rasponi, M., Valerio, L., Pappalardo, F., Bluestein, D., Fiore, G. B., & Redaelli, A. (2016). Microfluidic Approaches for the Assessment of Blood Cell Trauma: A Focus on Thrombotic Risk in Mechanical Circulatory Support Devices. The International Journal of Artificial Organs, 39(4), 184-193. doi:10.5301/ijao.5000485
• Slepian, M. J., Khalpey, Z. I., Crosby, J. R., DeCook, K. J., Tran, P. L., Betterton, E., Smith, R. G., Larson, D. F., & Burkhoff, D. (2016). A Physical Heart Failure Simulation System Utilizing the Total Artificial Heart and Modified Donovan Mock Circulation: PHYSICAL HEART FAILURE SIMULATION SYSTEM. Artificial Organs, 41(7), E52-E65. doi:10.1111/aor.12808
• Tamimi, E., Ardila, D. C., Haskett, D. G., Doetschman, T., Slepian, M. J., Kellar, R. S., & Vande Geest, J. P. (2016). Biomechanical Comparison of Glutaraldehyde-Crosslinked Gelatin Fibrinogen Electrospun Scaffolds to Porcine Coronary Arteries. Journal of biomechanical engineering, 138(1).
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  Cardiovascular disease (CVD) is the leading cause of death for Americans. As coronary artery bypass graft surgery (CABG) remains a mainstay of therapy for CVD and native vein grafts are limited by issues of supply and lifespan, an effective readily available tissue-engineered vascular graft (TEVG) for use in CABG would provide drastic improvements in patient care. Biomechanical mismatch between vascular grafts and native vasculature has been shown to be the major cause of graft failure, and therefore, there is need for compliance-matched biocompatible TEVGs for clinical implantation. The current study investigates the biaxial mechanical characterization of acellular electrospun glutaraldehyde (GLUT) vapor-crosslinked gelatin/fibrinogen cylindrical constructs, using a custom-made microbiaxial optomechanical device (MOD). Constructs crosslinked for 2, 8, and 24 hrs are compared to mechanically characterized porcine left anterior descending coronary (LADC) artery. The mechanical response data were used for constitutive modeling using a modified Fung strain energy equation. The results showed that constructs crosslinked for 2 and 8 hrs exhibited circumferential and axial tangential moduli (ATM) similar to that of the LADC. Furthermore, the 8-hrs experimental group was the only one to compliance-match the LADC, with compliance values of 0.0006±0.00018 mm Hg-1 and 0.00071±0.00027 mm Hg-1, respectively. The results of this study show the feasibility of meeting mechanical specifications expected of native arteries through manipulating GLUT vapor crosslinking time. The comprehensive mechanical characterization of cylindrical biopolymer constructs in this study is an important first step to successfully develop a biopolymer compliance-matched TEVG.
• Tamimi, E., Ardila, D. C., Haskett, D. G., Doetschman, T., Slepian, M. J., Kellar, R. S., & Vande, G. (2016). Biomechanical Comparison of Glutaraldehyde-Crosslinked Gelatin Fibrinogen Electrospun Scaffolds to Porcine Coronary Arteries. JOURNAL OF BIOMECHANICAL ENGINEERING-TRANSACTIONS OF THE ASME, 138(1).
• Tran, P. L., Kazui, T., Perovic, V., Mikail, P., Lick, S., Smith, R., Betterton, E. W., Venkat, R., Iwanski, J., Wong, R. K., Slepian, M. J., & Khalpey, Z. (2016). Case Report: Disparate flow in HeartMate II patient with extensive left ventricle repair. Perfusion, 31(4), 349-52.
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  This case study reports the operative management of a 63-year-old male patient following implantation of the HeartMate II (HMII) left ventricular assist device (LVAD), with a non-compliant left ventricle (LV) and a reduced right ventricular (RV) end-diastolic volume. Intraoperatively, the patient had a thin, fragile LV wall with laminated clot; a ventricular septal defect was encountered during removal of the clot. Along with an aortic valve repair, the LV and the septum were reconstructed with multiple bovine pericardium patches, thus, moderately reducing the RV and LV stroke volume. A difference in cardiac output via a Swan-Ganz catheter (approximately 1.5 l/min) was observed as opposed to the HMII's estimated flow. The result was later replicated and verified ITALIC! in vitrovia the Donovan Mock Circulation System (DMCS), where about 2 l/min lower flow on the HMII system was observed. In conclusion, the HMII flow rate displayed can be inaccurate and should only be used for trending.
• Valerio, L., Tran, P. L., Sheriff, J., Brengle, W., Ghosh, R., Chiu, W., Redaelli, A., Fiore, G. B., Pappalardo, F., Bluestein, D., & Slepian, M. J. (2016). Aspirin has limited ability to modulate shear-mediated platelet activation associated with elevated shear stress of ventricular assist devices. Thrombosis research, 140, 110-7.
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  Continuous flow ventricular assist devices (cfVADs) while effective in advanced heart failure, remain plagued by thrombosis related to abnormal flows and elevated shear stress. To limit cfVAD thrombosis, patients utilize complex anti-thrombotic regimens built upon a foundation of aspirin (ASA). While much data exists on ASA as a modulator of biochemically-mediated platelet activation, limited data exists as to the efficacy of ASA as a means of limiting shear-mediated platelet activation, particularly under elevated shear stress common within cfVADs. We investigated the ability of ASA (20, 25 and 125μM) to limit shear-mediated platelet activation under conditions of: 1) constant shear stress (30dynes/cm(2) and 70dynes/cm(2)); 2) dynamic shear stress, and 3) initial high shear exposure (70dynes/cm(2)) followed by low shear exposure - i.e. a platelet sensitization protocol, utilizing a hemodynamic shearing device providing uniform shear stress in vitro. The efficacy of ASA to limit platelet activation mediated via passage through a clinical cfVAD system (DeBakey Micromed) in vitro was also studied. ASA reduced platelet activation only under conditions of low shear stress (38% reduction compared to control, n=10, p0.5) with no limitation of platelet sensitization. ASA had limited ability (25.6% reduction in platelet activation rate) to modulate shear-mediated platelet activation induced via cfVAD passage. These findings, while performed under "deconstructed" non-clinical conditions by utilizing purified platelets alone in vitro, provide a potential contributory mechanistic explanation for the persistent thrombosis rates experienced clinically in cfVAD patients despite ASA therapy. An opportunity exists to develop enhanced pharmacologic strategies to limit shear-mediated platelet activation at elevated shear levels associated with mechanical circulatory support devices.
• Zimmerman, H., Coehlo-Anderson, R., Slepian, M., Smith, R. G., Sethi, G., & Copeland, J. G. (2016). Device malfunction of the CardioWest total artificial heart secondary to catheter entrapment of the tricuspid valve. ASAIO journal (American Society for Artificial Internal Organs : 1992), 56(5), 481-2.
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  We report two cases at a single institution, a 52-year-old man and a 25-year-old woman, who had failures of their CardioWest total artificial hearts (TAH) from central venous lines that caused obstruction of the right ventricular inflow valves. Each patient was noted to have decreasing TAH outputs for a few days before this catastrophic device arrest. Both patients died; one suddenly and one during a protracted period, as a result of catheter entrapment of the disc of the Medtronic Hall right ventricular inflow valve.
• Ammann, K. R., DeCook, K. J., Tran, P. L., Merkle, V. M., Wong, P. K., & Slepian, M. J. (2015). Collective cell migration of smooth muscle and endothelial cells: impact of injury versus non-injury stimuli. Journal of biological engineering, 9, 19.
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  Cell migration is a vital process for growth and repair. In vitro migration assays, utilized to study cell migration, often rely on physical scraping of a cell monolayer to induce cell migration. The physical act of scrape injury results in numerous factors stimulating cell migration - some injury-related, some solely due to gap creation and loss of contact inhibition. Eliminating the effects of cell injury would be useful to examine the relative contribution of injury versus other mechanisms to cell migration. Cell exclusion assays can tease out the effects of injury and have become a new avenue for migration studies. Here, we developed two simple non-injury techniques for cell exclusion: 1) a Pyrex® cylinder - for outward migration of cells and 2) a polydimethylsiloxane (PDMS) insert - for inward migration of cells. Utilizing these assays smooth muscle cells (SMCs) and human umbilical vein endothelial cells (HUVECs) migratory behavior was studied on both polystyrene and gelatin-coated surfaces.
• Armstrong, D. G., Kleidermacher, D. N., Klonoff, D. C., & Slepian, M. J. (2015). Cybersecurity Regulation of Wireless Devices for Performance and Assurance in the Age of "Medjacking". Journal of diabetes science and technology, 10(2), 435-8.
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  We are rapidly reaching a point where, as connected devices for monitoring and treating diabetes and other diseases become more pervasive and powerful, the likelihood of malicious medical device hacking (known as "medjacking") is growing. While government could increase regulation, we have all been witness in recent times to the limitations and issues surrounding exclusive reliance on government. Herein we outline a preliminary framework for establishing security for wireless health devices based on international common criteria. Creation of an independent medical device cybersecurity body is suggested. The goal is to allow for continued growth and innovation while simultaneously fostering security, public trust, and confidence.
• Bianchi, M., Ghosh, R. P., Marom, G., Slepian, M. J., & Bluestein, D. (2015). Simulation of Transcatheter Aortic Valve Replacement in patient-specific aortic roots: Effect of crimping and positioning on device performance. Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference, 2015, 282-5.
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  Calcific aortic valve disease (CAVD) is a cardiovascular condition that causes the progressive narrowing of the aortic valve (AV) opening, due to the growth of bone-like deposits all over the aortic root (AR). Transcatheter aortic valve replacement (TAVR), a minimally invasive procedure, has recently become the only lifesaving solution for patients that cannot tolerate the standard surgical valve replacement. However, adverse effects, such as AR injury or paravalvular leakage (PVL), may occur as a consequence of a sub-optimal procedure, due to the presence of calcifications in situ. Additionally, the crimping required for delivering the valve via stenting may damage the valve. The aim of the present study is to comparatively assess the crimping mechanics of the commercialized Edwards SAPIEN valve and an alternative polymeric valve (Polynova, Inc) and to evaluate the effect of different TAVR deployment positions using patient-specific numerical models. The optimal deployment location for achieving better patient outcomes was calculated and based on the interactions between the TAVR stent and the native AR. Results demonstrated that the Polynova valve withstands the crimping process better than the SAPIEN valve. Furthermore, deployment simulations showed the role that calcifications deposits may play in the TAVR sub-optimal valve anchoring to the AV wall, leading to the presence of gaps that result in PVL.
• Dagdeviren, C., Shi, Y., Joe, P., Ghaffari, R., Balooch, G., Usgaonkar, K., Gur, O., Tran, P. L., Crosby, J. R., Meyer, M., Su, Y., Chad Webb, R., Tedesco, A. S., Slepian, M. J., Huang, Y., & Rogers, J. A. (2015). Conformal piezoelectric systems for clinical and experimental characterization of soft tissue biomechanics. Nature materials, 14(7), 728-36.
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  Mechanical assessment of soft biological tissues and organs has broad relevance in clinical diagnosis and treatment of disease. Existing characterization methods are invasive, lack microscale spatial resolution, and are tailored only for specific regions of the body under quasi-static conditions. Here, we develop conformal and piezoelectric devices that enable in vivo measurements of soft tissue viscoelasticity in the near-surface regions of the epidermis. These systems achieve conformal contact with the underlying complex topography and texture of the targeted skin, as well as other organ surfaces, under both quasi-static and dynamic conditions. Experimental and theoretical characterization of the responses of piezoelectric actuator-sensor pairs laminated on a variety of soft biological tissues and organ systems in animal models provide information on the operation of the devices. Studies on human subjects establish the clinical significance of these devices for rapid and non-invasive characterization of skin mechanical properties.
• Dimasi, A., Rasponi, M., Sheriff, J., Chiu, W., Bluestein, D., Tran, P. L., Slepian, M. J., & Redaelli, A. (2015). Microfluidic emulation of mechanical circulatory support device shear-mediated platelet activation. Biomedical microdevices, 17(6), 117.
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  Thrombosis of ventricular assist devices (VADs) compromises their performance, with associated risks of systemic embolization, stroke, pump stop and possible death. Anti-thrombotic (AT) drugs, utilized to limit thrombosis, are largely dosed empirically, with limited testing of their efficacy. Further, such testing, if performed, typically examines efficacy under static conditions, which is not reflective of actual shear-mediated flow. Here we adopted our previously developed Device Thrombogenicity Emulation methodology to design microfluidic platforms able to emulate representative shear stress profiles of mechanical circulatory support (MCS) devices. Our long-term goal is to utilize these systems for point-of-care (POC) personalized testing of AT efficacy under specific, individual shear profiles. First, we designed different types of microfluidic channels able to replicate sample shear stress patterns observed in MCS devices. Second, we explored the flexibility of microfluidic technology in generating dynamic shear stress profiles by modulating the geometrical features of the channels. Finally, we designed microfluidic channel systems able to emulate the shear stress profiles of two commercial VADs. From CFD analyses, the VAD-emulating microfluidic systems were able to replicate the main characteristics of the shear stress waveforms of the macroscale VADs (i.e., shear stress peaks and duration). Our results establish the basis for development of a lab-on-chip POC system able to perform device-specific and patient-specific platelet activation state assays.
• Leung, S. L., Dimasi, A., Heiser, S., Dunn, A., Bluestein, D., & Slepian, M. (2015). Modulation of platelet membrane function via exogenous lipid moiety exposure alters platelet responsiveness to shear. Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference, 2015, 266-9.
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  Shear-induced platelet activation may cause life-threatening thrombosis, particularly in patients with mechanical support devices or coronary atherosclerosis. The majority of present anti-platelet agents target or interfere with biochemical, rather than physical mechanisms of platelet activation. Less data and understanding exists with regard to pharmacologic modulation of shear-mediated platelet activation. In this work, we hypothesized that modulating cell membrane properties, via alteration of membrane composition through addition of exogenous lipid moieties, would alter platelet responsiveness to shear. Here we tested fatty acids, lecithin and cholesterol as additive lipid compounds. We demonstrated that incorporation of fatty acids (DHA/EPA) or lecithin into the platelet membrane triggered enhanced sensitivity of platelets to shear-mediated activation. On the other hand, cholesterol incorporation provides significant protection, limiting the effect of shear on platelet activation. These findings provide valuable insight for the development of therapeutic strategies that can modulate shear-mediated platelet activation.
• Merkle, V. M., Martin, D., Hutchinson, M., Tran, P. L., Behrens, A., Hossainy, S., Sheriff, J., Bluestein, D., Wu, X., & Slepian, M. J. (2015). Hemocompatibility of Poly(vinyl alcohol)-Gelatin Core-Shell Electrospun Nanofibers: A Scaffold for Modulating Platelet Deposition and Activation. ACS applied materials & interfaces, 7(15), 8302-12.
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  In this study, we evaluate coaxial electrospun nanofibers with gelatin in the shell and poly(vinyl alcohol) (PVA) in the core as a potential vascular material by determining fiber surface roughness, as well as human platelet deposition and activation under varying conditions. PVA scaffolds had the highest surface roughness (Ra=65.5±6.8 nm) but the lowest platelet deposition (34.2±5.8 platelets) in comparison to gelatin nanofibers (Ra=36.8±3.0 nm and 168.9±29.8 platelets) and coaxial nanofibers (1 Gel:1 PVA coaxial, Ra=24.0±1.5 nm and 150.2±17.4 platelets. 3 Gel:1 PVA coaxial, Ra=37.1±2.8 nm and 167.8±15.4 platelets). Therefore, the chemical structure of the gelatin nanofibers dominated surface roughness in platelet deposition. Due to their increased stiffness, the coaxial nanofibers had the highest platelet activation rate, rate of thrombin formation, in comparison to gelatin and PVA fibers. Our studies indicate that mechanical stiffness is a dominating factor for platelet deposition and activation, followed by biochemical signals, and lastly surface roughness. Overall, these coaxial nanofibers are an appealing material for vascular applications by supporting cellular growth while minimizing platelet deposition and activation.
• Merkle, V. M., Tran, P. L., Hutchinson, M., Ammann, K. R., DeCook, K., Wu, X., & Slepian, M. J. (2015). Core-shell PVA/gelatin electrospun nanofibers promote human umbilical vein endothelial cell and smooth muscle cell proliferation and migration. Acta biomaterialia, 27, 77-87.
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  Cardiovascular disease is the leading cause of death in the world. In this study, coaxial electrospinning is employed to fabricate fibers in a core-shell structure with polyvinyl alcohol (PVA) in the core and gelatin in the shell for evaluation as a potential vascular tissue engineering construct. PVA, a synthetic polymer, provides mechanical strength to the biocompatible and weak gelatin sheath. The HUVEC (human umbilical vein endothelial cells) and rSMC (rat smooth muscle cells) demonstrated a flattened morphology with multiple attachment sites on the gelatin and coaxial scaffolds, with an increase in cell spreading seen as mechanical stiffness of the scaffold increased. Additionally, HUVEC had an increase in migration on the coaxial scaffolds, which was attributed to the increase in stiffness; however, this increase in migration was not seen with the rSMC, which had the highest outward migration on the flat surfaces (tissue culture polystyrene and gelatin film). Overall, these scaffolds are appealing substrates for vascular tissue engineering applications.
• Niihori, M., Platto, T., Igarashi, S., Hurbon, A., Dunn, A. M., Tran, P., Tran, H., Mudery, J. A., Slepian, M. J., & Jacob, A. (2015). Zebrafish swimming behavior as a biomarker for ototoxicity-induced hair cell damage: a high-throughput drug development platform targeting hearing loss. Translational research : the journal of laboratory and clinical medicine, 166(5), 440-50.
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  Hearing loss is one of the most common human sensory disabilities, adversely affecting communication, socialization, mood, physical functioning, and quality of life. In addition to age and noise-induced damage, ototoxicity is a common cause of sensorineural hearing loss with chemotherapeutic agents, for example, cisplatin, being a major contributor. Zebrafish (Danio rerio) are an excellent model to study hearing loss as they have neurosensory hair cells on their body surface that are structurally similar to those within the human inner ear. Anatomic assays of toxin-mediated hair cell damage in zebrafish have been established; however, using fish swimming behavior--rheotaxis--as a biomarker for this anatomic damage was only recently described. We hypothesized that, in parallel, multilane measurements of rheotaxis could be used to create a high-throughput platform for drug development assessing both ototoxic and potentially otoprotective compounds in real time. Such a device was created, and results demonstrated a clear dose response between cisplatin exposure, progressive hair cell damage, and reduced rheotaxis in zebrafish. Furthermore, pre-exposure to the otoprotective medication dexamethasone, before cisplatin exposure, partially rescued rheotaxis swimming behavior and hair cell integrity. These results provide the first evidence that rescued swimming behavior can serve as a biomarker for rescued hair cell function. Developing a drug against hearing loss represents an unmet clinical need with global implications. Because hearing loss from diverse etiologies may result from common end-effects at the hair cell level, lessons learned from the present study may be broadly used.
• Parvaneh, S., Howe, C. L., Toosizadeh, N., Honarvar, B., Slepian, M. J., Fain, M., Mohler, J., & Najafi, B. (2015). Regulation of Cardiac Autonomic Nervous System Control across Frailty Statuses: A Systematic Review. Gerontology, 62(1), 3-15.
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  Frailty is a geriatric syndrome that leads to impairment in interrelated physiological systems and progressive homeostatic dysregulation in physiological systems.
• Piatti, F., Sturla, F., Marom, G., Sheriff, J., Claiborne, T. E., Slepian, M. J., Redaelli, A., & Bluestein, D. (2015). Hemodynamic and thrombogenic analysis of a trileaflet polymeric valve using a fluid-structure interaction approach. Journal of biomechanics, 48(13), 3641-9.
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  Surgical valve replacement in patients with severe calcific aortic valve disease using either bioprosthetic or mechanical heart valves is still limited by structural valve deterioration for the former and thrombosis risk mandating anticoagulant therapy for the latter. Prosthetic polymeric heart valves have the potential to overcome the inherent material and design limitations of these valves, but their development is still ongoing. The aim of this study was to characterize the hemodynamics and thrombogenic potential of the Polynova polymeric trileaflet valve prototype using a fluid-structure interaction (FSI) approach. The FSI model replicated experimental conditions of the valve as tested in a left heart simulator. Hemodynamic parameters (transvalvular pressure gradient, flow rate, maximum velocity, and effective orifice area) were compared to assess the validity of the FSI model. The thrombogenic footprint of the polymeric valve was evaluated using a Lagrangian approach to calculate the stress accumulation (SA) values along multiple platelet trajectories and their statistical distribution. In the commissural regions, platelets were exposed to the highest SA values because of highest stress levels combined with local reverse flow patterns and vortices. Stress-loading waveforms from representative trajectories in regions of interest were emulated in our hemodynamic shearing device (HSD). Platelet activity was measured using our platelet activation state (PAS) assay and the results confirmed the higher thrombogenic potential of the commissural hotspots. In conclusion, the proposed method provides an in depth analysis of the hemodynamic and thrombogenic performance of the polymer valve prototype and identifies locations for further design optimization.
• Pothapragada, S., Zhang, P., Sheriff, J., Livelli, M., Slepian, M. J., Deng, Y., & Bluestein, D. (2015). A phenomenological particle-based platelet model for simulating filopodia formation during early activation. International journal for numerical methods in biomedical engineering, 31(3), e02702.
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  We developed a phenomenological three-dimensional platelet model to characterize the filopodia formation observed during early stage platelet activation. Departing from continuum mechanics based approaches, this coarse-grained molecular dynamics (CGMD) particle-based model can deform to emulate the complex shape change and filopodia formation that platelets undergo during activation. The platelet peripheral zone is modeled with a two-layer homogeneous elastic structure represented by spring-connected particles. The structural zone is represented by a cytoskeletal assembly comprising of a filamentous core and filament bundles supporting the platelet's discoid shape, also modeled by spring-connected particles. The interior organelle zone is modeled by homogeneous cytoplasm particles that facilitate the platelet deformation. Nonbonded interactions among the discrete particles of the membrane, the cytoskeletal assembly, and the cytoplasm are described using the Lennard-Jones potential with empirical constants. By exploring the parameter space of this CGMD model, we have successfully simulated the dynamics of varied filopodia formations. Comparative analyses of length and thickness of filopodia show that our numerical simulations are in agreement with experimental measurements of flow-induced activated platelets. Copyright © 2015 John Wiley & Sons, Ltd.
• Sheriff, J., Claiborne, T. E., Tran, P. L., Kothadia, R., George, S., Kato, Y. P., Pinchuk, L., Slepian, M. J., & Bluestein, D. (2015). Physical Characterization and Platelet Interactions under Shear Flows of a Novel Thermoset Polyisobutylene-based Co-polymer. ACS applied materials & interfaces, 7(39), 22058-66.
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  Over the years, several polymers have been developed for use in prosthetic heart valves as alternatives to xenografts. However, most of these materials are beset with a variety of issues, including low material strength, biodegradation, high dynamic creep, calcification, and poor hemocompatibility. We studied the mechanical, surface, and flow-mediated thrombogenic response of poly(styrene-coblock-4-vinylbenzocyclobutene)-polyisobutylene-poly(styrene-coblock-4-vinylbenzocylcobutene) (xSIBS), a thermoset version of the thermoplastic elastomeric polyolefin poly(styrene-block-isobutylene-block-styrene) (SIBS), which has been shown to be resistant to in vivo hydrolysis, oxidation, and enzymolysis. Uniaxial tensile testing yielded an ultimate tensile strength of 35 MPa, 24.5 times greater than that of SIBS. Surface analysis yielded a mean contact angle of 82.05° and surface roughness of 144 nm, which was greater than for poly(ε-caprolactone) (PCL) and poly(methyl methacrylate) (PMMA). However, the change in platelet activation state, a predictor of thrombogenicity, was not significantly different from PCL and PMMA after fluid exposure to 1 dyn/cm(2) and 20 dyn/cm(2). In addition, the number of adherent platelets after 10 dyn/cm(2) flow exposure was on the same order of magnitude as PCL and PMMA. The mechanical strength and low thrombogenicity of xSIBS therefore suggest it as a viable polymeric substrate for fabrication of prosthetic heart valves and other cardiovascular devices.
• Sheriff, J., Tran, P. L., Hutchinson, M., DeCook, T., Slepian, M. J., Bluestein, D., & Jesty, J. (2015). Repetitive Hypershear Activates and Sensitizes Platelets in a Dose-Dependent Manner. Artificial organs.
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  Implantation of mechanical circulatory support (MCS) devices-ventricular assist devices and the total artificial heart-has emerged as a vital therapy for advanced and end-stage heart failure. Unfortunately, MCS patients face the requirement of life-long antiplatelet and anticoagulant therapy to combat thrombotic complications resulting from the dynamic and supraphysiologic shear stress conditions associated with such devices, whose effect on platelet activation is poorly understood. We developed a syringe-capillary viscometer-the "platelet hammer"-that repeatedly exposed platelets to average shear stresses up to 1000 dyne/cm(2) for as short as 25 ms. Platelet activation state was measured using a modified prothrombinase assay, with morphological changes analyzed using scanning electron microscopy. We observed an increase in platelet activation state and post-high shear platelet activation rate, or sensitization, with an increase in stress accumulation (SA), the product of shear stress and exposure time. A significant increase in platelet activation state was observed beyond an SA of 1500 dyne-s/cm(2) , with a marked increase in pseudopod length visible beyond an SA of 1000 dyne-s/cm(2) . Utility of the platelet hammer extends to studies of other shear-dependent pathologies, and may assist development of approaches to enhance the safety and effectiveness of MCS devices and objective antithrombotic pharmacotherapy management.
• Sheriff, J., Tran, P. L., Hutchinson, M., DeCook, T., Slepian, M. J., Bluestein, D., & Jesty, J. (2015). The platelet hammer: In vitro platelet activation under repetitive hypershear. Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference, 2015, 262-5.
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  Mechanical circulatory support (MCS) devices, such as ventricular assist devices and the total artificial heart, have emerged as a vital therapy for advanced and end-stage heart failure. However, MCS patients face life-long antiplatelet and anticoagulant therapy to minimize thrombotic complications resulting from the dynamic and supraphysiologic device-associated shear stress conditions, whose effect on platelet activation is poorly understood. We repeatedly exposed platelets to average shear stresses up to 1000 dyne/cm(2) for as short as 25 ms in the "platelet hammer," a syringe-capillary viscometer. Platelet activation state was measured using a modified prothrombinase assay and morphological changes analyzed using scanning electron microscopy. An increase in stress accumulation (SA), the product of shear stress and exposure time, led to an increase in the platelet activation state and post-high shear platelet activation rate, or sensitization. A significant increase in platelet activation state was observed beyond an SA of 1500 dyne-s/cm(2), with a marked increase in pseudopod length visible beyond an SA of 1000 dyne-s/cm(2). The platelet hammer may be used to study other shear-dependent pathologies and may ultimately enhance the safety and effectiveness of MCS devices and objective antithrombotic pharmacotherapy management.
• Slepian, M. J., Armstrong, D. G., Kleidermacher, D. N., & Klonoff, D. C. (2015). Cybersecurity Regulation of Wireless Devices for Performance and Assurance in the Age of “Medjacking”. Journal of Diabetes Science and Technology, 10(2), 435-438. doi:10.1177/1932296815602100
• Slepian, M. J., Pothapragada, S., Zhang, P., Sheriff, J., Livelli, M., Deng, Y., & Bluestein, D. (2015). A phenomenological particle-based platelet model for simulating filopodia formation during early activation: A PHENOMENOLOGICAL PARTICLE-BASED PLATELET MODEL. International Journal for Numerical Methods in Biomedical Engineering, 31(3), e02702. doi:10.1002/cnm.2702
• Slepian, M. J., Sheriff, J., Claiborne, T. E., Tran, P. L., Kothadia, R., George, S., Kato, Y. P., Pinchuk, L., & Bluestein, D. (2015). Physical Characterization and Platelet Interactions under Shear Flows of a Novel Thermoset Polyisobutylene-based Co-polymer. ACS Applied Materials & Interfaces, 7(39), 22058-22066. doi:10.1021/acsami.5b07254
• Slepian, M. J., Sheriff, J., Tran, P. L., Hutchinson, M., DeCook, T., Bluestein, D., & Jesty, J. (2015). Repetitive Hypershear Activates and Sensitizes Platelets in a Dose-Dependent Manner: Platelet Activation Under Hypershear. Artificial Organs, 40(6), 586-595. doi:10.1111/aor.12602
• Slepian, M. J., Wong, R. K., Tran, P. L., Pietropaolo, M., Valerio, L., Brengle, W., Kazui, T., Khalpey, Z. I., Redaelli, A., Sheriff, J., & Bluestein, D. (2015). Hemolysate-mediated platelet aggregation: an additional risk mechanism contributing to thrombosis of continuous flow ventricular assist devices. Perfusion, 31(5), 401-408. doi:10.1177/0267659115615206
• Sun, J., Xiao, Y., Wang, S., Slepian, M. J., & Wong, P. K. (2015). Advances in techniques for probing mechanoregulation of tissue morphogenesis. Journal of laboratory automation, 20(2), 127-37.
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  Cells process various mechanical cues in the microenvironment to self-organize into high-order architectures during tissue morphogenesis. Impairment of morphogenic processes is the underlying cause of many diseases; as such, understanding the regulatory mechanisms associated with these processes will form the foundation for the development of innovative approaches in cell therapy and tissue engineering. Nevertheless, little is known about how cells collectively respond to mechanical cues in the microenvironment, such as global geometric guidance, local cell-cell interactions, and other physicochemical factors, for the emergence of the structural hierarchy across multiple length scales. To elucidate the mechanoregulation of tissue morphogenesis, numerous approaches based on biochemical, biomaterial, and biophysical techniques have been developed in the past decades. In this review, we summarize techniques and approaches for probing the mechanoregulation of tissue morphogenesis and illustrate their applications in vasculature development. The potential and limitations of these methods are also discussed with a view toward the investigation of a wide spectrum of tissue morphogenic processes.
• Tran, P. L., Pietropaolo, M., Valerio, L., Brengle, W., Wong, R. K., Kazui, T., Khalpey, Z. I., Redaelli, A., Sheriff, J., Bluestein, D., & Slepian, M. J. (2015). Hemolysate-mediated platelet aggregation: an additional risk mechanism contributing to thrombosis of continuous flow ventricular assist devices. Perfusion.
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  Despite the clinical success and growth in the utilization of continuous flow ventricular assist devices (cfVADs) for the treatment of advanced heart failure, hemolysis and thrombosis remain major limitations. Inadequate and/or ineffective anticoagulation regimens, combined with high pump speed and non-physiological flow patterns, can result in hemolysis which often is accompanied by pump thrombosis. An unexpected increase in cfVADs thrombosis was reported by multiple major VAD implanting centers in 2014, highlighting the association of hemolysis and a rise in lactate dehydrogenase (LDH) presaging thrombotic events. It is well established that thrombotic complications arise from the abnormal shear stresses generated by cfVADs. What remains unknown is the link between cfVAD-associated hemolysis and pump thrombosis. Can hemolysis of red blood cells (RBCs) contribute to platelet aggregation, thereby, facilitating prothrombotic complications in cfVADs? Herein, we examine the effect of RBC-hemolysate and selected major constituents, i.e., lactate dehydrogenase (LDH) and plasma free hemoglobin (pHb) on platelet aggregation, utilizing electrical resistance aggregometry. Our hypothesis is that elements of RBCs, released as a result of shear-mediated hemolysis, will contribute to platelet aggregation. We show that RBC hemolysate and pHb, but not LDH, are direct contributors to platelet aggregation, posing an additional risk mechanism for cfVAD thrombosis.
• Valerio, L., Consolo, F., Bluestein, D., Tran, P., Slepian, M., Redaelli, A., & Pappalardo, F. (2015). Shear-mediated platelet activation in patients implanted with continuous flow LVADs: A preliminary study utilizing the platelet activity state (PAS) assay. Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference, 2015, 1255-8.
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  Left ventricular assist devices (LVADs) have emerged as vital life-saving therapeutic systems for patients with advanced and end-stage heart failure (HF). Despite their efficacy, VAD systems remain limited by post-implantation thrombotic complications. Shear-mediated platelet activation is the major driver of such complications in these devices. Nowadays few platelet function assays are routinely utilized in assessing the degree of platelet activation in VAD implanted patients. No assays exist that specifically target shear-mediated platelet activation. The platelet activity state (PAS) is a novel assay that has been well validated in vitro, measuring thrombin release as a surrogate for shear-mediated platelet activation. To date limited data exist as to the utility of this assay in the clinical setting. In the present study we evaluated eight LVAD patients' platelet activation level using the PAS assay. Simultaneous measurements of conventional prothrombotic and hemolysis markers, - i.e. fibrinogen and lactate dehydrogenase (LDH) - were also performed. Trends as to alteration from baseline were studied. We observed that the PAS assay allowed detection of an abnormal level of platelet activation in one patient in our series who suffered from an overt thrombosis. Interestingly in the same patient no signal of major abnormality in fibrinogen or LDH was detected. Further for 7/8 patients who were free of thrombosis, no significant level of platelet activation was detected via PAS assay, while elevation in fibrinogen and LDH were observed. As such, from our observational series it appears that the PAS assay is a sensitive and specific indicator of shear-mediated platelet activation. Further patients' experience will help elucidate the role of this promising assay in the management of LVAD implanted patients.
• Vande Geest, J. P., Slepian, M. J., Doetschman, T., Tamimi, E., Ardila, D. C., Haskett, D. G., & Kellar, R. S. (2015). Biomechanical Comparison of Glutaraldehyde-Crosslinked Gelatin Fibrinogen Electrospun Scaffolds to Porcine Coronary Arteries. Journal of Biomechanical Engineering, 138(1). doi:10.1115/1.4031847
• Webb, R. C., Ma, Y., Krishnan, S., Li, Y., Yoon, S., Guo, X., Feng, X., Shi, Y., Seidel, M., Cho, N. H., Kurniawan, J., Ahad, J., Sheth, N., Kim, J., Taylor, J. G., Darlington, T., Chang, K., Huang, W., Ayers, J., , Gruebele, A., et al. (2015). Epidermal devices for noninvasive, precise, and continuous mapping of macrovascular and microvascular blood flow. Science advances, 1(9), e1500701.
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  Continuous monitoring of variations in blood flow is vital in assessing the status of microvascular and macrovascular beds for a wide range of clinical and research scenarios. Although a variety of techniques exist, most require complete immobilization of the subject, thereby limiting their utility to hospital or clinical settings. Those that can be rendered in wearable formats suffer from limited accuracy, motion artifacts, and other shortcomings that follow from an inability to achieve intimate, noninvasive mechanical linkage of sensors with the surface of the skin. We introduce an ultrathin, soft, skin-conforming sensor technology that offers advanced capabilities in continuous and precise blood flow mapping. Systematic work establishes a set of experimental procedures and theoretical models for quantitative measurements and guidelines in design and operation. Experimental studies on human subjects, including validation with measurements performed using state-of-the-art clinical techniques, demonstrate sensitive and accurate assessment of both macrovascular and microvascular flow under a range of physiological conditions. Refined operational modes eliminate long-term drifts and reduce power consumption, thereby providing steps toward the use of this technology for continuous monitoring during daily activities.
• Bluestein, D., & Slepian, M. J. (2014). Sticking with synthetic tissue sealants. The New England journal of medicine, 370(16), 1556-9.
• Bluestein, D., Soares, J. S., Zhang, P., Gao, C., Pothapragada, S., Zhang, N., Slepian, M. J., & Deng, Y. (2014). Multiscale Modeling of Flow Induced Thrombogenicity With Dissipative Particle Dynamics and Molecular Dynamics. Journal of medical devices, 8(2), 0209541-209542.
• Chiu, W. C., Girdhar, G., Xenos, M., Alemu, Y., Soares, J. S., Einav, S., Slepian, M., & Bluestein, D. (2014). Thromboresistance comparison of the HeartMate II ventricular assist device with the device thrombogenicity emulation- optimized HeartAssist 5 VAD. Journal of biomechanical engineering, 136(2), 021014.
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  Approximately 7.5 × 106 patients in the US currently suffer from end-stage heart failure. The FDA has recently approved the designations of the Thoratec HeartMate II ventricular assist device (VAD) for both bridge-to-transplant and destination therapy (DT) due to its mechanical durability and improved hemodynamics. However, incidence of pump thrombosis and thromboembolic events remains high, and the life-long complex pharmacological regimens are mandatory in its VAD recipients. We have previously successfully applied our device thrombogenicity emulation (DTE) methodology for optimizing device thromboresistance to the Micromed Debakey VAD, and demonstrated that optimizing device features implicated in exposing blood to elevated shear stresses and exposure times significantly reduces shear-induced platelet activation and significantly improves the device thromboresistance. In the present study, we compared the thrombogenicity of the FDA-approved HeartMate II VAD with the DTE-optimized Debakey VAD (now labeled HeartAssist 5). With quantitative probability density functions of the stress accumulation along large number of platelet trajectories within each device which were extracted from numerical flow simulations in each device, and through measurements of platelet activation rates in recirculation flow loops, we specifically show that: (a) Platelets flowing through the HeartAssist 5 are exposed to significantly lower stress accumulation that lead to platelet activation than the HeartMate II, especially at the impeller-shroud gap regions (b) Thrombus formation patterns observed in the HeartMate II are absent in the HeartAssist 5 (c) Platelet activation rates (PAR) measured in vitro with the VADs mounted in recirculation flow-loops show a 2.5-fold significantly higher PAR value for the HeartMate II. This head to head thrombogenic performance comparative study of the two VADs, one optimized with the DTE methodology and one FDA-approved, demonstrates the efficacy of the DTE methodology for drastically reducing the device thrombogenic potential, validating the need for a robust in silico/in vitro optimization methodology for improving cardiovascular devices thromboresistance.
• Chiu, W., Girdhar, G., Xenos, M., Alemu, Y., Soares, J. S., Einav, S., Slepian, M., & Bluestein, D. (2014). Thromboresistance Comparison of the HeartMate II Ventricular Assist Device With the Device Thrombogenicity Emulation-Optimized HeartAssist 5 VAD. JOURNAL OF BIOMECHANICAL ENGINEERING-TRANSACTIONS OF THE ASME, 136(2).
• Dagdeviren, C., Yang, B. D., Su, Y., Tran, P. L., Joe, P., Anderson, E., Xia, J., Doraiswamy, V., Dehdashti, B., Feng, X., Lu, B., Poston, R., Khalpey, Z., Ghaffari, R., Huang, Y., Slepian, M. J., & Rogers, J. A. (2014). Conformal piezoelectric energy harvesting and storage from motions of the heart, lung, and diaphragm. Proceedings of the National Academy of Sciences of the United States of America, 111(5), 1927-32.
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  Here, we report advanced materials and devices that enable high-efficiency mechanical-to-electrical energy conversion from the natural contractile and relaxation motions of the heart, lung, and diaphragm, demonstrated in several different animal models, each of which has organs with sizes that approach human scales. A cointegrated collection of such energy-harvesting elements with rectifiers and microbatteries provides an entire flexible system, capable of viable integration with the beating heart via medical sutures and operation with efficiencies of ∼2%. Additional experiments, computational models, and results in multilayer configurations capture the key behaviors, illuminate essential design aspects, and offer sufficient power outputs for operation of pacemakers, with or without battery assist.
• Dimasi, A., Redaelli, A., Bluestein, D., Rasponi, M., & Slepian, M. (2014). "HyperShear in A Channel": A Microfluidic Facsimile of Ventricular Assist Devices to Reduce Thrombotic Risk and Enhance Patient Safety. 2014 IEEE Healthcare Innovation Conference (HIC), 14-17.
• Kern, K. B., Boyella, R. R., Patel, R. M., & Slepian, M. J. (2014). Stent thrombosis after aggressive post resuscitation care: the beginning or the end?. Resuscitation, 85(6), 711-3.
• Khalpey, Z., Bin, R. I., Bilal, J., Hsu, C., Friedman, M., Smith, R., Stavoe, K., Slepian, M. J., & Poston, R. (2014). Robotic Implantation of Left Ventricular Assist Devices: A New Era in Cardiac Surgery. JOURNAL OF HEART AND LUNG TRANSPLANTATION, 33(4), S202-S202.
• Khalpey, Z., Sydow, N., Slepian, M. J., & Poston, R. (2014). How to do it: thoracoscopic left ventricular assist device implantation using robot assistance. The Journal of thoracic and cardiovascular surgery, 147(4), 1423-5.
• Marom, G., Chiu, W., Crosby, J. R., DeCook, K. J., Prabhakar, S., Horner, M., Slepian, M. J., & Bluestein, D. (2014). Numerical model of full-cardiac cycle hemodynamics in a total artificial heart and the effect of its size on platelet activation. Journal of cardiovascular translational research, 7(9), 788-96.
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  The SynCardia total artificial heart (TAH) is the only Food and Drug Administration (FDA) approved device for replacing hearts in patients with congestive heart failure. It pumps blood via pneumatically driven diaphragms and controls the flow with mechanical valves. While it has been successfully implanted in more than 1300 patients, its size precludes implantation in smaller patients. This study's aim was to evaluate the viability of scaled-down TAHs by quantifying thrombogenic potentials from flow patterns. Simulations of systole were first conducted with stationary valves, followed by an advanced full-cardiac cycle model with moving valves. All the models included deforming diaphragms and platelet suspension in the blood flow. Flow stress accumulations were computed for the platelet trajectories and thrombogenic potentials were assessed. The simulations successfully captured complex flow patterns during various phases of the cardiac cycle. Increased stress accumulations, but within the safety margin of acceptable thrombogenicity, were found in smaller TAHs, indicating that they are clinically viable.
• Marom, G., Chiu, W., Slepian, M. J., & Bluestein, D. (2014). Numerical model of total artificial heart hemodynamics and the effect of its size on stress accumulation. Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference, 2014, 5651-4.
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  The total artificial heart (TAH) is a bi-ventricular mechanical circulatory support device that replaces the heart in patients with end-stage congestive heart failure. The device acts as blood pump via pneumatic activation of diaphragms altering the volume of the ventricular chambers. Flow in and out of the ventricles is controlled by mechanical heart valves. The aim of this study is to evaluate the flow regime in the TAH and to estimate the thrombogenic potential during systole. Toward that goal, three numerical models of TAHs of differing sizes, that include the deforming diaphragm and the blood flow from the left chamber to the aorta, are introduced. A multiphase model with injection of platelet particles is employed to calculate their trajectories. The shear stress accumulation in the three models are calculated along the platelets trajectories and their probability density functions, which represent the `thrombogenic footprint' of the device are compared. The calculated flow regime successfully captures the mitral regurgitation and the flows that open and close the aortic valve during systole. Physiological velocity magnitudes are found in all three models, with higher velocities and increased stress accumulation predicted for smaller devices.
• Merkle, V. M., Zeng, L., Slepian, M. J., & Wu, X. (2014). Core-shell nanofibers: Integrating the bioactivity of gelatin and the mechanical property of polyvinyl alcohol. Biopolymers, 101(4), 336-46.
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  Coaxial electrospinning is used to fabricate nanofibers with gelatin in the shell and polyvinyl alcohol (PVA) in the core in order to derive mechanical strength from PVA and bioactivity from gelatin. At a 1:1 PVA/gelatin mass ratio, the core-shell nanofiber scaffolds display a Young's modulus of 168.6 ± 36.5 MPa and a tensile strength of 5.42 ± 1.95 MPa, which are significantly higher than those of the scaffolds composed solely of gelatin or PVA. The Young's modulus and tensile strength of the core-shell nanofibers are further improved by reducing the PVA/gelatin mass ratio from 1:1 to 1:3. The mechanical analysis of the core-shell nanofibers suggests that the presence of the gelatin shell may improve the molecular alignment of the PVA core, transforming the semi-crystalline, plastic PVA into a more crystallized, elastic PVA, and enhancing the mechanical properties of the core. Lastly, the PVA/gelatin core-shell nanofibers possess cellular viability, proliferation, and adhesion similar to these of the gelatin nanofibers, and show significantly higher proliferation and adhesion than the PVA nanofibers. Taken together, the coaxial electrospinning of nanofibers with a core-shell structure permits integration of the bioactivity of gelatin and the mechanical strength of PVA in single fibers.
• Riahi, R., Long, M., Yang, Y., Dean, Z., Zhang, D. D., Slepian, M. J., & Wong, P. K. (2014). Single cell gene expression analysis in injury-induced collective cell migration. Integrative biology : quantitative biosciences from nano to macro, 6(2), 192-202.
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  Collective cell behavior in response to mechanical injury is central to various regenerative and pathological processes. Using a double-stranded locked nucleic acid probe for monitoring real-time intracellular gene expression, we examined the spatiotemporal response of epithelial cells during injury-induced collective migration and compared to the blocker assay with minimal injury as control. We showed that cells ∼150 μm from the wound edge exhibit a gradient in response to mechanical injury, expressing different genes depending on the wounding process. While release of contact inhibition is sufficient to trigger the migratory behavior, cell injury additionally induces reactive oxygen species, Nrf2 protein, and stress response genes, including heat shock protein 70 and heme oxygenase-1, in a spatiotemporal manner. Furthermore, we show that Nrf2 has an inhibitory role in injury-induced epithelial-mesenchymal transition, suggesting a potential autoregulatory mechanism in injury-induced response. Taken together, our single-cell gene expression analyses reveal modular cell responses to mechanical injury, manipulation of which may afford novel strategies for tissue repair and prevention of tumor invasion in the future.
• Sheriff, J., Girdhar, G., Chiu, W. C., Jesty, J., Slepian, M. J., & Bluestein, D. (2014). Comparative efficacy of in vitro and in vivo metabolized aspirin in the DeBakey ventricular assist device. Journal of thrombosis and thrombolysis, 37(4), 499-506.
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  Ventricular assist devices (VADs) are implanted in patients with end-stage heart failure to provide both short- and long-term hemodynamic support. Unfortunately, bleeding and thromboembolic complications due to the severely disturbed, dynamic flow conditions generated within these devices require complex, long-term antiplatelet and anticoagulant therapy. While several studies have examined the effectiveness of one such agent, aspirin, under flow conditions, data comparing the efficacy of in vitro and in vivo metabolized aspirin is lacking. Two sets of studies were conducted in vitro with purified human platelets circulating for 30 min in a flow loop containing the DeBakey VAD (MicroMed Cardiovascular, Houston, TX, USA): (a) 20 μM aspirin was added exogenously in vitro to platelets isolated from aspirin-free subjects, and (b) platelets were obtained from donors 2 h (n = 14) and 20 h (n = 13) after ingestion of 1,000 mg aspirin. Near real-time platelet activation state (PAS) was measured with a modified prothrombinase-based assay. Platelets exposed to aspirin in vitro and in vivo (metabolized) showed 28.2 and 25.3 % reduction in platelet activation rate, respectively, compared to untreated controls. Our results demonstrate that in vitro treatment with antiplatelet drugs such as aspirin is as effective as in vivo metabolized aspirin in testing the effect of reducing shear-induced platelet activation in the VAD. Using the PAS assay provides a practical in vitro alternative to in vivo testing of antiplatelet efficacy, as well as for testing the thrombogenic performance of devices during their research and development.
• Slepian, M. J., Xia, J., Dagdeviren, C., Yang, B. D., Su, Y., Tran, P. L., Joe, P., Anderson, E., Doraiswamy, V., Dehdashti, B., Feng, X., Lu, B., Poston, R., Khalpey, Z., Ghaffari, R., Huang, Y., & Rogers, J. A. (2014). Conformal piezoelectric energy harvesting and storage from motions of the heart, lung, and diaphragm. Proceedings of the National Academy of Sciences, 111(5), 1927-1932. doi:10.1073/pnas.1317233111
• Slepian, M., Chiu, W., Girdhar, G., Xenos, M., Alemu, Y., Soares, J. S., Einav, S., & Bluestein, D. (2014). Thromboresistance Comparison of the HeartMate II Ventricular Assist Device With the Device Thrombogenicity Emulation-Optimized HeartAssist 5 VAD. Journal of Biomechanical Engineering, 136(2). doi:10.1115/1.4026254
• Wu, X., Wu, X., Slepian, M. J., Slepian, M. J., Merkle, V. M., Merkle, V. M., Zeng, L., & Zeng, L. (2014). Core-shell nanofibers: Integrating the bioactivity of gelatin and the mechanical property of polyvinyl alcohol: Core-Shell Nanofibers. Biopolymers, 101(4), 336-346. doi:10.1002/bip.22367
• Yamaguchi, J., Tran, P., Sen, N., DeCook, T., & Slepian, M. (2014). Desensitization of DMSO-treated platelets to common agonists via membrane modulation. FASEB JOURNAL, 28(1).
• Zhang, P., Gao, C., Zhang, N., Slepian, M. J., Deng, Y., & Bluestein, D. (2014). Multiscale Particle-Based Modeling of Flowing Platelets in Blood Plasma Using Dissipative Particle Dynamics and Coarse Grained Molecular Dynamics. Cellular and molecular bioengineering, 7(4), 552-574.
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  We developed a multiscale particle-based model of platelets, to study the transport dynamics of shear stresses between the surrounding fluid and the platelet membrane. This model facilitates a more accurate prediction of the activation potential of platelets by viscous shear stresses - one of the major mechanisms leading to thrombus formation in cardiovascular diseases and in prosthetic cardiovascular devices. The interface of the model couples coarse-grained molecular dynamics (CGMD) with dissipative particle dynamics (DPD). The CGMD handles individual platelets while the DPD models the macroscopic transport of blood plasma in vessels. A hybrid force field is formulated for establishing a functional interface between the platelet membrane and the surrounding fluid, in which the microstructural changes of platelets may respond to the extracellular viscous shear stresses transferred to them. The interaction between the two systems preserves dynamic properties of the flowing platelets, such as the flipping motion. Using this multiscale particle-based approach, we have further studied the effects of the platelet elastic modulus by comparing the action of the flow-induced shear stresses on rigid and deformable platelet models. The results indicate that neglecting the platelet deformability may overestimate the stress on the platelet membrane, which in turn may lead to erroneous predictions of the platelet activation under viscous shear flow conditions. This particle-based fluid-structure interaction multiscale model offers for the first time a computationally feasible approach for simulating deformable platelets interacting with viscous blood flow, aimed at predicting flow induced platelet activation by using a highly resolved mapping of the stress distribution on the platelet membrane under dynamic flow conditions.
• Bluestein, D., Girdhar, G., Einav, S., & Slepian, M. J. (2013). Device thrombogenicity emulation: a novel methodology for optimizing the thromboresistance of cardiovascular devices. Journal of biomechanics, 46(2), 338-44.
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  Thrombotic complications with mechanical circulatory support (MCS) devices remain a critical limitation to their long-term use. Device-induced shear forces may enhance the thrombotic potential of MCS devices through chronic activation of platelets, with a known dose-time response of the platelets to the accumulated stress experienced while flowing through the device-mandating complex, lifelong anticoagulation therapy. To enhance the thromboresistance of these devices for facilitating their long-term use, a universal predictive methodology entitled device thrombogenicity emulation (DTE) was developed. DTE is aimed at optimizing the thromboresistance of any MCS device. It is designed to test device-mediated thrombogenicity, coupled with virtual design modifications, in an iterative approach. This disruptive technology combines in silico numerical simulations with in vitro measurements, by correlating device hemodynamics with platelet activity coagulation markers-before and after iterative design modifications aimed at achieving optimized thrombogenic performance. The design changes are first tested in the numerical domain, and the resultant device conditions are then emulated in a hemodynamic shearing device (HSD) in which platelet activity is measured under device emulated conditions. As such, DTE can be easily incorporated during the device research and development phase-achieving minimization of the device thrombogenicity before prototypes are built and tested thereby reducing the ultimate cost of preclinical and clinical trials. The robust capability of this predictive technology is demonstrated here in various MCS devices. The presented examples indicate the potential of DTE for reducing device thrombogenicity to a level that may obviate or significantly reduce the extent of anticoagulation currently mandated for patients implanted with MCS devices for safe long-term clinical use.
• Claiborne, T. E., Sheriff, J., Kuetting, M., Steinseifer, U., Slepian, M. J., & Bluestein, D. (2013). In vitro evaluation of a novel hemodynamically optimized trileaflet polymeric prosthetic heart valve. Journal of biomechanical engineering, 135(2), 021021.
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  Calcific aortic valve disease is the most common and life threatening form of valvular heart disease, characterized by stenosis and regurgitation, which is currently treated at the symptomatic end-stages via open-heart surgical replacement of the diseased valve with, typically, either a xenograft tissue valve or a pyrolytic carbon mechanical heart valve. These options offer the clinician a choice between structural valve deterioration and chronic anticoagulant therapy, respectively, effectively replacing one disease with another. Polymeric prosthetic heart valves (PHV) offer the promise of reducing or eliminating these complications, and they may be better suited for the new transcatheter aortic valve replacement (TAVR) procedure, which currently utilizes tissue valves. New evidence indicates that the latter may incur damage during implantation. Polymer PHVs may also be incorporated into pulsatile circulatory support devices such as total artificial heart and ventricular assist devices that currently employ mechanical PHVs. Development of polymer PHVs, however, has been slow due to the lack of sufficiently durable and biocompatible polymers. We have designed a new trileaflet polymer PHV for surgical implantation employing a novel polymer-xSIBS-that offers superior bio-stability and durability. The design of this polymer PHV was optimized for reduced stresses, improved hemodynamic performance, and reduced thrombogenicity using our device thrombogenicity emulation (DTE) methodology, the results of which have been published separately. Here we present our new design, prototype fabrication methods, hydrodynamics performance testing, and platelet activation measurements performed in the optimized valve prototype and compare it to the performance of a gold standard tissue valve. The hydrodynamic performance of the two valves was comparable in all measures, with a certain advantage to our valve during regurgitation. There was no significant difference between the platelet activation rates of our polymer valve and the tissue valve, indicating that similar to the latter, its recipients may not require anticoagulation. This work proves the feasibility of our optimized polymer PHV design and brings polymeric valves closer to clinical viability.
• Gamboa, J. R., Mohandes, S., Tran, P. L., Slepian, M. J., & Yoon, J. (2013). Linear fibroblast alignment on sinusoidal wave micropatterns. Colloids & surfaces. B, Biointerfaces, 104, 318-325.
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  Micrometer and nanometer grooved surfaces have been determined to influence cellular orientation, morphology, and migration through contact guidance. Cells typically elongate along the direction of an underlying groove and often migrate with guidance provided by constraints of the pattern. This phenomenon has been studied primarily using linear grooves, post, or well patterns. We investigated the behavior of mouse embryonic fibroblasts on non-linear, sinusoidal wave grooves created via electron beam lithography on a polymethyl methacrylate (PMMA) substrate that was spin-coated onto a positively charged glass surface. Three different wave patterns, with varying wavelengths and amplitudes, and two different line patterns were created. Cell orientation and adhesion was examined after 4, 24, and 48 h after cell seeding. Attachment strength was studied via subjecting cells on substrates to centrifugal force following a 24-h incubation period. For all wave patterns studied, it was noted that cells did not reside within the groove, rather they were observed to cross over each groove, residing both inside and outside of each wave pattern, aligning linearly along the long axis of the pattern. For the linear patterns, we observed that cells tended to reside within the grooves, consistent with previous observations. The ability to add texture to a surface to manipulate cell adhesion strength and growth with only localized attachment, maintaining free space in curvilinear microtopography underlying the cell, may be a useful addition for tissue engineering and the fabrication of novel biomedical devices.
• McCracken, K. E., Tran, P. L., You, D. J., Slepian, M. J., & Yoon, J. (2013). Shear- vs. nanotopography-guided control of growth of endothelial cells on RGD-nanoparticle-nanowell arrays. Journal of biological engineering, 7(11).
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  Endothelialization of therapeutic cardiovascular implants is essential for their intravascular hemocompatibility. We previously described a novel nanowell-RGD-nanoparticle ensemble, which when applied to surfaces led to enhanced endothelialization and retention under static conditions and low flow rates. In the present study we extend our work to determine the interrelated effects of flow rate and the orientation of ensemble-decorated surface arrays on the growth, adhesion and morphology of endothelial cells. Human umbilical vascular endothelial cells (HUVECs) were grown on array surfaces with either 1 um x 5 um spacing (parallel to flow) and 5 um x 1 um spacing (perpendicular to flow) and were exposed to a range of shear stress of (0 to 4.7 +/- 0.2 dyn cm(-2)), utilizing a pulsatile flow chamber. Under physiological flow (4.7 +/- 0.2 dyn cm(-2)), RGD-nanoparticle-nanowell array patterning significantly enhanced cell adhesion and spreading compared with control surfaces and with static conditions. Furthermore, improved adhesion coincided with higher alignment to surface patterning, intimating the importance of interaction and response to the array surface as a means of resisting flow detachment. Under sub-physiological condition (1.7 +/- 0.3 dyn cm(-2)); corresponding to early angiogenesis), nanowell-nanoparticle patterning did not provide enhanced cell growth and adhesion compared with control surfaces. However, it revealed increased alignment along the direction of flow, rather than the direction of the pattern, thus potentially indicating a threshold for cell guidance and related retention. These results could provide a cue for controlling cell growth and alignment under varying physiological conditions.
• Merkle, V., Zeng, L., Teng, W., Slepian, M., Wu, X., Merkle, V., Zeng, L., Teng, W., Slepian, M., & Wu, X. (2013). Gelatin shells strengthen polyvinyl alcohol core-shell nanofibers. Polymer (United Kingdom), 54(21), 6003-6007.
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  Abstract: In this study, polyvinyl alcohol (PVA) and gelatin are coaxially electrospun into core-shell nanofibers to derive mechanical strength from PVA and bioactivity from gelatin. The core-shell nanofibers with PVA in the core and gelatin in the shell display an increased Young's modulus, improved tensile strength, and reduced plastic deformation than PVA nanofibers. When the order of gelatin and PVA is reversed in the core-shell nanofibers, however, the mechanical strengthening effects disappear. It thus suggests that the bioactive yet mechanically weak gelatin shell improves the molecular alignment of PVA in the core and transforms the weak, plastic PVA into a strong, elastic PVA. The use of a gelatin shell as a biological coating and a protecting barrier to strengthen the core in electrospinning presents a new strategy for fabricating advanced composite nanofibers. © 2013 Elsevier Ltd. All rights reserved.
• Sheriff, J., Soares, J. S., Xenos, M., Jesty, J., Slepian, M. J., & Bluestein, D. (2013). Evaluation of shear-induced platelet activation models under constant and dynamic shear stress loading conditions relevant to devices. Annals of biomedical engineering, 41(6), 1279-96.
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  The advent of implantable blood-recirculating devices such as left ventricular assist devices and prosthetic heart valves provides a viable therapy for patients with end-stage heart failure and valvular disease. However, device-generated pathological flow patterns result in thromboembolic complications that require complex and lifelong anticoagulant therapy, which entails hemorrhagic risks and is not appropriate for certain patients. Optimizing the thrombogenic performance of such devices utilizing numerical simulations requires the development of predictive platelet activation models that account for variations in shear-loading rates characterizing blood flow through such devices. Platelets were exposed in vitro to both dynamic and constant shear stress conditions emulating those found in blood-recirculating devices in order to determine their shear-induced activation and sensitization response. Both these behaviors were found to be dependent on the shear loading rates, in addition to shear stress magnitude and exposure time. We then critically examined several current models and evaluated their predictive capabilities using these results. Shear loading rate terms were then included to account for dynamic aspects that are either ignored or partially considered by these models, and model parameters were optimized. Independent optimization for each of the two types of shear stress exposure conditions tested resulted in different sets of best-fit constants, indicating that universal optimization may not be possible. Inherent limitations of the current models require a paradigm shift from these integral-based discretized power law models to better address the dynamic conditions encountered in blood-recirculating devices.
• Slepian, M. J., Alemu, Y., Girdhar, G., Soares, J. S., Smith, R. G., Einav, S., & Bluestein, D. (2013). The Syncardia(™) total artificial heart: in vivo, in vitro, and computational modeling studies. Journal of biomechanics, 46(2), 266-75.
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  The SynCardia(™) total artificial heart (TAH) is the only FDA-approved TAH in the world. The SynCardia(™) TAH is a pneumatically driven, pulsatile system capable of flows of >9L/min. The TAH is indicated for use as a bridge to transplantation (BTT) in patients at imminent risk of death from non-reversible bi-ventricular failure. In the Pivotal US approval trial the TAH achieved a BTT rate of >79%. Recently a multi-center, post-market approval study similarly demonstrated a comparable BTT rate. A major milestone was recently achieved for the TAH, with over 1100 TAHs having been implanted to date, with the bulk of implantation occurring at an ever increasing rate in the past few years. The TAH is most commonly utilized to save the lives of patients dying from end-stage bi-ventricular heart failure associated with ischemic or non-ischemic dilated cardiomyopathy. Beyond progressive chronic heart failure, the TAH has demonstrated great efficacy in supporting patients with acute irreversible heart failure associated with massive acute myocardial infarction. In recent years several diverse clinical scenarios have also proven to be well served by the TAH including severe heart failure associated with advanced congenital heart disease. failed or burned-out transplants, infiltrative and restrictive cardiomyopathies and failed ventricular assist devices. Looking to the future a major unmet need remains in providing total heart support for children and small adults. As such, the present TAH design must be scaled to fit the smaller patient, while providing equivalent, if not superior flow characteristics, shear profiles and overall device thrombogenicity. To aid in the development of a new "pediatric," TAH an engineering methodology known as "Device Thrombogenicity Emulation (DTE)", that we have recently developed and described, is being employed. Recently, to further our engineering understanding of the TAH, as steps towards next generation designs we have: (1) assessed of the degree of platelet reactivity induced by the present clinical 70 cc TAH using a closed loop platelet activity state assay, (2) modeled the motion of the TAH pulsatile mobile diaphragm, and (3) performed fluid-structure interactions and assessment of the flow behavior through inflow and outflow regions of the TAH fitted with modern bi-leaflet heart valves. Developing a range of TAH devices will afford biventricular replacement therapy to a wide range of patients, for both short and long-term therapy.
• Slepian, M. J., Bluestein, D., Soares, J. S., Zhang, P., Gao, C., Pothapragada, S., Zhang, N., & Deng, Y. (2013). Multiscale Modeling of Flow Induced Thrombogenicity With Dissipative Particle Dynamics and Molecular Dynamics. Journal of Medical Devices, 7(4). doi:10.1115/1.4027347
• Slepian, M. J., Claiborne, T. E., Sheriff, J., Kuetting, M., Steinseifer, U., & Bluestein, D. (2013). In Vitro Evaluation of a Novel Hemodynamically Optimized Trileaflet Polymeric Prosthetic Heart Valve. Journal of Biomechanical Engineering, 135(2). doi:10.1115/1.4023235
• Soares, J. S., Gao, C., Alemu, Y., Slepian, M., & Bluestein, D. (2013). Simulation of platelets suspension flowing through a stenosis model using a dissipative particle dynamics approach. Annals of biomedical engineering, 41(11), 2318-33.
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  Stresses on blood cellular constituents induced by blood flow can be represented by a continuum approach down to the μm level; however, the molecular mechanisms of thrombosis and platelet activation and aggregation are on the order of nm. The coupling of the disparate length and time scales between molecular and macroscopic transport phenomena represents a major computational challenge. In order to bridge the gap between macroscopic flow scales and the cellular scales with the goal of depicting and predicting flow induced thrombogenicity, multi-scale approaches based on particle methods are better suited. We present a top-scale model to describe bulk flow of platelet suspensions: we employ dissipative particle dynamics to model viscous flow dynamics and present a novel and general no-slip boundary condition that allows the description of three-dimensional viscous flows through complex geometries. Dissipative phenomena associated with boundary layers and recirculation zones are observed and favorably compared to benchmark viscous flow solutions (Poiseuille and Couette flows). Platelets in suspension, modeled as coarse-grained finite-sized ensembles of bound particles constituting an enclosed deformable membrane with flat ellipsoid shape, show self-orbiting motions in shear flows consistent with Jeffery's orbits, and are transported with the flow, flipping and colliding with the walls and interacting with other platelets.
• Tran, P. L., Gamboa, J. R., McCracken, K. E., Riley, M. R., Slepian, M. J., & Yoon, J. (2013). Nanowell-trapped charged ligand-bearing nanoparticle surfaces: a novel method of enhancing flow-resistant cell adhesion. Advanced healthcare materials, 2(7), 1019-1027.
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  Assuring cell adhesion to an underlying biomaterial surface is vital in implant device design and tissue engineering, particularly under circumstances where cells are subjected to potential detachment from overriding fluid flow. Cell-substrate adhesion is a highly regulated process involving the interplay of mechanical properties, surface topographic features, electrostatic charge, and biochemical mechanisms. At the nanoscale level, the physical properties of the underlying substrate are of particular importance in cell adhesion. Conventionally, natural, pro-adhesive, and often thrombogenic, protein biomaterials are frequently utilized to facilitate adhesion. In the present study, nanofabrication techniques are utilized to enhance the biological functionality of a synthetic polymer surface, polymethymethacrylate, with respect to cell adhesion. Specifically we examine the effect on cell adhesion of combining: 1. optimized surface texturing, 2. electrostatic charge and 3. cell adhesive ligands, uniquely assembled on the substrata surface, as an ensemble of nanoparticles trapped in nanowells. Our results reveal that the ensemble strategy leads to enhanced, more than simply additive, endothelial cell adhesion under both static and flow conditions. This strategy may be of particular utility for enhancing flow-resistant endothelialization of blood-contacting surfaces of cardiovascular devices subjected to flow-mediated shear.
• Claiborne, T. E., Slepian, M. J., Hossainy, S., & Bluestein, D. (2012). Polymeric trileaflet prosthetic heart valves: evolution and path to clinical reality. Expert review of medical devices, 9(6), 577-94.
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  Present prosthetic heart valves, while hemodynamically effective, remain limited by progressive structural deterioration of tissue valves or the burden of chronic anticoagulation for mechanical valves. An idealized valve prosthesis would eliminate these limitations. Polymeric heart valves (PHVs), fabricated from advanced polymeric materials, offer the potential of durability and hemocompatibility. Unfortunately, the clinical realization of PHVs to date has been hampered by findings of in vivo calcification, degradation and thrombosis. Here, the authors review the evolution of PHVs, evaluate the state of the art of this technology and propose a pathway towards clinical reality. In particular, the authors discuss the development of a novel aortic PHV that may be deployed via transcatheter implantation, as well as its optimization via device thrombogenicity emulation.
• Girdhar, G., Xenos, M., Alemu, Y., Chiu, W., Lynch, B. E., Jesty, J., Einav, S., Slepian, M. J., & Bluestein, D. (2012). Device thrombogenicity emulation: a novel method for optimizing mechanical circulatory support device thromboresistance. PloS one, 7(3), e32463.
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  Mechanical circulatory support (MCS) devices provide both short and long term hemodynamic support for advanced heart failure patients. Unfortunately these devices remain plagued by thromboembolic complications associated with chronic platelet activation--mandating complex, lifelong anticoagulation therapy. To address the unmet need for enhancing the thromboresistance of these devices to extend their long term use, we developed a universal predictive methodology entitled Device Thrombogenicity Emulation (DTE) that facilitates optimizing the thrombogenic performance of any MCS device--ideally to a level that may obviate the need for mandatory anticoagulation. DTE combines in silico numerical simulations with in vitro measurements by correlating device hemodynamics with platelet activity coagulation markers--before and after iterative design modifications aimed at achieving optimized thrombogenic performance. DTE proof-of-concept is demonstrated by comparing two rotary Left Ventricular Assist Devices (LVADs) (DeBakey vs HeartAssist 5, Micromed Houston, TX), the latter a version of the former following optimization of geometrical features implicated in device thrombogenicity. Cumulative stresses that may drive platelets beyond their activation threshold were calculated along multiple flow trajectories and collapsed into probability density functions (PDFs) representing the device 'thrombogenic footprint', indicating significantly reduced thrombogenicity for the optimized design. Platelet activity measurements performed in the actual pump prototypes operating under clinical conditions in circulation flow loops--before and after the optimization with the DTE methodology, show an order of magnitude lower platelet activity rate for the optimized device. The robust capability of this predictive technology--demonstrated here for attaining safe and cost-effective pre-clinical MCS thrombo-optimization--indicates its potential for reducing device thrombogenicity to a level that may significantly limit the extent of concomitant antithrombotic pharmacotherapy needed for safe clinical device use.
• Hwang, S. W., Tao, H., Kim, D. H., Cheng, H., Song, J. K., Rill, E., Brenckle, M. A., Panilaitis, B., Won, S. M., Kim, Y. S., Song, Y. M., Yu, K. J., Ameen, A., Li, R., Su, Y., Yang, M., Kaplan, D. L., Zakin, M. R., Slepian, M. J., , Huang, Y., et al. (2012). A physically transient form of silicon electronics. Science (New York, N.Y.), 337(6102), 1640-4.
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  A remarkable feature of modern silicon electronics is its ability to remain physically invariant, almost indefinitely for practical purposes. Although this characteristic is a hallmark of applications of integrated circuits that exist today, there might be opportunities for systems that offer the opposite behavior, such as implantable devices that function for medically useful time frames but then completely disappear via resorption by the body. We report a set of materials, manufacturing schemes, device components, and theoretical design tools for a silicon-based complementary metal oxide semiconductor (CMOS) technology that has this type of transient behavior, together with integrated sensors, actuators, power supply systems, and wireless control strategies. An implantable transient device that acts as a programmable nonantibiotic bacteriocide provides a system-level example.
• Kim, D., Ghaffari, R., Lu, N., Wang, S., Lee, S. P., Keum, H., D'Angelo, R., Klinker, L., Su, Y., Lu, C., Kim, Y., Ameen, A., Li, Y., Zhang, Y., de Graff, B., Hsu, Y., Liu, Z., Ruskin, J., Xu, L., , Lu, C., et al. (2012). Electronic sensor and actuator webs for large-area complex geometry cardiac mapping and therapy. Proceedings of the National Academy of Sciences of the United States of America, 109(49), 19910-5.
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  Curved surfaces, complex geometries, and time-dynamic deformations of the heart create challenges in establishing intimate, nonconstraining interfaces between cardiac structures and medical devices or surgical tools, particularly over large areas. We constructed large area designs for diagnostic and therapeutic stretchable sensor and actuator webs that conformally wrap the epicardium, establishing robust contact without sutures, mechanical fixtures, tapes, or surgical adhesives. These multifunctional web devices exploit open, mesh layouts and mount on thin, bio-resorbable sheets of silk to facilitate handling in a way that yields, after dissolution, exceptionally low mechanical moduli and thicknesses. In vivo studies in rabbit and pig animal models demonstrate the effectiveness of these device webs for measuring and spatially mapping temperature, electrophysiological signals, strain, and physical contact in sheet and balloon-based systems that also have the potential to deliver energy to perform localized tissue ablation.
• Rial, N. S., Choi, K., Nguyen, T., Snyder, B., & Slepian, M. J. (2012). Nuclear factor kappa B (NF-κB): a novel cause for diabetes, coronary artery disease and cancer initiation and promotion?. Medical hypotheses, 78(1), 29-32.
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  Obesity is a growing epidemic in the United States (US). Obesity has been recognized as a modifiable risk factor for many diverse diseases including diabetes, cardiovascular disease and cancer burden. Common contributors to obesity include a high fat diet, smoking and physical inactivity. Systemic effects of obesity include increased micro-inflammatory molecules such as nuclear factor kappa B (NF-κB) that influence the both endothelial and epithelial layers as well as the supportive stroma. An emerging risk factor for micro-inflammation also includes periodontal disease. These pro-inflammatory states are hypothesized to contribute to diabetes as well as cardiovascular disease and cancer through the direct activation of NF-κB. Therefore, a comprehensive health care strategy would include reduction of diabetes, cardiovascular and cancer risk through the decrease in micro-inflammation.
• Ashton, J. H., Mertz, J. A., Harper, J. L., Slepian, M. J., Mills, J. L., McGrath, D. V., & Vande Geest, J. P. (2011). Polymeric endoaortic paving: Mechanical, thermoforming, and degradation properties of polycaprolactone/polyurethane blends for cardiovascular applications. Acta biomaterialia, 7(1), 287-94.
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  Polymeric endoaortic paving (PEAP) is a process by which a polymer is endovascularly delivered and thermoformed to coat or "pave" the lumen of the aorta. This method may offer an improvement to conventional endoaortic therapy in allowing conformal graft application with reduced risk of endoleak and customization to complex patient geometries. Polycaprolactone (PCL)/polyurethane (PU) blends of various blend ratios were assessed as a potential material for PEAP by characterizing their mechanical, thermoforming and degradation properties. Biaxial tension testing revealed that the blends' stiffness is similar to that of aortic tissue, is higher for blends with more PCL content, and may be affected by thermoforming and degradation. Tubes of blends were able to maintain a higher diameter increase after thermoforming at higher PCL content and higher heating temperatures; 50/50 blend tubes heated to 55 °C were able to maintain 90% of the diameter increase applied. Delamination forces of the blends ranged from 41 to 235 N m⁻². In a Pseudomonas lipase solution, the 50/50 blend had a 94% lower degradation rate than pure PCL, and the 10/90 blend exhibited no degradation. These results indicate that PEAP, consisting of a PCL/PU blend, may be useful in developing the next generation of endoaortic therapy.
• Gu, Y., Lee, H. M., Sorsa, T., Salminen, A., Ryan, M. E., Slepian, M. J., & Golub, L. M. (2011). Non-antibacterial tetracyclines modulate mediators of periodontitis and atherosclerotic cardiovascular disease: a mechanistic link between local and systemic inflammation. Pharmacological research, 64(6), 573-9.
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  Periodontitis, one of the most common chronic inflammatory diseases afflicting man, is increasingly being recognized as a risk factor for atherosclerotic cardiovascular disease (ASCVD). Non-antimicrobial tetracyclines are known to have inhibitory effects on inflammatory mediators and effector molecules, including cytokines and matrix metalloproteinases (MMPs), associated with both diseases. In this paper, we discuss the evidence that doxycycline and related non-antibiotic chemically modified tetracyclines (e.g., CMT-3) can effectively reduce cytokine (TNF-α, IL-6, and MCP-1) production by human mononuclear inflammatory cells when stimulated either by endotoxin (LPS) or by a complex of C-reactive protein/oxidized LDL cholesterol relevant to the pathogenesis of periodontal disease and ASCVD, respectively. This inhibition by tetracycline compounds appears to be mediated at least in part by a suppression of the phosphorylation/activation of the NFκB cell signaling pathway. We are currently conducting clinical trials on patients who exhibit both diseases, and our preliminary data suggest that virtually all acute coronary syndrome (ACS) patients exhibit moderate-to-severe periodontitis, a higher incidence of this oral inflammatory disease than that seen in the population at large. In other studies, a non-antimicrobial formulation of doxycycline (SDD) has been found to dramatically reduce hsCRP, IL-6 and MMP-9 levels in plasma of ACS patients, and SDD has also been found to significantly increase serum levels of both cardio-protective HDL cholesterol and its core molecule apolipoprotein A-I in ASCVD-vulnerable patients with periodontitis. Our current research suggests that one mechanism involved may be the ability of SDD to inhibit MMP-mediated HDL loss by protecting apolipoprotein A-I from proteinase attack. These pleiotropic mechanisms of non-antimicrobial tetracyclines provide significant therapeutic potential to treat chronic inflammatory diseases including both periodontitis and ASCVD.
• Kim, D., Lu, N., Ghaffari, R., Kim, Y., Lee, S. P., Xu, L., Wu, J., Kim, R., Song, J., Liu, Z., Viventi, J., de Graff, B., Elolampi, B., Mansour, M., Slepian, M. J., Hwang, S., Moss, J. D., Won, S., Huang, Y., , Litt, B., et al. (2011). Materials for multifunctional balloon catheters with capabilities in cardiac electrophysiological mapping and ablation therapy. Nature materials, 10(4), 316-23.
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  Developing advanced surgical tools for minimally invasive procedures represents an activity of central importance to improving human health. A key challenge is in establishing biocompatible interfaces between the classes of semiconductor device and sensor technologies that might be most useful in this context and the soft, curvilinear surfaces of the body. This paper describes a solution based on materials that integrate directly with the thin elastic membranes of otherwise conventional balloon catheters, to provide diverse, multimodal functionality suitable for clinical use. As examples, we present sensors for measuring temperature, flow, tactile, optical and electrophysiological data, together with radiofrequency electrodes for controlled, local ablation of tissue. Use of such 'instrumented' balloon catheters in live animal models illustrates their operation, as well as their specific utility in cardiac ablation therapy. The same concepts can be applied to other substrates of interest, such as surgical gloves.
• Martin, J. L., & Slepian, M. (2011). Use of low-molecular-weight heparins during percutaneous coronary intervention. The Journal of invasive cardiology, 23(1), 1-8.
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  Patients with acute coronary syndromes (ACS) may transition to percutaneous coronary intervention (PCI) after an initial phase of medical management that includes anticoagulation. When patients come to the catheterization laboratory, it is important to consider previously received anticoagulation. Enoxaparin has emerged as a more effective, yet simple, agent for use in the emergency room or upon initial encounter of the ACS patient. However, there may be uncertainty among physicians on the adequacy and way to use anticoagulation in the transition to the catheterization laboratory. Recently, new data have emerged on the use of enoxaparin in the catheterization laboratory. Dosing schedules based on pharmacodynamic and clinical data offer a seamless transition for enoxaparin from the medical management phase to PCI. In this paper, the pharmacokinetics of enoxaparin are reviewed and recommendations for anticoagulant regimens provided based upon the timing of presentation and pre-catheterization dosing.
• Payne, J. B., Golub, L. M., Stoner, J. A., Lee, H. M., Reinhardt, R. A., Sorsa, T., & Slepian, M. J. (2011). The effect of subantimicrobial-dose-doxycycline periodontal therapy on serum biomarkers of systemic inflammation: a randomized, double-masked, placebo-controlled clinical trial. Journal of the American Dental Association (1939), 142(3), 262-73.
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  Periodontitis has been reported to be associated with coronary artery disease (CAD). Research is needed to determine if therapies that improve periodontal health also reduce systemic measures of inflammation associated with both diseases.
• Xenos, M., Girdhar, G., Alemu, Y., Jesty, J., Slepian, M., Einav, S., & Bluestein, D. (2010). Device Thrombogenicity Emulator (DTE)--design optimization methodology for cardiovascular devices: a study in two bileaflet MHV designs. Journal of biomechanics, 43(12), 2400-9.
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  Patients who receive prosthetic heart valve (PHV) implants require mandatory anticoagulation medication after implantation due to the thrombogenic potential of the valve. Optimization of PHV designs may facilitate reduction of flow-induced thrombogenicity and reduce or eliminate the need for post-implant anticoagulants. We present a methodology entitled Device Thrombogenicty Emulator (DTE) for optimizing the thrombo-resistance performance of PHV by combining numerical and experimental approaches. Two bileaflet mechanical heart valves (MHV) designs, St. Jude Medical (SJM) and ATS, were investigated by studying the effect of distinct flow phases on platelet activation. Transient turbulent and direct numerical simulations (DNS) were conducted, and stress loading histories experienced by the platelets were calculated along flow trajectories. The numerical simulations indicated distinct design dependent differences between the two valves. The stress loading waveforms extracted from the numerical simulations were programmed into a hemodynamic shearing device (HSD), emulating the flow conditions past the valves in distinct 'hot-spot' flow regions that are implicated in MHV thrombogenicity. The resultant platelet activity was measured with a modified prothrombinase assay, and was found to be significantly higher in the SJM valve, mostly during the regurgitation phase. The experimental results were in excellent agreement with the calculated platelet activation potential. This establishes the utility of the DTE methodology for serving as a test bed for evaluating design modifications for achieving better thrombogenic performance for such devices.
• Martin, J. L., Fry, E. T., Martin, T., Atherley, T. H., Martin, S. S., & Slepian, M. J. (2009). The pharmacodynamics of enoxaparin in percutaneous coronary intervention with precise rapid enoxaparin loading (PEPCI-PRE study). Journal of thrombosis and thrombolysis, 28(2), 224-8.
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  We evaluated the early pharmacodynamic profile of the combined 30 mg intravenous and 1 mg/kg subcutaneous enoxaparin loading utilized in the TIMI 11B and ExTRACT TIMI 25 trials.
• Slepian, M., & Gottehrer, N. R. (2009). Oral-body inflammatory connection. Dentistry today, 28(1), 138, 140, 142-3.
• Copeland, J. G., Smith, R. G., Bose, R. K., Tsau, P. H., Nolan, P. E., & Slepian, M. J. (2008). Risk factor analysis for bridge to transplantation with the CardioWest total artificial heart. The Annals of thoracic surgery, 85(5), 1639-44.
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  Safety and efficacy studies of various mechanical circulatory support devices are important, but may not be strictly comparable. Lacking prospective randomized studies for different devices, we believe that comparison of risk factor analyses may give the surgeon a tool more powerful than current studies for matching a patient with an appropriate device. In this paper, we report risk factor profiles for bridge to transplantation with the CardioWest total artificial heart and summarize reports for other devices.
• Slepian, M. J., & Copeland, J. G. (2008). The total artificial heart in refractory cardiogenic shock: saving the patient versus saving the heart. Nature clinical practice. Cardiovascular medicine, 5(2), 64-5.
• Copeland, J. G., Smith, R. G., Arabia, F. A., Nolan, P. E., McClellan, D., Tsau, P. H., Sethi, G. K., Bose, R. K., Banchy, M. E., Covington, D. L., & Slepian, M. J. (2004). Total artificial heart bridge to transplantation: a 9-year experience with 62 patients. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation, 23(7), 823-31.
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  The SynCardia CardioWest total artificial heart (CardioWest TAH) is a biventricular, orthotopic, pneumatic, pulsatile blood pump driven by an external console. For each ventricle, the length of the blood-flow path is shorter and the inflow and outflow valves are larger than in any other bridge-to-transplant device, resulting in greater blood flow at smaller pre-load. Such a device should be optimal for bridging transplant candidates who have biventricular failure and for whom all other therapies have failed.
• Copeland, J. G., Smith, R. G., Arabia, F. A., Nolan, P. E., Sethi, G. K., Tsau, P. H., McClellan, D., Slepian, M. J., & , C. T. (2004). Cardiac replacement with a total artificial heart as a bridge to transplantation. The New England journal of medicine, 351(9), 859-67.
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  The CardioWest Total Artificial Heart orthotopically replaces both native cardiac ventricles and all cardiac valves, thus eliminating problems commonly seen in the bridge to transplantation with left ventricular and biventricular assist devices, such as right heart failure, valvular regurgitation, cardiac arrhythmias, ventricular clots, intraventricular communications, and low blood flows.
• Emery, R. W., Carrel, T., Wolf, R. K., Slepian, M. J., & Tweden, K. S. (2004). Description and evaluation of a ventriculo-coronary artery bypass device that provides bi-directional coronary flow. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery, 25(1), 43-50.
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  The objective of this study was to assess acute patency of a new myocardial revascularization device that connects the left ventricular cavity to a coronary artery (termed ventriculo-coronary artery bypass, VCAB) thereby providing proximal and distal blood flow from the site of the anastomosis.
• Slepian, M. J. (2004). Seamless anticoagulation therapy utilizing enoxaparin for acute coronary syndromes: Measure or not, here it comes!. Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions, 61(2), 171-2.
• Butman, S. M., Jamison, K., Slepian, M., Edling, N., Arabia, F., & Copeland, J. G. (2003). Percutaneous intervention for unprotected left main disease prior to explantation of a left ventricular assist device. Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions, 59(4), 471-4.
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  Percutaneous coronary intervention of unprotected left main coronary arterial disease is an alternative to surgical revascularization in selected patients. In this report, a patient with an implanted left ventricular assist device (LVAD) underwent successful coronary intervention prior to its planned removal. The implanted LVAD clearly assisted the technical performance of the intervention.
• Copeland, J. G., Arabia, F. A., Tsau, P. H., Nolan, P. E., McClellan, D., Smith, R. G., & Slepian, M. J. (2003). Total artificial hearts: bridge to transplantation. Cardiology clinics, 21(1), 101-13.
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  The CardioWest TAH was created and initially tested at the same time as the Thoratec, Novacor, and HeartMate devices. It was designed as a permanent artificial heart and was the first-ever mechanical circulatory device to be used as destination therapy. Twenty years have passed since that early experience. Pneumatic technology is still current and being developed as in existing or new implantable Thoratec VADs the pneumatic HeartMate, and the Abiomed BVS 5000 pumps. Portable pneumatic drivers have been available since 1982, and in recent times have allowed discharge to home of substantial numbers of patients, thus reducing the length of hospital stays and making mechanical device support less expensive to society and more tolerable to patients. Within months, a portable driver for the CardioWest will be available. The documented benefits of the CardioWest TAH include rescue of: critically ill patients with advanced heart failure; patients with biventricular failure especially those with significant right heart failure, elevated pulmonary vascular resistance, or pulmonary edema; patients with renal or hepatic failure secondary to low cardiac output; patients with massive myocardial damage such as those with post-\infarction VSD or irreversible cardiac graft rejection; patients with mechanical valves or native valve disease; and patients with intractable arrhythmias and heart failure. High device outputs with restoration of normal filling pressures result in high perfusion pressures that have led to dramatic recoveries, convalescence, and return to levels of activity compatible with normal life. The average device output with the CardioWest TAH is higher than any other approved or investigational device. The reason for this resides in design simplicity this device has the shortest and largest inflow pathway. Stroke, in the authors' own series, is rare with a linearized rate of 0.068 events per patient year. If the experiences of La Pitie and the University of Arizona are combined, there has been one stroke in 25 patient years (0.04 events/patient year). Serious infections have been rare (12% of patients). No clinical mediastinitis has occurred. Drivelines have healed in tightly and never caused an "ascending" infection. There has not been a case of device endocarditis. Using a broad definition of bleeding, including takeback reoperation for bleeding, bleeding more than 8 units in the first postoperative 24 hours or 5 units over any other 48-hour period, a 25% to 36% incidence has been documented. No cases of fatal exsanguination have resulted, as there have been with the HeartMate. The incidence of bleeding as an adverse event is about 17% lower than the rate reported for the HeartMate VE LVAD, and it is about the same as that reported for Novacor and for Thoratec. Implantation of this device is relatively easy and often done (with attending help) by the authors' residents. If one follows the guidelines for fitting the device, and takes the recommended advice for implantation, hemostasis is excellent and restoration of immediate cardiac function with high flows is nearly automatic. Use of a neopericardium of 0.1 mm EPTFE at the time of implantation assures atraumatic and relatively quick re-entry for transplantation and prevents the normal inflammatory mediastinal reaction that might be desirable in a destination application. In selected patients the CardioWest TAH is the device of choice for bridge to transplantation. When a portable driver becomes available, out of hospital management of CardioWest TAH patients will be feasible and consideration of use of this device for longer term applications, (e.g., "destination therapy,") will be reasonable. A wearable driver, even smaller than a portable, will improve quality of life and expand the patient population that may be therapeutically served with this system. In short, the CardioWest TAH has come nearly full circle. It was first used as a destination device. It has since been used as a bridge to transplantation in nearly 200 patients as the Jarvik-7/Symbion TAH and, since 1993, in over 225 patients as CardioWest. The results have improved with time. Thromboembolism and infection rates have been competitive with currently available devices. Device reliability and durability have been excellent. Survival rates have been very high in a group of perhaps the sickest patients to be supported with any pulsatile device. Pneumatic technology has improved with portability and miniaturization, and there is reason to believe that it will become even better. Application of modern manufacturing techniques to this very simple device raises the possibility of significant manufacturing cost reduction, in an era of prohibitive cost for other devices. All of this establishes the CardioWest as a valuable device for any program that is seriously interested in end-stage heart disease and a likely device for permanent use in appropriately selected patients.
• Brosh, D., Higano, S. T., Slepian, M. J., Miller, H. I., Kern, M. J., Lennon, R. J., Holmes, D. R., & Lerman, A. (2002). Pulse transmission coefficient: a novel nonhyperemic parameter for assessing the physiological significance of coronary artery stenoses. Journal of the American College of Cardiology, 39(6), 1012-9.
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  We sought to test the hypothesis that the pulse transmission coefficient (PTC) can serve as a nonhyperemic physiologic marker for the severity of coronary artery stenosis in humans.
• Ramakumar, S., Roberts, W. W., Fugita, O. E., Colegrove, P., Nicol, T. M., Jarrett, T. W., Kavoussi, L. R., & Slepian, M. J. (2002). Local hemostasis during laparoscopic partial nephrectomy using biodegradable hydrogels: initial porcine results. Journal of endourology, 16(7), 489-94.
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  Despite the advance of laparoscopic partial nephrectomy, significant technical limitations remain with regard to control of bleeding and closure of the collecting system. An attractive approach on the horizon for local hemostatic and wound control is the use of local tissue sealants. To date, sealants remain largely derived from natural biologic products and are difficult to apply laparoscopically with precise local control. In this study, we examined the novel strategy of forming occlusive tissue-adherent hydrogels utilizing a synthetic biodegradable polyethylene glycol-lactide copolymer (PEG-lactide) as an in situ occlusive barrier for hemostasis and wound control. Specifically, the objects of this study were to determine if PEG-lactide hydrogels could be formed intraperitoneally on renal tissue, to test the adhesiveness of the hydrogels to injured renal parenchyma, and to evaluate the ability of adherent hydrogel barriers to limit renal parenchymal bleeding and collecting system leakage following renal pole amputation or wedge excision.
• Slepian, M. J., Ramakumar, S., Roberts, W. W., Fugita, O. E., Colegrove, P., Nicol, T. M., Jarrett, T. W., & Kavoussi, L. R. (2002). Local Hemostasis during Laparoscopic Partial Nephrectomy Using Biodegradable Hydrogels: Initial Porcine Results. Journal of Endourology, 16(7), 489-494. doi:10.1089/089277902760367458
• Slepian, M. J. (2001). Mechanical Myocardial Injury and Angiogenesis: An Association with Therapeutic Potential for Advanced Ischemic Coronary Artery Disease. Current interventional cardiology reports, 3(3), 218-232.
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  The healing response of tissue after mechanical injury is a highly evolved complex response that serves as a natural defense mechanism. Tissue wounds typically heal in a temporal sequence of stages. A vital phase of wound healing is the generation of loose reparative tissue that is neovascularized and rich in angiogenic substrates--that of granulation tissue formation. A therapeutic strategy that has emerged for the treatment of patients with advanced atherosclerotic ischemic coronary disease is to therapeutically manipulate the wound healing process and induce injury in the myocardium to stimulate islands of neovascularization. This paper reviews the response of tissue, particularly the myocardium, to various forms of injury. Also discussed is the emerging hypothesis of a threshold of injury (balancing adequate injury to induce neovascularizatioin versus excessive injury resulting in adjacent myocardial damage with contractile dysfunction without additional angiogenic benefit). Initial animal and human studies from our laboratory and that of collaborators, with a new method of injury-induced angiogenesis referred to as mechanical myocardial channeling, are reviewed.
• Fasol, R., Lakew, F., Pfannmüller, B., Slepian, M. J., & Joubert-Hubner, E. (2000). Papillary muscle repair surgery in ischemic mitral valve patients. The Annals of thoracic surgery, 70(3), 771-6; discussion 776-7.
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  Ischemic mitral regurgitation (MR), when ischemia/infarction has resulted in fibrotic degeneration and elongation of papillary muscles, carries a high risk for the patient and a technical challenge for the surgeon. We have developed a papillary-shortening plasty for this specific pathology.
• Slepian, M. J., Massia, S. P., Dehdashti, B., Fritz, A., & Whitesell, L. (1998). β ₃ -Integrins Rather Than β ₁ -Integrins Dominate Integrin-Matrix Interactions Involved in Postinjury Smooth Muscle Cell Migration. Circulation, 97(18), 1818-1827. doi:10.1161/01.cir.97.18.1818
• Slepian, M. J., Massia, S. P., Dehdashti, B., Fritz, A., & Whitesell, L. (1998). Beta3-integrins rather than beta1-integrins dominate integrin-matrix interactions involved in postinjury smooth muscle cell migration. Circulation, 97(18), 1818-27.
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  Smooth muscle cell (SMC) migration is a vital component in the response of the arterial wall to revascularization injury. Cell surface integrin-extracellular matrix interactions are essential for cell migration. SMCs express both beta1- and beta3-integrins. In this study, we examined the relative functional roles of beta1- and beta3-integrin-matrix interactions in postinjury SMC migration.
• Slepian, M. J. (1996). Polymeric endoluminal gel paving: therapeutic hydrogel barriers and sustained drug delivery depots for local arterial wall biomanipulation. Seminars in interventional cardiology : SIIC, 1(1), 103-16.
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  Polymeric endoluminal paving is a process in which biodegradable polymers may be locally applied percutaneously to blood vessels as endoluminal liners, resurfacing or 'paving', the underlying vascular wall. Depending upon the type of polymer selected, endoluminal polymer layers may function as wall supports, barriers, therapeutic biomaterials or depots for local sustained drug delivery. In the original description of the paving process, that is solid paving, structural polymers were utilized. In this article a second form of paving--gel paving is described. In this process, hydrogel polymers are locally applied or polymerized on vascular endoluminal surfaces. Endoluminal hydrogel layers have been demonstrated to function as physical non-pharmacological barriers limiting cell and protein deposition and effectively reducing underlying arterial wall thrombogenicity. Hydrogel paving layers also provide a means for prolonged local arterial wall drug delivery. In this report an update on gel paving is provided. The overall process of polymeric endoluminal paving is initially reviewed. Gel paving and the rationale for this approach is described. Both thermoreversible as well as photopolymerizable PEG-lactide hydrogel paving systems are outlined. Recent experimental studies with gel paving examining polymer application, haemocompatability and endoluminal surface thromboprotection, effects on post-injury neointimal thickening and local drug delivery, are then reviewed. Finally, the role of gel paving in future approaches to vascular therapy is discussed.
• Slepian, M. J., Massia, S. P., & Whitesell, L. (1996). Pre-conditioning of smooth muscle cells via induction of the heat shock response limits proliferation following mechanical injury. Biochemical and biophysical research communications, 225(2), 600-7.
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  Arterial smooth muscle cell (SMC) proliferation is a significant component of post-angioplasty restenosis. We evaluated whether pre-conditioning of SMCs, via induction of the heat shock response prior to actual physical injury, would result in an alteration in cell proliferation following injury. Rat aortic SMCs were pretreated with either chemical or thermal heat shock inducers and then subjected to scrape-wound injury in vitro. Cell proliferation at 24 hrs was measured via 3H-thymidine (Tdr) incorporation and compared with scrape wounded unstressed controls. A significant decline in cell proliferation post scrape-wound injury was observed for both chemical and thermal heat shock pre-conditioned cultures, compared to untreated controls. Increased expression of heat shock protein 72 was confirmed serially throughout the 24 hr study period for both chemical and thermal inducers. Despite reduced proliferation heat shocked cells remained viable as evidenced by fluorescent cell viability assay and preserved migration. Pre-conditioning of SMCs through induction of the heat shock response prior to physical injury may be a useful approach to limit aggressive proliferation observed with mechanical revascularization injury.
• Hill-West, J. L., Chowdhury, S. M., Slepian, M. J., & Hubbell, J. A. (1994). Inhibition of thrombosis and intimal thickening by in situ photopolymerization of thin hydrogel barriers. Proceedings of the National Academy of Sciences of the United States of America, 91(13), 5967-71.
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  Thin hydrogel barriers formed on the inner surface of injured arteries by interfacial photopolymerization dramatically reduced thrombosis and intimal thickening in rat and rabbit models of vascular injury. This polymerization technique allowed the synthesis of a thin hydrogel barrier that conformed to the vessel wall, directly blocking contact between blood and the damaged vessel. The illumination conditions could be varied to control the thickness of the barrier from 10 microns to > 50 microns. The hydrogel was designed to degrade by nonenzymatic hydrolysis. In rats in which the carotid artery had been severely injured by crushing, treatment with the hydrogel barrier completely eliminated thrombosis (P < 0.01) and preserved long-term patency (P < 0.01). Treatment in a rabbit model of balloon injury inhibited thrombosis (P < 0.02) and reduced long-term intimal thickening by approximately 80% (P < 0.003). These results suggest that blood-borne signals acting in the early phases of healing play an important role in stimulating thickening of the intima.
• Slepian, M. J. (1994). Polymeric endoluminal paving. A family of evolving methods for extending endoluminal therapeutics beyond stenting. Cardiology clinics, 12(4), 715-37.
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  This article briefly reviews the background and rationale for the development of polymer paving. The process of endoluminal paving is described both in its generic form as well as in three experimental embodiments. Several experimental studies with two forms of paving, solid paving and gel paving, are reviewed. Finally, the envisioned future clinical role for both solid and gel paving is described.
• Slepian, M. J. (1991). Application of intraluminal ultrasound imaging to vascular stenting. International journal of cardiac imaging, 6(3-4), 285-311.
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  Over the past few years catheter-based intraluminal ultrasound (IVUS) has emerged as a promising and imaginative technique which can significantly extend our understanding of atherosclerotic lesions both before and following interventions. In relation to stent implantation intravascular ultrasound appears well suited as an imaging modality--providing information as to lumen shape lesion surface and topography, as well as wall composition. To this end arteriography is unable to provide such detailed information. The purpose of this review is to outline the characteristics of stents and endoluminal support devices, currently under investigation, and the role of ultravascular ultrasound in this respect.
• Kadish, A. H., Weisman, H. F., Veltri, E. P., Epstein, A. E., Slepian, M. J., & Levine, J. H. (1990). Paradoxical effects of exercise on the QT interval in patients with polymorphic ventricular tachycardia receiving type Ia antiarrhythmic agents. Circulation, 81(1), 14-9.
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  We analyzed the results of exercise testing performed in the absence of all antiarrhythmic drugs in 11 case patients with newly documented polymorphic ventricular tachycardia in response to type Ia antiarrhythmic agents. These results were compared with those found in 11 control patients matched for age, sex, and heart disease to determine whether the response of the QT interval to exercise testing was abnormal in patients who developed worsening of arrhythmia while taking antiarrhythmic drugs. QT, RR, and QTc intervals (by Bazett's method) were evaluated at rest and at 3 minutes of exercise in both groups. At rest, there was no significant difference in the QT interval (410 +/- 13 vs. 386 +/- 11 msec), RR interval (890 +/- 56 vs. 781 +/- 43 msec), or corrected QT interval (438 +/- 10 vs. 438 +/- 4 msec) in the case patients and the control patients. Both groups demonstrated a similar chronotropic response to exercise. The QT interval shortened in both groups with exercise (p less than 0.001), but the degree of shortening tended to be greater in the control patients (to 310 +/- 9 msec) than in the case patients (to 357 +/- 11 msec) (p = 0.06). Thus, there was a paradoxical increase in the QTc interval in the patients who experienced a proarrhythmic effect of type Ia drugs but not in the control patients (to 482 +/- 8 vs. 431 +/- 5 msec; p less than 0.001). Ten of 11 case patients but only one of 11 control patients had an increase in QTc interval of more than 10 msec with exercise (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
• Slepian, M., Levine, J. H., Watkins, L., Brinker, J., & Guarnieri, T. (1987). Automatic implantable cardioverter defibrillator/permanent pacemaker interaction: loss of pacemaker capture following AICD discharge. Pacing and clinical electrophysiology : PACE, 10(5), 1194-7.
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  A 78-year-old man treated with amiodarone for recurrent ventricular tachycardia, had sequential placement of a bipolar VVI pacemaker and an automatic implantable cardioverter defibrillator (AICD). During defibrillation threshold testing, there was failure to capture of the pacer in the post-shock period. The time of failure to capture appeared energy-related: the greater the energy delivered, the longer the failure to capture. Careful attention will be necessary in constructing combined AICD/pacemaker units.

Proceedings Publications

• Roveda, J. M., Slepian, M. J., Perfect, M. M., Quan, S. F., & Rahman, F. (2017, Feb). Embedded systems in Medical devices and their integration with medical data, EMR and Big Data. In International Conference on Biomedical and Health Informatics (BHI).
• Nicolini, A. M., Cohn, C. M., Gamboa, J. R., Slepian, M. J., Wu, X., & Yoon, J. (2014, Apr). Fabrication of a pro-adhesive surface using electrospun PCL nanofibers interspersed with peptide conjugated polystyrene particles. In IEEE-NEMS 2014.
• Slepian, M. J., Bluestein, D., Soares, J. S., Zhang, P., Gao, C., Pothapragada, S., Zhang, N., & Deng, Y. (2013). Multiscale Modeling of Flow Induced Thrombogenicity With Dissipative Particle Dynamics (DPD) and Molecular Dynamics (MD). In American Society of Mechanical Engineers.
• Slepian, M. J., Yoon, J., McCracken, K. E., Tran, P. L., & Gamboa, J. R. (2013). Interaction With Nanoscale Topography: The Use of Nanowell-Trapped Charged Ligand-Bearing Nanoparticle Surfaces To Modulate Physiological Focal Adhesions in Endothelial Cells. In American Society of Mechanical Engineers.
• Slepian, M., Chiu, W., Alemu, Y., Lynch, B., Einav, S., & Bluestein, D. (2013). Comparative Studies of Axial Ventricular Assist Devices (VAD) and the Effect of Outflow Cannulation. In American Society of Mechanical Engineers.
• Wu, X., Slepian, M. J., Ammann, K. R., Merkle, V. M., DeCook, K. J., & Tran, P. L. (2013). In Vitro Biocompatibility of Coaxial Electrospun Scaffolds for Cardiovascular Tissue Engineering. In American Society of Mechanical Engineers.
• Slepian, M., Chiu, W., Xenos, M., Alemu, Y., Girdhar, G., Lynch, B., Jesty, J., Einav, S., & Bluestein, D. (2012). Thrombogenicity Comparison of Axial Ventricular Assist Devices by DTE Methodology: MicroMed HeartAssist 5 and Thoratec Heartmate II. In American Society of Mechanical Engineers.
• Slepian, M., Claiborne, T. E., Xenos, M., Girdhar, G., Alemu, Y., Sheriff, J., Pinchuk, L., Jesty, J., Einav, S., & Bluestein, D. (2011). Dynamic Numerical and Experimental Evaluation of Trileaflet Polymer Prosthetic Heart Valves. In American Society of Mechanical Engineers.
• Mills, J. L., Slepian, M. J., Ashton, J. H., Mertz, J. A., Alexander, M. J., & Vande Geest, J. P. (2010). Functional Endoluminal Paving (FELP): Thermoforming, Biodegradation, and Mechanical Properties of a Novel Polymer Graft for Abdominal Aortic Aneurysms. In American Society of Mechanical Engineers.
• Slepian, M., Girdhar, G., Sheriff, J., Xenos, M., Alemu, Y., Claiborne, T., Jesty, J., Einav, S., & Bluestein, D. (2009). Dynamic Shear Stress Induced Platelet Activation in Blood Recirculation Devices: Implications for Thrombogenicity Minimization. In American Society of Mechanical Engineers.

Presentations

• Nicolini, A. M., Cohn, C. M., Slepian, M. J., Wu, X., & Yoon, J. (2014, Mar). Fabrication of a pro-adhesive surface using electrospun PCL nanofibers interspersed with peptide conjugated polystyrene particles. Annual Meeting of IBE. Lexington, KY: IBE.
• Tran, P. L., Martin, D. A., Gamboa, J. R., Yoon, J., & Slepian, M. J. (2014, Apr). Nanopost Fence: A Novel Strategy of Preventing Smooth Muscle Cells Topographic Migration. Society for Biomaterials (SFB) 2014 Annual Meeting and Exposition. Denver, CO: Society for Biomaterials (SFB).
• Gamboa, J. R., Tran, P. L., Slepian, M. J., Yoon, J., Gamboa, J. R., Tran, P. L., Slepian, M. J., & Yoon, J. (2012, Mar). Linear fibroblast alignment on sinusoidal wave micropatterns. Annual Meeting of IBE. Indianapolis, IN: IBE.
• Tran, P. L., Gamboa, J. R., McCracken, K. E., Riley, M. R., Slepian, M. J., & Yoon, J. (2011, Mar). Confluent and aligned growth of endothelial cells on nanoparticle arrays through focal adhesion and endocytitic mechanisms. Annual Meeting of IBE. Atlanta, GA: IBE.
• Tran, P. L., Gamboa, J. R., McCracken, K. E., Riley, M. R., Slepian, M. J., & Yoon, J. (2011, Oct). Nanowell-trapped charged ligand-bearing nanoparticle surfaces - a novel method of enhancing flow resistant cell adhesion. BioInterface 2011 Workshop and Symposium. Minneapolis, MN: Surfaces in Biomaterials Foundation.
• Tran, P. L., Gamboa, J. R., McCracken, K. E., Riley, M. R., Slepian, M. J., Yoon, J., Tran, P. L., Gamboa, J. R., McCracken, K. E., Riley, M. R., Slepian, M. J., Yoon, J., Tran, P. L., Gamboa, J. R., McCracken, K. E., Riley, M. R., Slepian, M. J., & Yoon, J. (2011, Apr). Confluent and aligned growth of endothelial cells on nanoparticle arrays through focal adhesion and endocytitic mechanisms. Society for Biomaterials (SFB) 2011 Annual Meeting and Exposition. Orlando, FL: Society for Biomaterials (SFB).

Poster Presentations

• Gamboa, J. R., Yoon, J., Smith, R. G., Slepian, M. J., Gamboa, J. R., Yoon, J., Smith, R. G., Slepian, M. J., Gamboa, J. R., Yoon, J., Smith, R. G., & Slepian, M. J. (2012, Mar). Evaluation of the performance of a left ventricular assist device in a novel in vitro heart failure model. Annual Meeting of IBE. Indianapolis, IN.
• McCracken, K. E., Tran, P. L., Slepian, M. J., & Yoon, J. (2012, Mar). Nanoscale patterning under shear stress for guided endothelial cell growth. Annual Meeting of IBE. Indianapolis, IN.