Marvin J Slepian
- Professor, Medicine
- Clinical Professor, Biomedical Engineering
- Associate Department Head, Clinical / Industrial Affairs
- Professor, Materials Science and Engineering
- Professor, Medical Imaging
- Professor, BIO5 Institute
Marvin J. Slepian, MD, is Professor of Medicine, Professor and Associate Department Head of BioMedical Engineering and McGuire Scholar in the Eller College of Management, all at the University of Arizona. Dr. Slepian is the Director of the newly created Arizona Center for Accelerated Biomedical Innovation (ACABI) – a “creativity engine,” focused on novel solution development for unmet medical needs. Dr. Slepian attended Princeton (AB Biochemical Sciences and Science in Human Affairs ’77) and received his MD from the University of Cincinnati College of Medicine (’81 AOA). He completed his residency in Internal Medicine at New York University–Bellevue Hospital in New York, where he served as Chief Resident in Medicine; clinical and research fellowships in Cardiology at Johns Hopkins University School of Medicine in Baltimore, Maryland; and clinical and research fellowships in Interventional Cardiology and a research fellowship in Artificial Organs at the Cleveland Clinic in Cleveland, Ohio. In addition Dr Slepian also received post-doctoral training in Chemical Engineering and Polymer Chemistry at MIT.
In parallel with his clinical career Dr. Slepian has had an extensive research career leading to the development of innovative diagnostics and therapeutics for cardiovascular diseases. His work has focused on the development and use of novel biomaterials for tissue engineering, drug delivery and medical device development. His lab has developed many novel diagnostics and therapeutics which have found their way into clinical use today including: drug-eluting stent technologies, stent coatings, “polymer paving,” surgical anti-adhesive barriers, stretchable and biodegradable electronics, synthetic tissue sealants, myocardial revascularization and cell delivery methods and cardiovascular prosthetic devices - including the total artificial heart. Dr. Slepian’s lab has also, for years, been heavily involved in basic science concentrating on three main areas: 1. the role of cell-matrix interactions in vascular disease, 2. basic aspects of cell-material interactions and 3. the impact of physical forces (notably shear and sound) on platelet activation.
Dr Slepian is the author or coauthor of more than 250 articles, textbook chapters and abstracts, published in journals such as Science, Nature Materials, PNAS, PlosOne, Circulation, the New England Journal of Medicine, and Cardiovascular Pathology, and serves on several editorial review boards. He is a prolific inventor with more than 55 issued and filed patents and has been the founder of numerous medical device companies including FOCAL (NASDAQ), Endotex, Angiotrax, Hansen Medical (NASDAQ), Arsenal, 480 BioMedical, MC10 and SynCardia, and has been involved with bringing many new devices through the FDA regulatory process into clinical use, including most notably the total artificial heart. He has received multiple awards and recognition for his academic and translational research activities including: the American Heart Association Award for the Most Significant Advance in Cardiovascular Medicine, election as fellow of the American Institute for Medical and Biological Engineering and as fellow of the National Academy of Inventors, is the the Immediate Past President of the International Society for Mechanical Circulatory Support (ISMCS), and is President-elect of the American Society for Artificial Internal Organs (ASAIO). In 2017 he received the AZBio Pioneer Award for Lifetime Achievement in Biomedical Science Innovation.
- University of Cincinnati, Cincinnati, Ohio, United States
- Platelet Aggregating Lymphokine: An Novel Connection of Immune and Thrombotic Mechanisms
- B.A. Biochemical Sciences and Science in Human Affairs
- Princeton University, Princeton, New Jersey, United States
- The Role of Histocompatibility Antigens and Tumor Associated Antigens In Development and Neoplasia
- Professor, Medical Imaging, University of Arizona, Tucson, Arizona (2017 - Ongoing)
- Professor of Materials Sceinces and Engineering, University of Arizona, Tucson, Arizona (2016 - Ongoing)
- Director, Arizona Center for Accelerated BioMedical Innovation, University of Arizona, Tucson, Arizona (2015 - Ongoing)
- Professor of Medicine (Tenured), University of Arizona, Tucson, Arizona (2012 - Ongoing)
- Professor and Associate Department Head-BioMedical Engineering, University of Arizona, Tucson, Arizona (2011 - Ongoing)
- McGuire Scholar - Eller College of Management, University of Arizona, Tucson, Arizona (2010 - Ongoing)
- Director, Interventional Cardiology, University of Arizona, Tucson, Arizona (2003 - 2015)
- Director, Tissue Engineering Research Lab, University of Arizona, Tucson, Arizona (1997 - Ongoing)
- Cardiology Fellowship Teaching Award-Teacher of the Year-University of Arizona
- Spring 1996
- Clinical Scholar-Eli Lilly Research Laboratories
- Spring 1989
- Cleveland Clinic Foundation-Research Project Committee Grants (2)
- Spring 1988
- Basic Reserarch Suport Grant, Department of Medicine, NYU School of Medicine
- Spring 1983
- Alpha Omega Alpha, University of Cincinnati College of Medicine
- Spring 1981
- Research Award, University of Cincinnati College of Medicine
- Spring 1979
- Dean's Summer Research Fellowship, University of Cincinnati
- Spring 1978
- Science in Human Affairs Certificate-Princeton University
- Spring 1977
- American Society for Microbiology Undergraduate Scholarship
- Spring 1976
- Ohio Rheumatism Society, Research Award
- Spring 1976
- WNEW Channel 5 Metromedia Community Service Award
- Spring 1976
- American Chemical Society Research Award
- Spring 1973
- American Society for Microbiology Award (ISEF)-First Place
- Spring 1973
- Gold Key-New York Biology Teachers Award
- Spring 1973
- Highest Award in Biology-Stuyvesant High School
- Spring 1973
- International Science and Engineering Fair (ISEF) Award in Microbiology-First Place
- Spring 1973
- Manhattan Science Fair-First Place
- Spring 1973
- Spring 1972
- Member, New York Academy of Sciences
- Spring 1973
- New York City Inventors Fair-Second Place "New Technique for Rapid Bacterial Identification and Diagnosis
- Spring 1973 (Award Finalist)
- New York City Mayor's Office Diamond Jubilee Award
- Spring 1973
- New York City Science Fair-First Place
- Spring 1973
- Spring 1972
- United States Air Force Award-Medicine and Health
- Spring 1973
- United States Army Research Award
- Spring 1973
- United States Atomic Energy Commission Research Award
- Spring 1973
- United States Nave Science Cruiser Award
- Spring 1973
- United States Student Representative to the Nobel Prize Ceremonies, Stockholm, Sweden
- Spring 1973
- Waldemar Medical Research Foundation Award
- Spring 1973
- Westinghouse Science Talent Search-National Honors
- Spring 1973
- American Society for Microbiology Award (ISEF)
- Spring 1972
- Future Scientists of America Award
- Spring 1972
- International Science and Engineering Fair (ISEF) Award in Microbiology
- Spring 1972
- Distinguished Alumnus of the Year-University of Cincinnati College of Medicine
- Spring 2016
- Elected Fellow-National Academy of Inventors
- Spring 2016
- Elected-Faculty Senate, University of Arizona
- Spring 2016
- Elected Program Chair-Annual Meeting ASAIO (American Society for Artificial Internal Organs (for 2016 and 2017 Meeting)
- Spring 2015
- Medical Company of the Year Award-Arizona Business (SynCardia)
- Spring 2015
- Mentor-1st Place Scholarship Award (A. Dimasi)-International Cooperative Research of the International Society for Rotary Blood Pumps (ISRBP)
- Spring 2015
- Edison Award Innovation Finalist-for Portable Driver (SynCardia)
- Spring 2014
- Elected President-International Society of Rotary Blood Pumps (ISRBP)
- Spring 2014
- Fast Company Innovation by Design Award-MC10 Reebok Checklight
- Spring 2014
- Global 250 Top Private Companies-MC10
- Spring 2014
- MC10-International CES Innovations Design and Engineering Award, Best of Innovations
- Spring 2014
- MassTLC Innovative Technologies Award-MC10 Biostamp Technologies
- Spring 2014
- New Economy Award for Best medical Device (SynCardia)
- Spring 2014
- SynCardia-Innovator of the Year-Arizona Governors Celebration of Innovation/Arizona Technology Council/Arizona Commerce Authority
- Spring 2014
- University of Arizona Catapult Ward-Tech Launch Arizona "Advancing Impactful Inventions in BioMedical and Life Science of the U of A to the World"
- Spring 2014
- Appointed Member-Biomedical Engineering Materials and Applications (BEMA) Roundtable, National Research Council of the National Academies
- Spring 2013
- MC10-CES Innovations 2014 Design and Engineering Award
- Spring 2013
- MC10-Time Magazine-"10 Ideas That Make a Difference"
- Spring 2013
- MC10-World Economic Forum-Technology Pioneer
- Spring 2013
- Mentor-1st Place Scholarship Award (L. Valerio)-International Cooperative Research of the International Society for Rotary Blood Pumps (ISRBP)
- Spring 2013
- SynCardia-Recognized for SynCardia as a "100 Most Promising Companies (69/100)-Forbes
- Spring 2013
- ASAIO-Board of Trustees
- Spring 2012
- Elected Fellow-American Institute for Medical and Biological Engineering (AIMBE)
- Spring 2012
- International Society for Rotary Blood Pumps-Board of Trustees
- Spring 2012
- SynCardia-Medical Device Design Excellence Award (MDEA)-Freedom Portable Driver
- Spring 2012
- Wall Street Journal Technology Innovation Award-Semiconductors-MC10
- Spring 2012
- MC10-Recognized for Innovation: "Electronics That Can Bend"-Inc. Magazine
- Spring 2011
- SynCardia-Recognized for SynCardia as a "100 Most Promising Companies"-(78/100)-Forbes
- Spring 2011
- SynCardia-Recognized for SynCardia being #20/50 of the "Top 50 Innovation Companies"-Fast Company
- Spring 2011
- McGuire Scholar, Eller School of Business/Management, University of Arizona
- Spring 2010
- Alumnus of the Year Award-University of Cincinnati
- Spring 2006
- Arizona Small Business Association Award-"Companies to Watch"
- Spring 2006
- Entrepreneur and Entrepreneurial Company of the Year-Medical Devices Frost and Sullivan
- Spring 2005
- Madison's Who's Who of Executives and Professionals (to date)
- Spring 2004
- Most Significant Advance in Cardiovascular Medicine (#1 of 10 in "Top Ten List of Advances") American Heart Association
- Spring 2004
- Marquis Who's Who (to date)
- Spring 2002
Licensure & Certification
- Arizona Medical License (1991)
- New York State Medical License (1982)
- Ohio Medical License (1988)
- Maryland Medical License (1985)
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 Healthcare
Innovation, Translation and Entrepreneurship;Medical Device Development;Science and Technology Administration;Thrombosis; Biomaterial Science;Mechanical Circulatory Support and Heart failure;Interventional Cardiology;Medicine;Cardiology;
Assess Erly Stg Medical TechENTR 581A (Spring 2019)
DissertationBME 920 (Spring 2019)
Innovation/Translation & ENTRBME 481A (Spring 2019)
Innovation/Translation & ENTRENGR 481A (Spring 2019)
Innovation/Translation & ENTRSOC 481A (Spring 2019)
Directed ResearchCHEM 392 (Fall 2018)
DissertationBME 920 (Fall 2018)
Honors ThesisPSIO 498H (Fall 2018)
Independent StudyBME 599 (Fall 2018)
Internship in Applied BiosciABS 593A (Fall 2018)
Senior CapstoneBIOC 498 (Fall 2018)
Assess Erly Stg Medical TechENGR 581A (Spring 2018)
Assess Erly Stg Medical TechENTR 581A (Spring 2018)
Assess Erly Stg Medical TechOPTI 581A (Spring 2018)
Directed ResearchPSIO 492 (Spring 2018)
Directed RsrchMCB 492 (Spring 2018)
DissertationBME 920 (Spring 2018)
Innovation/Translation & ENTRBME 481A (Spring 2018)
Innovation/Translation & ENTRENGR 481A (Spring 2018)
Innovation/Translation & ENTRENTR 481A (Spring 2018)
Innovation/Translation & ENTRPATH 481A (Spring 2018)
DissertationBME 920 (Fall 2017)
Rsrch Meth Biomed EngrBME 597G (Fall 2017)
ThesisCMM 910 (Fall 2017)
Assess Erly Stg Medical TechENGR 581A (Spring 2017)
Assess Erly Stg Medical TechENTR 581A (Spring 2017)
Assess Erly Stg Medical TechMED 581A (Spring 2017)
Assess Erly Stg Medical TechOPTI 581A (Spring 2017)
Assess Erly Stg Medical TechPATH 581A (Spring 2017)
Directed ResearchBME 492 (Spring 2017)
Directed ResearchPSIO 492 (Spring 2017)
Directed RsrchMCB 392 (Spring 2017)
DissertationBME 920 (Spring 2017)
Innovation/Translation & ENTRBME 481A (Spring 2017)
Innovation/Translation & ENTRENGR 481A (Spring 2017)
Innovation/Translation & ENTRENTR 481A (Spring 2017)
Innovation/Translation & ENTROPTI 481A (Spring 2017)
Innovation/Translation & ENTRSOC 481A (Spring 2017)
Rsrch Meth Biomed EngrBME 597G (Spring 2017)
Directed ResearchBME 492 (Fall 2016)
Directed ResearchPSIO 492 (Fall 2016)
Directed RsrchMCB 492 (Fall 2016)
DissertationBME 920 (Fall 2016)
- Giovinco, N. A., Giovinco, N. A., Slepian, M. J., Slepian, M. J., Armstrong, D. G., Armstrong, D. G., Mahmoud, A. Z., & 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:10.1007/978-1-4939-2671-8More infoLatifi R, Rhee P, and Gruessner R (eds)
- Rankin, T., Rankin, T., Slepian, M. J., Slepian, M. J., Armstrong, D. G., & Armstrong, D. G. (2015). Augmented Reality in Surgery. In Technological Advances in Surgery, Trauma, and Critical Care. Media, Pennsylvania: Springer Science.More infoLatifi 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:10.1007/978-1-4939-2671-8More infoLatifi R, Rhee P, and Gruessner R (eds)
- 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.More infoIn 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.
- 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
- 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.More infoCongenital 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.More infoRemote 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., 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.More infoTo 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.More infoWe 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.More infoThere 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.More infoThrombus 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.
- 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.More infoCoronary 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., 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).More infoPersistent 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.
- 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., 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.More infoShear-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.
- 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.More infoTest the choice of 16S rRNA gene amplicon and data analysis method on the accuracy of identification of clinically important bacteria utilizing a benchtop sequencer.
- 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.More infoUsing 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.More infoTranscatheter 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.More infoSepsis-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).More infoVentricular 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.More infoMechanical 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.More infoFor 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.More infoWith 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.More infoThe 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.More infoTo 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.
- 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.More infoRecently, 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.More infoLeft 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).More infoThe 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.More infoLeft 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.More infoCapabilities 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.More infoPlatelets, 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.More infoPhysiological 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., Luu, C., Larson, E., Rankin, T. M., Slepian, M. J., & 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.
- 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).More infoCardiovascular 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.
- 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.More infoThis 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.More infoContinuous 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.More infoWe 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.More infoCell 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.More infoWe 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.
- Attaran, R. R., Habibzadeh, M. R., Baweja, G., & Slepian, M. J. (2015). 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.More infoCongenital 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.
- 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.More infoCalcific 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.
- Copeland, J., Copeland, H., Nolan, P., Gustafson, M., Slepian, M., & Smith, R. (2015). 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.More infoFor 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., Smith, R. G., Larson, D. F., Khalpey, Z. I., Burkhoff, D., & Slepian, M. J. (2015). 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.More infoThe 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.
- 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.More infoMechanical 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.More infoThrombosis 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.
- El Banayosy, A., Kizner, L., Arusoglu, L., Morshuis, M., Brehm, C., Koerfer, R., Schuermann, C., Smith, R. G., Copeland, J. G., & Slepian, M. J. (2015). 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.More infoTo 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.
- 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. (2015). 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.More infoRecently, 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. (2015). 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.More infoLeft 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., Sydow, N., Paidy, S., Slepian, M. J., Friedman, M., Cooper, A., Marsh, K. M., Schmitto, J. D., & Poston, R. (2015). 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.More infoLeft 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.
- 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.More infoShear-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.More infoIn 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.More infoCardiovascular 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.
- Movahed, M. R., Kern, K., Thai, H., Ebrahimi, R., Friedman, M., & Slepian, M. (2015). Coronary artery bifurcation lesions: a review and update on classification and interventional techniques. Cardiovascular revascularization medicine : including molecular interventions, 9(4), 263-8.More infoCoronary 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.
- 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.More infoHearing 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.More infoFrailty 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.More infoSurgical 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.More infoWe 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.More infoOver 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.More infoImplantation 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.More infoMechanical 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.
- 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.More infoCells 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.More infoDespite 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.More infoLeft 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.
- 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.More infoContinuous 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.
- Zimmerman, H., Coehlo-Anderson, R., Slepian, M., Smith, R. G., Sethi, G., & Copeland, J. G. (2015). 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.More infoWe 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.
- 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.
- 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.More infoHere, 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.
- 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., 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.More infoThe 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.More infoThe 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.
- 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.More infoVentricular 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.
- 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.More infoWe 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.More infoThrombotic 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.More infoCalcific 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.More infoMicrometer 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).More infoEndothelialization 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.
- 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.More infoThe 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.More infoThe 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.
- 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.More infoStresses 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.More infoAssuring 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.More infoPresent 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.More infoMechanical 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.
- 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.More infoCurved 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.More infoObesity 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.More infoPolymeric 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.
- 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.More infoDeveloping 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.More infoPatients 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.More infoPeriodontitis 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.More infoPatients 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.More infoWe 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.More infoSafety 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.More infoThe 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.More infoThe 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.More infoThe 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.More infoPercutaneous 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.More infoThe 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.More infoWe 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.More infoDespite 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. (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.More infoThe 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.More infoIschemic 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). Beta3-integrins rather than beta1-integrins dominate integrin-matrix interactions involved in postinjury smooth muscle cell migration. Circulation, 97(18), 1818-27.More infoSmooth 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.More infoPolymeric 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.More infoArterial 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.More infoThin 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.More infoThis 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.More infoOver 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.More infoWe 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.More infoA 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.
- 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.
- 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).
- 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.