Scott L. Diamond Associate Director, IME Department of Chemical Engineering Department of Bioengineering Director, Biotechnology Program   1024 Vagelos Research Laboratories Philadelphia, PA 19104-6383 (215) 573-5704, phone (215) 573-7227, fax sld@seas.upenn.edu Education Ph.D. (1990) Chemical Engineering, Rice University, Houston, TX B.S. (1986) Chemical Engineering, Cornell University, Ithaca, NY Professional Experience Professor of Chemical Engineering, Bioengineering and Pharmacology, University of Pennsylvania, 1997 - present Associate Editor, Annals of Biomedical Engineering, 1997 - present Director, Center for Bioengineering SUNY at Buffalo , 1996 to 1997 Associate Professor of Chemical Engineering, SUNY at Buffalo, 1995 - 1997 Assistant Professor of Chemical Engineering, SUNY at Buffalo, 1990 - 1997 Adjunct Associate Professor of Biological Sciences, SUNY at Buffalo, 1992 - 1997 Awards 1999 American Institute of Chemical Engineers Allan P. Colburn Award 1999 American Heart Association Established Investigator Award 1993 NSF National Young Investigator Award 1992 NIH FIRST Award 1992 University Teaching Scholar, State University of New York 1988 Teaching Incentive Grant, General Electric Foundation 1987 Nominee, National Research Service Award, National Institutes of Health 1986 Graduate Fellowship, Robert A. Welch Foundation, Rice University Research Interests Mechanobiology, Cardiovascular biorheology, Coupled reaction-transport systems, Fluorescence spectroscopy and imaging, Heterogeneous bioreaction systems, Gene therapy. Endothelial Cell Mechanobiology This research ultilizes molecular and cell biology approches to explore issues related to cardiovascular disease of the arterial system. Our focus is on how physical forces generated by blood flow (hemodynamics) regulate blood vessel wall biology. Vascular surgeons and pathologists have long recognized that atherosclerotic lesions are localized at sites of disturbed blood flow. Additionally, physiologists have recognized that the endothelium plays an important role in matching the vessel diameter to the blood flow through vessel. Yet how does an endothelial cell respond to its hemodynamic environment? To date, our investigations have shown that the expression of several genes is altered when endothelial cells are exposed to arterial levels of physical forces. We have found that the gene for the blood clot dissolver, tissue plasminogen activator (tPA) is upregulated. Also, we have found that the expression of two separate dilatory pathways involving nitric oxide synthase type III (endothelial NOS, eNOS) and C-type natriuretic peptide (CNP) are induced by flow. Both eNOS and CNP are generally associated with inhibitory activity against smooth muscle cell intimal hyperplasia. Conversely, the expression of the potent vasoconstrictor and smooth muscle cell mitogen, endothelin, is shut off by arterial shear forces. Recently, we discovered the molecular mechanisms of 150-year old paradox in cardiovascular hemodynamics call poststenotic dilatation. This hemodynamic maladaptation is due to overproduction of nitric oxide by endothelium exposed to high speed vortexes downstream of a stenosis. We are interested in defining and promoting the hemodynamic regulation of endothelial phenotypes associated with enhanced vasodilatory activity and smooth muscle cell growth antagonism. Thrombosis and Thrombolytics Thrombolytic therapy is well established in the US as a treatment for acute MI as well as for peripheral arterial and venous thrombosis. Thrombolytic treatment of stroke is in the developmental stage. However, the therapies are still evolving and much remains to be done to improve efficacy and safety. Presently, there is not a suitable theoretical basis by which clinical outcomes are quantitatively linked in mechanistic terms to pharmacodynamics. A goal of our research is the advancement of large scale computations to simulate intravenous, intracoronary, or intrathrombic delivery of a combination of lytic agents to a given clot structure/comoposition for coronary, peripheral artery, and venous thrombolysis. A number of unresolved issues still exist regarding thrombolytic therapy. It is not clear why reperfusion rates decrease so dramatically if therapy is initiated after 4 to 6 hr after onset of MI symptoms. Changes in biochemistry, clot structure, and transport phenomena may play a role. Also, it is not clear why some clot structures and some patient subsets are poor candidates for thrombolytic therapy. We are conducting experimental and theoretical investigations of blood clotting and blood clot dissolving reactions under realistic hemodynamic conditions. We seek to define the quantitative relationship between the pharmacodynamics of a given thrombolytic therapy, the composition and location of a thrombus, and the consequent reperfusion time and reperfusion flow rate. Particular attention is placed on the penetration rates of plasma constituents into thrombi (driven by hemodynamic pressures) and the consequent dissolution dynamics. We are advancing the use of computer simulation of the cellular aggregation, fibrin polymerization, and clot dissolving reactions using biphasic, multicomponent convection-dispersion-reaction equations for erodible clot structures with heterogeneous adsorption and reaction. Coupled with pharmacodynamic modeling of the systemic circulation, these computer simulations help predict rates of clotting, clot dissolution, causes of clot cannulation, as well as, help evaluate therapeutic approaches for annular clots remaining after cannulation. Endothelial Gene Therapy Gene transfer by nonviral methodologies (e.g. lipofection) are not efficient in cell populations with low mitotic rates. Unfortunately, cells are not actively dividing in many in vivo tissues that are potential clinical targets for gene therapy. While receptor targeting, fusigenic peptides, or endosome disrupting agents help overcome some of the first barriers that limit liposome-based gene delivery, virus free gene transfer using liposomes will have limited clinical utility because of the difficulty of transporting genetic material into the nucleus of a nondividing cell. We propose research to understand and potentially overcome this final rate limit of nuclear entry encounted with lipofection of nondividing cells. We seek to develop methodologies for delivering large genetic packages into the nucleus of nondividing cells. This will be critical for the success of nonviral mediated gene therapy in vivo and various tissue engineering applications where the low mitotic index of target cells would greatly limits the impact of many potential therapies. Research will use: cultured bovine and human endothelial cells and other mammalian cell types, various liposome chemistries, and viral and cellular-derived components that may facilitate nuclear penetration of plasmids with marker genes that include b-galactosidase and mutant forms of green fluorescent protein (GFP). Also, epifluorescence microscopy and fluorescence spectroscopy will be used to identify cellular localization and quantities of fluorescent proteins or reaction products. Liposome mediated gene transfer is a potentially important clinical alternative to viral routes since there is less risk of immune response. From a regulatory, manufacturing, economic, and ease-of-use standpoint, liposomal routes offer many advantages over viral routes. For lipofection routes to succeed, however, a major problem to overcome is low transfection efficiency of nondividing cells. Similarly, retrovirus gene transfer may benefit from such approaches. Selected Publications M. Goel, S. L. Diamond. Thrombosis. Encyclopedia of Biomaterials and Biomedical Engineering. Marcel Dekker, Inc. (2003). J. M. Abrahams, S. L. Diamond. Biological and Future Management of Aneuryms. In "Management of Cerebral Aneurysms." Eds. P.D. LeRoux and H.R. Winn. Elsevier Science. In press (2003). M. Goel, S. L. Diamond. Adhesion of normal erythrocytes to activated neutrophils, activated platelets, and fibrin polymerized from plasma at depressed venous shear rates. Blood. 100, 3797 (2002). T. A. Doggett, G. Girdhar, A. Lawshe, D. W. Schmidtke, I. J. Laurenzi, S. L. Diamond, T. G. Diacovo. Selectin-like Kinetics and Biomechanics Promote Rapid Platelet Adhesion in Flow: The GPIba-vWF Tether Bond. Biophysical J. 83, 194 (2002). M. Frojmovic, G. Nash, S.L. Diamond. Cell Aggregation and Cell Adhesion in Flow. Thromb. Haem. 87, 771 (2002). I. J. Laurenzi, J.D. Bartels, S.L. Diamond. A general algorithm for exact numerical simulation of multi-component aggregation. J. Comput. Phys. 177, 418 (2002). J. M. Abrahams, C Song, MS Grady, SL Diamond, RJ Levy. Endovascular Microcoil Gene Delivery Using Immobilized Anti-adenovirus Antibody for Vector Tethering. Stroke. 33, 1376 (2002). I. J. Laurenzi, S.L. Diamond. Multicomponent Aggregation and Gel Formation via Simultaneous Convection and Diffusion. I.E.C.&R. 40: 413 (2002). C.K. Byrnes, P. H. Nass, M. D. Duncan, S.L. Diamond, J. W. Harmon. Assessment of a nuclear targeting peptide scaffold (M9) to improve plasmid DNA transfection efficiency. Surg. Forum. 102, 538 (2001). M. Goel, S.L. Diamond. Neutrophil enhancement of fibrin deposition under flow though platelet-independent and platelet-dependent mechanisms. Arteriol. Thromb. Vasc. Biol. 21, 2093 (2001). J. M. Abrahams, M. S. Forman, M. S. Grady, and S. L. Diamond. Biodegradable polyglycolide endovascular coils promote wall thickening and drug delivery in a rat aneurysm model. Neurosurgery. 49, 1187 (2001). S. L. Diamond. Reaction complexity in flowing human blood. Biophysical J. 80, 1031(2001). J.M. Abrahams, S.L. Diamond, R.W. Hurst, E.L. Zager, M.S. Grady. Surface modifications enhancing biological activity of Guglielmi detachable coils in treating intracranial aneurysms. Surgical Neurology. 54, 34 (2000). D.W. Schmidtke, S.L. Diamond. "High resolution imaging of membrane tethers form during neutrophil attachment to adherent platelets or P-selectin in physiological shear flow." J. Cell Biol. 149, 719 (2000). S. L. Diamond, P. Tandon, D. Schmidtke, I. Laurenzi. "Cellular aggregation in blood flow" Comments Theoret. Biol 5, 413 (2000). A. Subramanian, P. Ranganathan, S. L. Diamond. "Nuclear targeting peptide scaffold for lipofection of nondividing mammalian cells." Nature Biotechnology. 17, 873 (1999). I. Laurenzi, S. L. Diamond. "Monte Carlo simulation of the heterotypic aggregation kinetics of platelets and neutrophils." Biophysical J. 77, 1733. (1999). S. L. Diamond. "Engineering Design of Optimal Strategies for Blood Clot Dissolution" Annual Reviews Biomedical Engineering. 1, 427 (1999). W. J. Calvo, G. Hajduczok, J.A. Russell, and S.L. Diamond. "Inhibition of nitric oxide but not prostacyclin prevents poststenotic dilatation in rabbit femoral artery." Circulation. 99, 1069 (1999). P. Tandon, S. L. Diamond. "Kinetics of b2-integrin and L-selectin bonding during neutrophil aggregation in shear flow." Biophysical J. 75, 3163 (1998). W. Wang, S.L. Diamond. Does elevated nitric oxide production enhance the release of prostacyclin from shear stressed aortic endothelial cells? Biochem. Biophys. Res. Comm. 233, 748 (1997). A. Subramanian, S.L. Diamond. "Enhancement of nonviral gene transfer to endothelial cells using lipofection of histone complexed DNA." Tissue Engineering 3, 39 (1997). S. Anand and S. L. Diamond. "Computer Simulation of Systemic Circulation and Clot Lysis Dynamics During Thrombolytic Therapy That Accounts for Inner Clot Transport and Reaction." Circulation 94, 763 (1996). V. Ranjan, S. Z. Xiao, and S. L. Diamond. "Constitutive NOS Expression in Cultured Endothelial Cells is Elevated by Fluid Shear Stress." Amer. J. Physiol. 268, H550 (1995). J. H. Wu and S. L. Diamond. "Tissue Plasminogen Activator Inhibits Plasmin Degradation of Fibrin: A Mechanism that Slows tPA-mediated Fibrinolysis but Does Not Require a2-antiplasmin or Leakage of Intrinsic Plasminogen." J. Clinical Investigation 95, 2483 (1995). J. H. Wu and S. L. Diamond, "A Fluorescence Quench and Dequench Assay for Fibrinogen Polymerization, Fibrinogenolysis, or Fibrinolysis." Analytical Biochem. 224, 83 (1995). J. H. Wu, K. A. Siddiqui, and S. L. Diamond. "Transport Phenomena and Clot Dissolving Therapy: An Experimental Investigation of Diffusion-Controlled and Permeation-Enhanced Fibrinolysis." Thrombosis Haemostasis 72, 105 (1994). V. Ranjan and S. L. Diamond, "Fluid Shear Stress Induced Synthesis and Nuclear Localization of c-Fos in Cultured Human Endothelial Cells." Biochem. Biophys. Res. Comm. 196, 79 (1993). W. Sigurdson, F. Sachs, and S. L. Diamond, "Mechanical Perturbation of Cultured Human Endothelial Cells Causes Rapid Increases of Intracellular Calcium." Amer. J. Physiology 264, H1745 (1993). J. B. Sharefkin, S. L. Diamond, S. G. Eskin, C. Dieffenbach, and L. V. McIntire, "Fluid Flow Decreases Endothelin mRNA Levels and Suppresses Endothelin Peptide Release in Human Endothelial Cells." J. Vasc. Surg. 14, 1 (1991). S. L. Diamond, S. G. Eskin, and L. V. McIntire, "Fluid Flow Stimulates Tissue Plasminogen Activator Secretion by Cultured Human Endothelial Cells." Science 243, 1483 (1989). Back to IME Home Page