Faculty Biographies

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James M. Anderson, M.D., Ph.D.
Professor
Pathology, Macromolecular Science & Biomedical Engineering, CWRU
Phone: (216) 844-1012
Fax: (216) 844-8004

Education
1963 B.S. Chemistry, Wisconsin State University at Eau Claire.
1967 Ph.D. Oregon State University, Corvallis, OR.
1976 M.D. Case Westem Reserve University School of Medicine.

Research Interests
Our research is directed towards developing a greater understanding of the complexity of host/material interactions that comprise the inflammatory cell responses to biomaterials and to acquire fundamental knowledge and perspective necessary for the design of new materials. Awide variety of in vitro and in vivo techniques are utilized to study host/material interactions and these include confocal fluorescence laser microscopy, cell culture, and the rat cage implant system. Studies of lymphocyte/macrophage interactions on biomaterials focus on the differential participation of Thl and Th2 Iymphocyte subsets in monocyte/ macrophage-mediated inflammatory responses and the development of foreign body giant cells at the tissue/biomaterial interface. These studies also include the pivotal role of interleukin-4 on foreign body giant cell formation. Studies on the long-term biodegradation of elastomeric biomaterials are directed toward developing a fundamental understanding of biocompatibility and biostability/biodegradation of polyurethanes. Our project on cell adhesion and cytokine release from biomedical polymers has as its overall goal the evaluation of the effect of biomedical polymers with varying surface properties on the activation and cytokine production of adherent monocytes/macrophages. Our project on the infection mechanisms with cardiovascular prostheses has as its goal the comprehensive characterization of human blood and Staphylococcus epidermidis interactions with cardiovascular materials with emphasis on sur face interactions.

Selected Publications

1. Schubert, M.A., Wiggins, M.J., Schaefer, M.P., Hiltner, A., and Anderson, J.M., "Oxidative Biodegradation Mechanisms of Biaxially Strained Poly(etherurethaneurea) Elastomers", J. Biomed. Mater. Res.,29, 337-347 (1995).
2. Cosofret, V.V., Erdosy, M., Buck, R.P., Kao, W.J., Anderson, J.M., Lindner, E., Neuman, M.R., "Electroanalytical and Biocompatibility Studies on Carboxylated Poly(vinyl chloride) Membranes for Microfabricated Array Sensors", Analyst, 119, 2283-2292 (1995).
3. Stokes, K., McVenes, R., Anderson, J.M., "Polyurethane Elastomer Biostability", J. Biomat. AppL, 9, 321-354 (1995).
4. Brunstedt, M.R., Rubin, K.R., Kieswetter, K.M., Sapatnekar, S., Ziats, N.P., Merritt, K., Anderson, J.M.,"Bacteria/Blood/Material Interactions. 1. Injected and Preseeded Slime Forming Staphylococcus epidermidis in Flowing Blood with Biomaterials," J. Biomed. Mater. Res., 29, 455-466 (1995).
5. Sapatnekar, S., Kieswetter, K.M., Merritt, K., Anderson, J.M., Cahalan, L., Verhoeven, M., Hendriks, M., Fouache, B., Cahalan, P., "Blood/Biomaterial Interactions in a Flow System in the Presence of Bacteria: Effect of Protein Adsorption," J. Biomed. Mater. Res., 29, 247-256 (1995).

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Ravi V. Bellamkonda, Ph.D.
Assistant Professor
Biomedical Engineering, CWRU
Phone: (216) 368-4195
Fax: (216) 368-4969
e-mail: rvb@po.cwru.edu

Education
1989, B.Tech. Biomedical Engineering, Osmania University, India.
1994, Ph.D. Biomaterials and Medical Science, Brown University.

Research Interests
Our laboratory's primary research interests lie in the fields of biomaterials, cell, and tissue engineering. Our lab proposes to use specially designed two and three-dimensional biomaterials to present cells, growth factors, and extracellular matrix molecules to the compromised tissue environment to promote tissue regeneration. Some of the techniques involved in this work include: thin film, hydrogel synthesis, and characterization; biomaterial surface modification and characterization; tissue culture; gene transfec tion and expression; biochemical and microscopic analysis of cellular response to biomaterials; microsurgical implantation of tissue templates and histological analysis of explanted materials/tissue. Current projects in the lab include a) development of a biosynthetic hydrogel based 'regenerative paste' to enhance nerve regeneration and b) development of a genetically engineered synthetic vascular graft to improve the patency of small diameter vascular grafts. Research data from our laboratory may influence therapeutic strategies for the treatment of spinal and peripheral nerve injuries, and the treatment of coronary artery disease.

Selected Publications

1. Bellamkonda, R., Ranieri, J.P., Bouche, N., Aebischer, P., "A hydrogel based three dimensional matrix for neural cells," J. Biomed.Mater. Res., 29, 663-671 (1995).
2. Bellamkonda, R., Ranieri, J.P., Aebischer, P., "Laminin oligopeptide derivatized agarose gels allow three dimensional neurite extension in vitro," J. Neurosci. Res., 41, 501-509 (1995).
3. Bellamkonda, R., and Aebischer, P., "Tissue engineering in the nervous system," CRC Handbook of Bio medical Engineering, J.D. Bronzino, ed., CRC Press, Boca Raton 118, 1754-1773,
4. 1995. Ranieri, J.P., Bellamkonda, R., Bekos, E.J., Gardella Jr, J.A., Aebischer, P., "Neuronal cell attachment to fluorinated ethylene propylene films with covalently immobilized laminin oligopeptides YIGSR and IKVAV. ll.,"J. Biomed.Mater. Res., 29, 779-785 (1995). Fine, E.G., Valentine, R.F.,
5. Bellamkonda, R., Aebischer, P., "Improved nerve regeneration through piezo electric vinylidenefluoride-trifluoroethylene copolymer guidance channels," Biomaterials, 12, 775 780 (1991).

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Stanley E. D'Souza, Ph.D.
Assistant Staff
Joseph J. Jacobs Center for Thrombosis and Vascular Biology, CCF
Phone: (216) 445-8205
Fax: (216)445-8204

Education
1968, B.Sc. Chemistry, St. Xavier's College, Bombay, India.
1985, Ph.D. Biochemistry, University of Melbourne, Australia.

Research Interests
The adhesive interactions involving cell surface integrin receptors initiate primary signaling events affecting diverse processes such as cell growth and development, immune response, inflammation, and hemostasis and thrombosis. Integrins on leukocytes and adhesive ligands on endothelial cells (EC) particifpate in the adhesion and migration of leukocytes from the blood stream to sites of inflammation. This process involves the interaction of leukocyte integrin IL-2 and Intercellular CellAdhesion Molecule (ICAM 1) on EC. In chronic inflammatory diseases, such as atherosclerosis, monocyte-macrophages and T-lymphocytes are localized to endothelium that overlies early foam cell lesions. An increased expression of ICAM-1 on EC, and smooth muscle cells is detectable on early and advanced atherosclerotic lesions. The aims of this laboratory are to define the structural and functional elements within ICAM-1 that are required for association with specific regions within IL-2. Such investigation will lead to a better understanding of integrin function and of factors that mediate inflammation in the vessel endothelium. Platelets play an important role in the initiation of occlusion of arteries at the site of stenosis or rup tured athetomatous plaques. Agonist activated platelets bind fibrinogen (fg) primarily through integrin IL-3 (GPIIb-IIIa). The binding of fg leads to platelet aggregation and in the formation of an occlusive thrombus. The adherence of activated platelets to cultured endothelial cells is being investigated to study the possible role of these cells in cellular injury. Results indicate that adhesive interaction between plate lets and EC is highly augmented when fg is bound to activated platelets. Fg bound to IL-3 on platelets is anchored via ICAM-1 on EC. ICAM-1, in addition to binding IL-2, is also involved in the bridging process of activated platelets to stimulated EC. This cellular bridging mechanism appears to be novel and may be important in chronic inflammatory processes wherein platelets become adherent to EC.

Selected Publications

1. D'Souza, S.E., Ginsberg, M.H., Burke, T.A., Plow, E.F., "The ligand binding site of the platelet integrin receptor GPIIb-IIIa is proximal to the second calcium binding domain of its alpha subunit," J.Biol.Chem., 265, 3440-3446 (1990).
2. D'Souza, S.E., Ginsberg, M.H, Matsueda, G.R., Plow, E.F., "A discrete sequence in a platelet integrin is involved in ligand recognition," Nature, 350, 66-68 (1991).
3. Plow, E.F., D'Souza, S.E., Ginsberg, M.H., "Ligand binding to GPIIb-IIIa: Astatus report," Semin.Thromb. Hemost, 18, 324-332 (1992).
4. Plow, E.F., D'Souza, S.E., "Interaction of adhesive proteins with the platelet receptor, GPIIb-IIIa," In Atherosclerosis Reviews, 25, ed. by P.C. Weber andA. Leaf, Raven Press, New York, 1993, pp. 29-38.
5. D'Souza, S.E., Haas, T.A., Piotrowicz, R.S. et al., "Ligand and cation binding are dual functions of a discrete segment of the integrin beta-3 subunit: cation displacement from this site is implicated in ligand binding," Cell, 79, 659-667 (1994).

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   Steven J. Eppell, Ph.D.
   Senior Research Associate
   Biomedical Engineering, CWRU
   Phone: (216) 368-4067
   Fax: (216) 368-4969
   e-mail: sje@po.cwru
   

   Education
   1984, B.A. Physics, Carleton College.
   1991, Ph.D. Experimental Condensed Matter Physics, Case Western Reserve University.
   

   Research Interests
   Our research interests consist primarily of the elucidation of structure-function relationships of thrombogenic proteins in the region 1 to 100 angstroms above a surface. This is the region in which a ligand must be appropriately aligned before obtaining a successful coupling with a surface bound receptor. We are developing procedures to prepare samples and measure their physical properties so that a more profound understanding of this precursor stage to lock-and- key registration may be obtained. We are currently focused on preparing fibrinogen samples using model substrates like mica, crystalline graphite, single crystal silicon and self assembled monolayers on glass. Our analysis techniques are primarily atomic force microscopy (AFM) and high resolution scanning electron microscopy. We are developing novel AFM techniques which allow us to measure sub-molecular scale physical properties of the molecules/ surfaces of interest. Currently, we can measure three dimensional topography on a nanometer scale and forces of adhesion on a nanonewton scale. We are working on methods to reliably map out electrostatic forces pertinent to single domains within a molecule. In addition, we are developing techniques to mea sure compressibility of a molecule/surface with nanometer spatial resolution and nanonewton force resolu tion. Finally, we are developing techniques to analyze our data so that the complete instrument response function of the AFM is taken into account. This requires careful measurement of the shape of the probe which interacts with the surface as well as a complete characterization of the temporal response of the instrument. With this data in hand, we will be able to develop computer algorithms that substantially improve the quantitative aspect of our measurements.

    

   Selected Publications

   1. Wilson, D.L., Kump, K.S., Eppell, S.J., Marchant, R.E., "Morphological Restoration of Atomic Force Microscopy Images," Langmuir, 11, 265-272 (1995).
   2. Eppell, S.J., Simmons, S.R., Albrecht, R.M., Marchant, R.E., "Cell-Surface Receptors and Proteins on Platelet Membranes Imaged by Scanning Force Microscopy and High Resolution Scanning Electron Microscopy Using Immunogold Contrast Enhancement," Biophysical Journal, 68, 671-680 (1995).
   3. Siedlecki, C.A., Eppell, S.J., Marchant, R.E., "Interactions of Human von Willebrand Factor with a Hydro phobic Self-Assembled Monolayer Studied by Atomic Force Microscopy," J. Biomed. Mat. Res., 28, 971 (1994)
   4. Eppell, S.J., Marchant, R.E., Zypman, F.R., "Probing the Resolution Limits and Tip Interactions of AFM in the Study of Globular Proteins," Langmuir, 9, 2281-2288 (1993).
   5. Carmi, Y., Dahm, A.J., Eppell, S.J., Marchant, R.E., Michael, G., "Atomic Force Microscopy and Auger Electron Microscopy Studies of Thin Film Ultrasmooth Au-Cr Films on Mica," J. Vacuum Sci. Tech. B, 10, 2302 (1992).

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   Paul L. Fox, Ph.D.
   Assistant Staff
   Cell Biology, CCF
   Phone: (216) 444-8053
   Fax: (216) 444-9404
   e-mail: foxp@ccsmtp.ccf.org
   

   Education
   1969, B.A. Mathematics, Cornell University, Ithaca, NY.
   1983, Ph.D. Biochemistry, Cornell University, Ithaca, NY.
   

   Research Interests
   Our primary research interests are in two areas: (1) the structure and oxidant function of the plasma protein ceruloplasmin, and (2) the regulation of endothelial cell motility. One part of our program includes collaborative studies (with Dr. Linda Graham, Dept. of Surgery, CWRU) in both research areas as they participate in the healing of synthetic vascular grafts implanted in animal models of atherosclerosis. In particular, we are studying the ability of synthetic grafts to activate macrophages to produce the oxidant protein ceruloplasmin and cause oxidative modification of low density lipoprotein (LDL), a particle asso ciated with atherogenesis. We are also investigating the signal transduction processes that regulate the motility of vascular endothelial cells and smooth muscle cells in culture and on vascular graft surfaces.

    

   Selected Publications

   1. Margolin, D.A., Kaufman, B.R, DeLuca, D.J., Fox, P.L., Graham, L.M., "Increased platelet derived growth factor production and intimal thickening during healing of Dacron grafts in a canine model," J. Vasc. Surg., 17, 858-867 (1993).
   2. Murugesan, G., Chisolm, G.M., Fox, P.L., "Oxidized low density lipoprotein inhibits the migration of aortic endothelial cells in vitro," J. Cell Biol., 120, 1011-1019 (1993).
   3. Murugesan, G., Sa, G., Fox, P.L., "High-density lipoprotein stimulates endothelial cell movement by a mechanism distinct from basic fibroblast growth factor," Circ. Res., 74, 1149-1156 (1994).
   4. Sa, G., Fox, P.L., "Basic fibroblast growth factor-stimulated endothelial cell movement is mediated by a pertussis toxin-sensitive pathway regulating phospholipase A2 activity," J. BioL Chem., 269, 3219 3225 (1994).
   5. Fox, P.L., Sa, G., Dobrowolski, S.F., Stacey, D.W., "The regulation of endothelial cell motility by p21 ras," Oncogene, 9, 3519-3526 (1994).
   6. Ehrenwald, E., Fox, P.L., "Isolation of nonlabile human ceruloplasmin by chromatographic removal of a plasma metalloproteinase,"Arch. Biochem. Biophys., 309, 392-395 (1994).
   7. Ehrenwald, E., Chisolm, G.M., Fox, P.L., "Intact human ceruloplasmin oxidatively modifies low density lipoprotein," J. Clin. Invest., 93, 1493-1501 (1994).
   8. Fox, P.L., Mukhopadhyay, C., Ehrenwald, E., "Structure, oxidant activity, and cardiovascular mechanisms of human ceruloplasmin," Life Sciences, 56, 1749-1758 (1995).
   9. Sa, G., Murugesan, G., Jaye, M., Ivashchenko, Y., Fox, P.L., "Activation of cytosolic phospholipase A2 by basic fibroblast growth factor via a p42 mitogen-activated protein kinase-dependent phosphorylation pathway in endothelial cells," J. Biol. Chem., 270, 2360-2366 (1995).

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   Robert S. Franco, Ph.D.
   Research Professor
   Hematology/Oncology Division, Internal Medicine, UC
   Phone: (513) 558-3241
   Fax: (513) 559-6703
   

   Education 1966, B.S. Chemical Engineering, Drexel Institute of Technology.
   1971, Ph.D. Chemical Engineering, University of Cincinnati.
   

   Research Interests Recent investigations in our laboratory have focused on sickle cell disease, with particular empha sis on the factors which determine the shortened red blood cell survival time in this disease. Sickle RBC are subjected to severe dehydration in the circulation, with many cells becoming very dense shortly after release from the bone marrow while still at the reticulocyte level of differentiation. We have shown that RBC lacking a fetal form of hemoglobin (HbF) are prone to severe dehydration during this time period. The reason for water loss from the cells is a marked reduction in their potassium content. A major empha sis of our research has been to determine the membrane cation transport pathway(s) responsible for potas sium loss. Recent studies have indicated that KCl cotransport, a chloride-dependent pathway normally present in immature erythroid cells, plays an important role in at least the initial phase of reticulocyte dehydration. Other pathways, including a high capacity, calcium-dependent channel, may be more impor tant in subsequent severe dehydration and in the slower process which takes place in older cells. Recently, we have begun in vivo investigations in which autologous RBC are labeled with biotin and reinfused. Flow cytometric analysis of subsequent blood samples allow a detailed description of the survival characteristics of the RBC in the circulation, including changes in hydration status. This versatile cellular biotinylation methodology may be used to follow multiple populations of labeled cells concurrently and is applicable to platelets as well as RBC.

   Selected Publications

   1. Franco, R.S., Lee, K.N., Barker-Gear, R., Gates, R., Menitove, J.E., "Bi-level biotinylation to measure in vivo recovery and survival of two concurrent rabbit platelet populations," Transfusion, 34, 784-789 (1994).
   2. Franco, R.S., Barker-Gear, R., Williams, S.M., Miller, M.A., Joiner, C.H., Rucknagel, R.L., "Quantitation of HbF in transferrin receptor positive (TfR+) dense sickle reticulocytes,"Blood, 84, 2013-2020 (1994).
   3. Franco, R.S., Palascak, M., Thompson, H., Joiner, C.H., "KCl cotransport activity in light vs. dense trans ferrin receptor-positive sickle reticulocytes," J. Clin. Inv., 95, 2573-2580 (1995).
   4. Joiner, C.K., Jiang, M., Franco, R.S., "Deoxygenation-induced cation fluxes in sickle cells. IV. Modula tion by external calcium," Am. J. Physiol., 269(Cell PhysioL, 38), C403-C409 (1995).
   5. Joiner, C.K., Franco, R.S., Jiang, M., Franco, M.S., Barker, J.E., Lux, S.E., "Increased cation permeability in mutant mouse red cells with defective membrane skeletons," Blood, In Press.
   6. Franco, R.S., Palascak, M., Thompson, H., Rucknagel, D.I., Joiner, C.H., "Dehydration of TfR+ reticulo cytes during continuous or cyclic deoxygenation: Role of KCI cotransport and extracellular calcium," Submitted for publication.

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   Stevin H. Gehrke, Ph.D.
   Associate Professor
   Department of Chemical Engineering, UC
   Phone: (513) 556-2766
   Fax: (513) 556-3473
   email: : sgehrke@alpha.che.uc.edu
   

   Education
   1980, B.S. Chemical Engineering, Kansas State University.
   1983, M.S. Chemical Engineering, University of Minnesota.
   1986, Ph.D. Chemical Engineering, University of Minnesota.
   

   Research Interests
   Our research program is centered around the synthesis, characterization and application development of hydrogels: water-swellable crosslinked polymers. The focus is on the synthesis of novel hydrogels (some now under commercial development), thermodynamics and mass transfer kinetics of polymer-water and polymer-protein and polymer-drug interactions. Development of novel separation, drug delivery and biomaterial applications has been a focus as well; several patent applications in these areas have been filed. Thus the cardiovascular biomaterials research currently underway in the laboratory involves development of novel coatings for cardiovascular devices. There are two project areas currently funded in this area: drug delivery from balloon angioplasty catheters and surface modification of polymers for enhanced hemocompatibility. In the angioplasty project, balloon coatings are being developed which enable site specific drug delivery of therapeutic drugs like heparin and urokinase, which will ameliorate the vessel trauma and reduce clotting induced by exposure of the arterial plaque to the blood following the procedure, while avoiding the need for systemic infusion of these drugs. The project involves synthesis of novel hydrogel coating materials and fundamental studies of the hydrogel thermodynamics and mass transfer of proteins within gels. Development of thrombus-resistant surface coatings for polymeric cardiovascular devices is a related research focus. These coatings are examined for their hemocompatibility as a function of hydrophilic/hydrophobic balance and surface charge. The current project uses a Langmuir-Blodgett trough to coat materials like polyethylene with Pluronico surfactants (PEO-PPO triblock polymeric surfactants) in a controlled fashion. The central hypothesis is that the clotting cascade requires orientation specific deposition of fibrinogen onto the surface. Our evidence to date suggests that fibrinogen orientation can be controlled via coating technique, and thus enabling reduction of the degree of surface-activated thrombosis. We are also initiating work in creating molecular scaffolds for tissue engineering, using arti ficial proteins and modified polysaccharides as the basis for structures of relatively high strength and controlled porosity.

   Selected Publications

   1. Gehrke, S., Braun, J., Conticello, V., Terrell, D., Cantor, E., Foumier, M., Mason, T., "Biosynthesis of Model Protein Compounds for Hydrogel Transport Studies,"ExtendedAbstracts: 1994AnnualAlChE Meeting, AlChE Press, New York, 138 (1994).
   2. Gehrke, S., Uhden, L., Schiller, M., "Enhanced Loading and Activity Retention in Hydrogel Delivery Systems," Proceed. Intern. Symp. Control. Rel. Bioact. Mater., 22, 145-146 (1995).
   3. Harsh, D.C., Gehrke, S.H., "Environmentally Responsive Gels," in The Polymeric Materials Encyclope dia: Synthesis, Properties and Applications, J.C. Salamone, ed., CRC Press, Boca Raton, FL in press (1995).

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   Tibor Jack Greenwalt, M.D.
   Hoxworth Blood Center, UC
   Phone: (513) 558-1520
   Fax: (513) 558-1522
   e-mail: greenwtj@uc.edu
   

   Education
   1934, B.A., Washington Square College, New York University.
   1937, M.D., New York University.
   

   Research Interests
   My research has been concerned with the genetics of the red blood cell blood group antigens, studies of the characteristics and the quantitation of blood group antibodies, and the metabolism and the structure of the membrane of the red blood cell. We have sought ways by which it would possible to map the distribution of the blood group receptors (antigens) on the surface of the red cell. Earlier investigators have attempted to do this by using red cell ghosts and elctron microscopy. Unfortunately the methods necessary to prepare the ghosts disturb the true relationships between the components of the corpuscular membrane. Atomic force microscopy (AFM) makes it possible to devise methods to map the topography of antigens on the surfaces of intact red blood cells. Preliminary studies established that it is possible to fix red blood cells and to attach them to surfaces suitable for studying surface topography by AFM. We were unable to localize any blood group receptors. Most recently we have used gold-labeled antiglobulin to mark recep tors for anti-D (Rh) antibodies. We have not analyzed the resulting data at this time.

   Selected Publications

   1. Greenwalt, T.J., McGuinness, C.G., Dumaswala, U.J., "Studies in Red Blood Cell Preservation IV: Plasma Vesicle Hemoglobin Exceeds Free Hemoglobin,"Vox. Sang, 62 (1992).
   2. Dumaswala, U.J., Oreskovic, R.T., Petrosky, T.L., Greenwalt, T.J., "Studies in Red Blood Cell Preserva tion V: Determining the Limiting Concentrations of NH4Cl and Na2HPO4 Needed to Maintain RBC ATP Storage," Vox. Sang., 62, 136 (1992).
   3. Greenwalt, T.J., Dumaswala, U.J., Siongco, A., Domino, M.M., "An Enzyme-Linked antibody Test to Quantify Red Cell Globulins after Gluteraldehyde Fixation," Transfusion, 63, 262-267 (1992).
   4. Greenwalt, T.J., Dumaswala, U.J., Domino, M.M., "An Enzyme-Linked antibody Test to Quantifying Nano gram Quantities of IgG on Polystyrene Microbeads," Transfusian, 63, 272-275 (1992).
   5. Greenwalt, T.J., Domino, M.M., Dumaswala, U.J., "An Enzyme-Linked antibody Test with Gluteraldehyde Fixation for Quantifying Fetomaternal Hemorrage," Transfusion, 63, 268-271 (1992).
   6. Dumaswala, U.J., Petrosky, T.L., Greenwalt, T.J., "Studies in Red Blood Cell Preservation VI: Red Cell Membrane Remodelling during Rejuvenation," Vox. Sang, 63, 12 (1992).
   7. Oreskovic, R.T., Dumaswala, U.J., Greenwalt, T.J., "Expression of Blood Group Antigens on Red Cell Microvesicles," Transfusion, 32, 848-849 (1992). Greenwalt, T.J., "Red but Not Dead: Not a hapless Sac of Hemoglobin," Immuno. Invest., 24(1&2), 3-21 (1995).
   8. Greenwalt, T.J., Dumaswala, U.J., Rugg, N., "Studies in Red Blood Cell Preservation 10: 5lCr Recovery of Red Cells after Liquid Storage in a Glycerol-Containing Additive Solution," Vox. Sang, In press.
   9. Dumaswala, U.J., Dumaswala, R.U., Levin, D.S., Greenwalt, T.J., "Improved RBC Preservation Corre lates with Decreased Loss of Bands 3, 4.1, Acetylcholinesterase and Lipids in Microvesicles," Blood, To appear Feb. 1996.

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   Kandice Kottke-Marchant, M.D., Ph.D.
   Director, Hemostasis and Thrombosis Laboratory Clinical Pathology, CCF
   Phone: (216) 444-2484
   Fax: (216) 445-9444
   e-mail: marchak@ccsmtp.ccf.org
   

   Education
   1979, B.S. Biomedical Engineering, Northwestem University, Evanston, IL.
   1985, Ph.D. Macromolecular Science, Case Westem Reserve University.
   1986, M.D. Case Westem Reserve University.
   

   Research Interests
   Our research is focused on the elucidation of the effect of polymeric substrate interfacial properties on the growth and coagulant function of endothelial cells under flow conditions. To accomplish this, we have developed two flow systems, both a rotating disc and parallel plate system. We specifically study plasminogen activator production, plasminogen activator inhibitor-1 (PAI-1) production, von Willebrand's factor production, tissue factor activity, prostacyclin production, and expression of adhesion proteins by human endothelial cells on biomaterial surfaces under flow conditions. We are also interested in the interaction of the hemostatic system with biomaterials to address the problem of surface-induced thrombogenicity. To investigate this, we are studying the functionality of platelets and proteins (von Willebrand's factor, fibrinogen, fibronectin) adsorbed onto biomaterials sur faces by biochemical assays and quantifying antibody binding to the adsorbed species by nano-scale atomic force microscopy. On a collaborative basis, we are interested in investigating the in vivo hemostatic effects of new cardiovascular devices and antithrombotic and antiplatelet drugs, such as hirudin, Iloprost, tick anticoagu lant peptide, Integrelin and other glycoprotein IIb/IIIa antagonists. These studies involve platelet flow cytometry, platelet aggregation, and assays of coagulation activation products, such as fibrinopeptide A (FpA), prothrombin F1.2, and thrombin-antithrombin complexes.

   Selected Publications

   1. Kottke-Marchant, K., Marchant, R.E., "Coagulant function of human aortic endothelial cells cultured on plasma polymerized interface materials,"J. Biomed. Mater. Res., In Press, 1995.
   2. Wang, I-W, Kottke-Marchant, K., Vargo, R.L., McCarthy, P.M., "Hemostatic profiles of 19 HeartMate ventricular assist device recipients," Trans. ASAIO, In Press 1995.
   3. Pasha, R., Benavides, M., Kottke-Marchant, K., Harasaki, H., "Reduced expression of platelet surface glycoprotein receptor IIb/IIIa at hyperthermic temperatures," Lab. Investig, In Press 1995.
   4. McCarthy, P.M., Nakatani, S., Vargo, R., Kottke-Marchant, K., Harasaki, H., James, K.B., Savage, R.M., Thomas, J.D., "Structural and left ventricular histologic changes after implantable LVAD insertion," Ann Thorac. Surg., 59, 609-613(1995).
   5. Tcheng, J.E., Harrington, R.A., Kottke-Marchant, K., Kleiman, N.S., Ellis, S.G., Kereiakes, D.J., Mick, M.J., Navetta, F.I., Smith, J.E., Worley, S.J., Miller, J.A., Joseph, D.M., Sigmon, K.N., Kitt, M.M., du Mee, C.P., Califf, R.M., Topol, E.J., "Multicenter, randomized, double-blind, placebo-controlled trial of the platelet integrin glycoprotein IIb/IIIa blocker integrelin in elective coronary intervention," Cir culation, 91, 2151-2157 (1995).

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   Jerome B. Lando, Ph.D.
   Professor Macromolecular Science
   C W RU Phone: (216)368-4284
   Fax: (216)368-4202
   e-mail: jbl2@po.cwru.edu
   

   Education
   1953, A.B. Chemistry, Cornell University, Ithaca, NY.
   1963, Ph.D. Physical Chemistry (Polymer Science), Polytechnic Institute of Brooklyn, NY.

   Research Interests:
   Organic reactions in the solid state. Solid state polymerization. Polymer crystal structure. Synthesis of stereoregularpolymers. Pyroelectric and nonlinear optical polymers. Electronic properties of polymers and thin films.

   Selected Publications

   1. Walsh, S.P., Lando, J.B., "Monolayer-Properties of an Amine-Basaed Diacetylene", Langmuir, 10, 252 (1994).

   2. Ou, S. H., Percec, V., Mann, J.A., Lando, J.B., "Noncentrosymmetric Langmuir-Blodgett Films Contain ing Nitrobiphenyl Groups", Langmuir, 10, 905 (1994).

   3. Wang, H.Y., Lando, J.B., "Gas Sensing Mechanism of Phthalocyanine Langmuir-Blodgett Films",Langmuir, 10, 790 (1994).

   4. Walsh, S.P., Lando, J.B., "Long Period Structure of Langmuir-Blodgett MultilayerAssemblies", Mol. Cryst. Liq. Cryst., 240, 201 (1994).

   5. Angkaew, S., Wang, H.Y., Lando, J.B., "Diacetylenes for Novel Molecular Composites", Chem. Mater., 6, 1444 (1994).

   6. Lando, J.B., Hanes, M.D., "Molecular Modeling of Poly(Vmyl Fluoride)", Macromolecules, 28, 1135 (1995).

   7. Lando, J.B., Hanes, M.D., "X-ray Analysis of Poly(Vmyl Fluoride)", Macromolecules, 28, 1142 (1995).

   8. Hana, H., Johnson, D., Albarici, A., Lando, J.B., "Novel Method of Obtaining Pretilt Angle in Liquid Crystal Alignment with Polyamide Langmuir-Blodgett Films", Jpn. J. Appl. Phys., 34 (1995).

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A. Michael Lincoff, M.D.
Director, Experimental Interventional Laboratory Cardiology
CCF Phone: (216) 444-2367
Fax: (216) 444-8050

Education
1982, B.S. Chemical and Biomedical Engineering, Carnegie-Mellon University.
1986, M.D. Medicine, Johns Hopkins University.

Research Interests
Our experimental interventional and thrombosis research programs encompass a range of investi gative activities carried out in several different animal models. The major topics of research can be broadly dassified as: 1) prevention of restenosis following percutaneous coronary revascularization, comprising investigations into various techniques for local site-specific drug delivery as well as systemic or local administration of novel therapeutic agents, 2) elucidation of the mechanisms of restenosis, including the roles of the thrombotic and thrombolytic pathways and cell surface adhesion molecules, 3) the optimiza tion of myocardial reperfusion during acute coronary ischemic syndromes, through evaluation of new thrombo~ytic agents or exploration of various novel antithrombotic and antiplatelet agents employed as adjuncts to thrombolytic therapy or devices for mechanical thrombus dissolution, and 4) induction- of angiogenesis with experimental growth factors for the treatment of acute or chronic myocardial ischemia. Additionally, the animal laboratories are utilized for the evaluation of new devices or techniques for percutaneous coronary or peripheral arterial revascularization, intravascular ultrasonography, and in travascular contrast echocardiography. These experiments are conducted in animal models or with surgi cal or autopsy human tissue.

Selected Publications

1. Lincoff, A.M., Popma, J.J., Ellis, S.G., Vogel, R.A., Topol, E.J., "Percutaneous support devices for high risk or complicated coronary angioplasty,"JAmer. Coll. Cardio., 17, 770-780 (1991).

2. Lincoff, A.M., Topol, E.J., "Illusion of reperfusion: Does anyone achieve optimal reperftision during acute myocardial infarction?," Circulation, 87, 1792-1805 (1993) (Erratum 88, 1361-1375, 1993).

3. Jang, Y., Lincoff, A.M., Plow, E.F., Topol, E.J., "Cell adhesion molecules in coronary artery disease," J Amer. Coll. Cardio., 24,1591-1601 (1994).

4. Lincoff, A.M., Topol, E.J., Ellis, S.G., "Local drug delivery for the prevention of restenosis: fact, fancy, and future," Circulation, 90, 2070-2084 (1994).

5. Zidar, J.P., Lincoff, A.M., Stack, R.S., "Biodegradable Stents," in Textbook of interventional Cardiology, 2nd Edition, E.J. Topol, ed., W.B. Saunders, Philadelphia, Pennsylvania, 1994, pp. 787-802.

6. Jang, Y., Guzman, L., Lincoff, A.M., Gottsauner-Wolf, M., Forudi, F., Hart, C.E., Ellis, S.G., Topol, E.J., "The influence of blockade at specific levels of the coagulation cascade on restenosis in the rabbit atherosclerotic femoral artery injury model," Circulation, in press.

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Roger E. Marchant, Ph.D.
Associate Professor Biomedical Engineering
CWRU Phone: (216) 368-3005 Fax: (216) 368-4969
e-mail: rxm4@po.cwru.edu

Education
1978, B.Sc.(Hons.) Polymer Chemistry, University of Sussex, England.
1982, M.S. Macromolecular Science & Engineering, Case Westem Reserve University.
1984, Ph.D. Macromolecular Science/Biomaterials, Case Westem Reserve University.

Research Interests
Our research is concerned with interfacial studies of biopolymers and synthetic biomaterials with blood; and the surface modification of biomaterials to achieve improved biologic function and blood compatibility. Surface-activated thrombosis and associated sequelae including bacterial adhesion are major clinical problems with blood-contacting biomaterials. Studies at the cell and molecular level assist our understanding of the underlying mechanisms, so that novel biomedical interfaces may be designed, prepared, and characterized. We then examine biomolecular and cell-surface interactions with the modified biomaterials. Interfacial studies include using optical and electron microscopic techniques for studies at the cell level, while atomic force microscopy is used for obtaining molecular-level information on the structure and interactions of blood platelets, and plasma glycoproteins such as von Willebrand factor (vWF) and fibrinogen, with biomaterial surfaces. A recent example is our successful molecular-level imaging by AFM of vWF adsorbed on a hydrophobic self-assembled monolayer. As part of these studies, we are also attempting to quantify probe tip-surface interactions and to examine interfacial and receptor-ligand forces. Surface modification studies include synthesis and physisorption of novel oligosaccharide surfactant mol ecules which are being studied as potential inhibitors of surface-induced protein adsorption and thrombus formation; radiofrequency plasma polymerization of ionomer materials are being studied as potential permselective membranes for implantable sensor devices.

Selected Publications

1. Siedlecki, C.A., Eppell, S.J., and Marchant, R.E., "Interactions of Human von Willebrand Factor with a Hydrophobic Self-Assembled Monolayer Studied by Atomic Force Microscopy," J. Biomed. Mater. Res., 28, 971-980 (1994).

2. Marchant, R.E., Yuan, S., and Szakalas-Gratzl, G., "Interactions of Plasma Proteins with a Novel Polysac charide Surfactant Physisorbed to Polyethylene," J. Biomater. Sci. (Polym. Ed.), 6, 549-564 (1994).

3. Zhang, T., Marchant, R.E., "Novel Polysaccharide Surfactants; Synthesis of Model Compounds and Dex tran Based Surfactants," Macromolecules, 27, 7302-7308 (1994).

4. Wilson, D.L., Kump, K.S., Eppell, S.J., Marchant, R.E., "Morphological Restoration of AFM Images," Langmuir, 11, 265-272 (1995).

5. Eppell, S.J., Simmons, R.S., Albrecht, R.M., Marchant, R.E., "Cell-Surface Receptors and Proteins on Platelet Membranes Imaged by Scanning Force Microscopy Using Immunogold Contrast Enhance ment," Biophys. J., 68, 671-680 (1995).

6. Wang, I-W., Anderson, J.M., Marchant, R.E., "Adhesion of Staphylococcus epidermidis to Biomedical Polymers: Contributions of Surface Thermodynamics and Hemodynamic Shear Conditions,"J. Biomed. Mater. Res., 29, 485-494 (1995).

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Patrick M. McCarthy, M.D.
Staff Surgeon Thoracic & Cardiovascular Surgery
CCF Phone: (216) 444-0648
Fax: (216) 444-0777

Education
1977, B.A. Anthropology, University of Notre Dame.
1980, M.D., Loyola University.

Research Interests
We have developed an active clinical program for mechanical circulatory support for patients in end stage heart failure. Currently we are among the three most active centers in the world. In addition, we have strong clinical and basic research studies focusing on patients with the HeartMate~9 implantable left ventricular assist device (LVAD). Clinical studies include hemodynamic and physiologic changes during LVAD support, neurohormone and renal changes during support, infection of the LVAD and percutaneous drivelines, echocardiographic measurements of morphologic change in the heart during support, exercise physiology with LVAD support, and quality of life studies. In addition basic studies have included changes in ventricular histology after the initiation of LVAD support, improvement in coagulation parameters (re lated to recovery of liver function), and characterization of cell deposits on the textured blood contacting surfaces inside the pump. We are prepared to begin permanent implants of the LVAD as definitive therapy for patients with end stage heart disease (as an altemative to heart transplantation) within the next year. In addition, other active areas of research include continued development of a totally sealed, implantable, electrically-powered total artificial heart (with support from an NIH grant), and multiple associated projects with the total artificial heart including human fitting studies, exercise physiology in vivo, and hemody namic studies.

Selected Publications

1. McCarthy, P.M., Fukamachi, K., Fukumura, F., et al., "The Cleveland Clinic-Nimbus total artificial heart: in vivo hemodynamic performance in calves and preclinical studies," J. Thorac Cardiovasc. Surg., 108, 420-428 (1994).

2. McCarthy, P.M., James, K., Savage, R.M., et al., "Implantable left ventricular assist device: Approaching an altemative for end-stage heart failure," Circulahon, 90:II, 83-86 (1994).

3. McCarthy, P.M., Savage, R.M., Fraser, C.D., et al., "Hemodynamic and physiologic changes during sup port with an implantable left ventricular assist device," J. ThoraG Cardiovasc. Surg, 109, 409-418 (1995).

4. McCarthy, P.M., Nakatani, S., Vargo, et al., "Structural and left ventricular histological changes following implantable LVAD insertion,"Ann. Thorac. Surg., 59, 609-613 (1995).

5. McCarthy, P.M., "HeartMate~ implantable left ventricular assist device: Bridge to transplantation and future applications,"Ann. Thorac. Surg., 59, S46-51 (1995).

6. McCarthy, P.M., Schmitt, S.K., Vargo, et al., "Infection in implantable left ventricular assist device pa tients: Implications for permanent use of the device," J. Thorac. Cardiovasc. Surg., In press.

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Ronald W. Millard
Professor Pharmacology & Cell Biophysics, UC

Education
1963, B.S. Chemistry, Tufts University.
1969, Ph.D. Physiology, Boston University.

Selected Publications

1. Hardy, R.I., I.W. James, R.W. Millard, S. Kaplan, "Regional myocardial blood flow and cardiac mechanics in dog hearts with C02 laser-induced intramyocardial revascularization,"BasicRes. CardioL, 85, 179 197(1990)

2. Rigel, D.F., R.W. Millard, "Aconundrum with reciprocal cardiorespiratory variables: Illustration by differ ential baroreflex control of heart period and heart rate in selected vertebrates," In Physiological it Adaptations in Vertebrates, Eds. S.C. Wood et al., Marcel Dekker, Inc., N.Y. 1991, p. 201-212.

3. Elsner, R., M. De B. Daly, A. Maseri, R.W. Millard, F.C. White, "Coronary circulation in seals," In Physi ologicalAdaptations in Vertebrates, Eds. S.C. Wood et al., Marcel Dekker, Inc., N.Y. 1991, pp 363 376.

4. Takemura, G., T. Onodera, R.W. Millard, M. Ashraf, "Demonstration of hydroxyl radical and its role in hydrogen peroxide-induced myocardial injury: Hydroxyl radical dependent and independent mecha nisms,"FreeRad. Biol. Med., 15, 13-25 (1993).

5. Holt, B.D., R.A. Walsh, Y. Shao, M. Gabel, R.W. Millard, "Comparative assessment of regional left atrial perfusion by LASER Doppler and radionuclide microsphere techniques," Cardiovascular Res., 27, 508-514 (1993).

6. Blaustein, A.S., K. Ramrakhyani, B.D. Holt, R. Matoba, L.F. Wexler, M. Gabel, M. Ashraf, R.W. Millard, "Characteristics of chronic left ventricular dysftmction induced by coronary embodization in a canine model,"Am. J. Cardiovasc. Pathol., (in press), 1993.

7. Gerson, M.C., R.W. Millard, N.J. Roszell, A.J. McGoron, M. Gabel, L.C. Washbum, D.0. Biniakiewicz, D. Blankenship, W.H. Mallin, R.C. Elder, E. Deutsch, R.A. Walsh, "Kinetic properties of 99mTc-Q 1 2 in canine myocardium," Circulation, 89, 1291-1300 (1994).

8. Thomas, S.R., R.G. Pratt, R.W. Millard, R.C. Samaratunga, Y. Shiferaw, L.C. Clark, Jr., R.E.Hoffmann, "Evaluation of the influence of the aqueous phase bioconstituent envirom-nent on the F-1 9 T I of perfluorocarbon blood substitute emulsions," J. Magn. Reson. Imaging, 4. 631-63 5 (1994).

9. Millard, R.W. Oxygen solubility, rheology and hemodynamics of perfluorocarbon emulsion blood substi tutes," Biomat. Art. Cells & Inunobil. Biotech., 22, 235-244 (1994).

10. Thomas, S.R., R.W. Millard, R.G. Pratt, "Quantitative P02 imaging in vivo with perfluorocarbon F- 1 9 NMR: Tracking oxygen from the airway through the blood to organ tissues," Biomat. Art. Cells & Inunobil. Biotech., In press, 1994.

11. Millard, R.W., McGoron, A.J.," Function of beagle or pig lungs containing perfluorooctyl-bromide (PFOB) or perfluorotributylamine (PFTA)," Submitted to Biomat. Art. Cells & Immobil. Biotech., In press, 1994.

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Edward F. Plow, Ph.D.
Head of Research Joseph J. Jacobs Center for Thrombosis and Vascular Biology
CCF Phone: (216) 445-8200
Fax: (216) 445-8204

Education
1967, B.A. Biology, University of Pennsylvania, PA.
1970, Ph.D. Biochemistry, West Virginia University, Morgantown, WV.

Research Interests
Research in my laboratory focuses on two aspects of cell adhesion and migration. First, we are seeking to understand the structural basis of ligand recognition by members of the integrin family of cell adhesion receptors. The major platelet integrin, IL- 3 (GPIIb/IIIa), which mediates platelet aggregation by serving as a receptor for fibrinogen, serves as a prototypic integrin for these analyses. We are seeking to define ligand contacts within the a and ~ subunits of this heterodimeric receptor utilizing chemical cross linking, monoclonal antibody, synthetic peptide, and mutational analyses. Ligand binding to integrins is cation dependent, and we are seeking to define the interrelationship between cation and ligand contact sites within the receptor. At the same time, we are seeking to establish how the cytoplasmic domains of GPIIb/IIIa control its activation states. Interactions of the cytoplasmic tail with intercellular signalling pathways in cytoskeletal elements are being examined. Our approaches range from construction of unique synthetic peptides to molecular modeling. The second major theme in the laboratory relates to the interaction of components of the plasmino gen system with cell surfaces. Receptors for plasminogen are being identified and characterized. These receptors are subject to up- and down-regulation, and we are seeking to define the molecular basis for such modulation. The consequences of plasminogen binding is to enhance its conversion to the active cell bound protease, plasmin. The biological consequences of plasmin formation on cell surface are being assessed.

Selected Publications

1. Muchowski, P.J., Zhang, L., Chang, E.R., Soule, H.R., Plow, E.F., Moyle, M., "Functional interaction between the integrin antagonist NIF and the I domain of CDllb/CD18," J. BioL Chem., 269, 26419 26423 (1994).

2. Redlitz, A., Fowler, B.J., Plow, E.F., Miles, L.A.,"The role of an enolase-related molecule in Dlasmino_en bindino to cells." Eur. J. Biochem., 227, 407-415 (1995). v

3. Villa, A.E., Guzman, L.A., Poptic, E.J., Labhasetwar, V., D'Souza, S., Farrell, C.L., Plow, E.F., Levy, R.J., DiCorleto, P., Topol, E.J., "Effects of antisense c-myb oligonucleotides on vascular smooth muscle cell proliferation and response to vessel wall injury," Cir. Res., 76, 505-513 (1995).

4. Ugarova,T.P., Zamarron, C., Veklich, Y., Bowditch, R.D., Ginsberg, M.H., Weisel, J.W., Plow, E.F., "Con formational transitions in the cell binding domain of fibronectin," Biochemistry, 34, 4457-4466 (1995).

5. Miles, L.A., Fless, G.M., Scanu, A.M., Baynham, P., Sebald, M.T., Skocir, P., Curtiss, L.K., Levin, E.G., Hoover-Plow, J.L., Plow, E.F., "Interaction of Lp(a) with plasminogen binding sites on cells," Thromb. Haemost., 83, 458-465 (1995).

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Gregory S. Retzinger, M.D., Ph.D.
Associate Professor Pathology and Laboratory Medicine
UC Phone: (513) 558-3447
Fax: (513) 558-2289

Education
1977, B.A. (Hons.) Biology, The University of Chicago.
1981, Ph.D. Immunology, The University of Chicago.
1983, M.D. (Hons.), The University of Chicago.

Research Interests
Of all the plasma proteins, fibrinogen, the precursor of the blood clot matrix, adsorbs most rapidly and preferentially to surfaces in contact with blood. Once bound, fibrinogen is predisposed to form blood clots. Afrequently observed consequence of this predisposition is the "clotting of P' of circulatory prosthetics. Thus, an aim of biomedical materials research is the generation of synthetic materials that do not bind fibrinogen in vivo. But fibrinogen does not adsorb to synthetic materials alone. Indeed, a host of naturally occurring, lipid surfaces bind fibrinogen when these surfaces contact blood. Such surfaces include the atherosclerotic plaque, the cell wall of bacteria, and the cytoplasmic membrane of platelets, macrophages and tumor cells. On these surfaces, too, fibrinogen is predisposed to clot. The glue-like character of the adsorbed protein confers to the surface an adhesive property that operates during a number of important processes as seemingly unrelated as platelet plug formation, phagocytosis, metastasis, and artherogenesis. By studying fibrinogen adsorbed to lipid surfaces Dr. Retzinger hopes to glean mechanistic insight relevant not only to the formulation of haemocompatible materials but also to the treatment of human disease. He uses well-defined, lipid surfaces to study the influence of lipid microenvironment on the processivity and adhesivity of adsorbed fibrinogen. His work indicates that physicochemical properties of lipids affect the orientation/conformation of fibrinogen at an interface. The orientation/conformation of fibrinogen, in turn, exposes and/or masks certain reactive sites of the protein. Information derived from Dr. Retzinger's study of fibrinogen at lipid interfaces has been/is being used by him to develop: 1) haemocompatible, lipid coatings for circulatory prosthetics, 2) a platelet substitute, 3) a fibrin-specific, drug delivery system, 4) an adjuvant for general use with vaccines, and 5) a method for inhibiting tumor cell metastasis.

Selected Publications

1. Retzinger, G.S., Chandler, L.J., Cook, B.C., "Complexation with heparin prevents adhesion between fibrin coated surfaces," J. Biol. Chem., 267, 24356-24362 (1992).

2. Cook, B.C., Retzinger, G.S., "Lipid microenvironment influences the processivity of adsorbed fibrin(ogen): enzymatic processing and adhesivity, of the bound protein," J. Colloid Interface Sci., 162, 171-181 (1994).

3. Retzinger, G.S., Cook, B.C., DeAnglis, A.P., "The binding of fibrinogen to surfaces and the identification of two distinct surface-bound species of the protein," J. Colloid Interface Sci, 168, 514-521 (1994).

4. DeAnglis,A.P., Retzinger, G.S., "Preparation and characterization of fibrinogen-coated, reversibly adhesive, lecithin/cholesterol vesicles," J. Pharm. Sci., in press. Retzinger, G.S., "Adsorption and coagulability of fibrinogen on atheromatous lipid surfaces,"Arterioscler. Thromb. Vasc. Biol., in press.

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John R Shainoff, Ph.D.
Member of the Foundation Res. Inst.
CCF Phone: (216) 444-5851
Fax: (216) 445-5480
e-mail: shainoj@ccsmtp.ccf.org

Education
1951, B.S. Zoology, Chemistry, Physics, University of Pittsburgh, Pittsburgh, PA.
1954, M.S. Biophysics, University of Pittsburgh, Pittsburgh, PA.
1956, Ph.D. Biophysics, University of Pittsburgh, Pittsburgh, PA.

Research Interests
Our research concerns the biophysical and physiologic chemistry of fibrinogen and Its association with wound healing, thrombosis, and vascular disease. These interests stem from early identifications of mark ers for (1) intravascular fibrin formation, (2) intimal fibrinogen deposition through direct cross-linking by tissue-transglutaminase, and (3) receptor-mediated mechanisms of clearance of fibrin from blood and vascular lesions. Important contributions of our laboratory to these problems include the discovery of soluble fibrin complexes in blood, the initial use of fibrinopeptides to assess intravascular fibrin formation, the identification of the aggregation site that is unmasked by fibrinopeptide B, and the definition of the clearance of circulating fibrin as a saturable and receptor-mediated process. Currently, our research is heavily focused on our recent isolation and characterization of the initial derivative in the fibrinogen/fibrin conversion which had eluded description until now because its properties were too close to those of fi brinogen itself at ambient or physiologic temperatures. It was only recently identified as a non-aggregat ing derivative by a novel electrophoretic method that uses peptide analogs of the fibrin-aggregation site to elicit gel-shifts that distinguish aggregating from non-aggregating derivatives in the coagulation reaction. We plan to use atomic-force-microscopy to establish the structural basis for non-aggregation of the deriva tive at ambient temperature and its dimerization at low temperature.

Selected Publications

1. Shainoff, J.R., Estafanous, F.G., Yared, J.P., DiBello, P.M., Kottke-Marchant, K., Loop, F.D., "Low factor XIIIA levels are associated with increased blood loss after coronary artery bypass grafting,"J. ThoraG Cardiovasc. Surg., 108, 437-445 (1994).

2. Shainoff, J.R., Smejkal, G.B., Mitkevich, O.V., DiBello, P.M., "Preparative electrophoresis on linear polacrylamide-agarose composite gels," Electrophoresis, 1995 (in press).

3. Odrljin, R.M., Shainoff, J.R., Lawrence, S.O., Haidaris, P.J.S., "Thrombin cleavage enhances exposure of a heparin binding domain in the N-terminus of the fibrin b-chain" 1995, (Submitted).

4. Mitkevich, O.V., Sobel, J.H., Shainoff, J.R., Vlasik, T.N., Kalantarov, G.F., Trakht, I.N., Streltsova, Z.A., Samokhin, G.P., "A monoclonal antibody that is directed to a segment (Aa#529-5393 near the C terminus of the fibrinogen Aa-chain and inhibits a-chain crosslinking by transglutaminases," 1995, (Submitted).

5. Shainoff, J.R., Smejkal, G.B., DiBello, P.M., Mitkevich, O.V., Levy, P.J., Lill, H., Dempfle, C.E., "The fibrin-intermediate arising from cleavage of one fibrinopeptide A from fibrinogen. Its identification and characterization as a non-aggregating fibrin-precursor, and the kinetics of its conversion to fi brin," (Submitted).

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David M. Shlaes, M.D., Ph.D.
Professor, Medicine, CVVRU Chief, Infectious Diseases Section, DVMC
Cleveland Phone: (216) 791-3800 ext. 4798
Fax: (216)231-3482
e-mail: dms@po.cwru.edu

Education
1969, B.A. Biology-Chemistry (Magna cum laude), Lawrence University, Appleton, WI.
1975, Ph.D. Microbiology, Case Westem Reserve University.
1976, M.D., Case Westem Reserve University.

Research Interests
Our major interest is in the molecular mechanisms of bacterial resistance to antibiotics and the mode of transmission of resistant bacteria and bacterial genes encoding antibiotic resistance. We have two major projects in this domain. 1) We are trying to understand how staphylococci, some of which are virulent pathogens, become resistant to the remaining class of antibiotics which are still active against these organ isms, the glycopeptides, including vancomycin and teicoplanin. Towards this end, we have recently, iden tified and cloned a gene in Staphylococcus aureus which is required for the expression of this resistance. We have just succeeded in characterizing the entire peptidoglycan (cell wall) structure of two species of staphylococci expressing resistance or not. 2) We are studying structure function relationships in an en zyme which is produced by bacteria and which hydrolyzes the penicillin and cephalopsorin antibiotics rendering strains resistant. We are exploring the active site of the enzyme using site-directed mutagenesis and enzyme kinetics, followed by modeling in three dimensions. We hope this will lead to a better under standing of enzyme activity and that this will allow the synthesis of more active antibiotics. A second, but important area of interest for us is the adhesion of bacteria to biomaterials. With Drs. Marchant and Anderson, we have studied factors important for the adhesion of both staphylococci and an important pathogen in the urinary tract, Providencia stuartii, to biomaterials. We have shown that certain surface molecules thought to be important for staphylococcal adhesion are not, and we are about to attempt to identify both genetically, and biophysically, cell surface molecules which are required for adsorption of staphylococci to biomaterials. We have also created a series of mutants in Providencia using a method which will allow us to identify genes that have been altered, which have lost their adherence to biomaterials these mutants will allow us to identify surface components necessary in adhesion of these Gram negative pathogens as well.

Selected Publicaffons

1. Wingart, E., Shlaes, J.H., Mortimer, E.A., Shlaes, D.M., "Evidence for nursing hand mediated transmis sion of trimethoprim-resistant Gram negative bacilli on a nursing home," Clin. Infect. Dis., 16, 75-81 (1993).

2. Rice, L.B., Carias, L., Shlaes, D.M., "Resistance to cefoperazone-sulbactam in Klebsiella pneumoniae: Evidence for enhanced resistance resulting from the coexistence of two different resistance mecha nisms," Antimicrobial Agents and Chemother, 37, 1061-1064 (1993).

3. Chow, J.W., Kuritza, A., Shlaes, D.M., Green, M., Sahm, D.F., Zervos, M.J., "Clonal spread of vancomycin resistant Enterococcus faecium between patients in three hospitals in two states," J. Clin. Microbiol., 31, 1609-11 (1993).

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Chaim N. Sukenik
Professor Chemistry
CWRU Phone: (216) 368-2611
Fax: (216) 368-3006
e-mail: cns@po.cwru.edu

Education
1972, B.A. (Magna Cum Laude), Yeshiva University.
1976, Ph.D. Chemistry, California Institute of Technology.

Research Interests
Self-assembled and Langmuir Blodgett monolayer films. Organic reaction mechanisms in organized mediabiomimetic synthesis of mineral oxide thin films. Monolayer based immunosensors; monolayer modification of biomaterial surfaces. High performance, high temperature polymers and composites

Selected Publications

1. Zull, J.E., Reed-Mundell, J., Lee, Y.W., Vezenov, D., Ziats, N.P., Anderson, J.M., Sukenik, C.N., "Prob lems and Approaches in Covalent Attachment of Peptides and Proteins to Inorganic Surfaces for BiosensorApplications,"J. Indust. Microbiol., 13, 137-143 (1994).

2. Cheng, S.S., Chittur, K.K., Sukenik, C.N., Culp, L.A., Lewandowska, K, "The Conformation of Fibronectin on Self-Assembled Monolayers with Different Surface Composition: An FT-IR/ATR Study," J. Col loid Interface Sci., 162, 135-143 (1994).

3. Jin, Z.H., Vezenov, D.V., Lee, Y.W., Zull, J. E., Sukenik, C.N., Savinell, R.F., "Alternating Current Imped ance Characterization of the Structure of Alkylsiloxane Self-Assembled Monolayers on Silicon," Langmuir, 10, 2662-2671 (1994).

4. Culp, L.A., Sukenik, C.N., "Glass and Metal Surfaces Derivatized with Self-Assembled Monolayers: Cell Type Specific Modulation of Fibronectin Adhesion Functions," J. Tissue Culture Methods, 1995, In Press.

5. Shin, H., Collins, R.J., DeGuire, M.R., Heuer, A.H., Sukenik, C.N., "Synthesis and Characterization of TiO2 Thin Films on Organic Self-Assembled Monolayers: I. Film Formation from Aqueous Solu tions,"J. Mat. Res., 10, 692-698 (1995).

6. Shin, H., Collins, R.J., DeGuire, M.R., Heuer, A.H., Sukenik, C.N., "Synthesis and Characterization of TiO2 Thin Films on Organic Self-Assembled Monolayers: II. Film Formation via an Organometallic Route,"J. Mat. Res., 10, 699-703 (1995).

7. Deng, K., Collins, R.J., Mehregany, M., Sukenik, C.N., "Performance Impact of Monolayer Coating of Polysilicon Micromotors,"J. Electrochem. Soc., 142, 1278-1285 (1995).

8. Cheng, S.S., Scherson, D.A., Sukenik, C.N., "In Situ FTIR-ATR Spectroscopy of Carboxylate-Bearing, Siloxane-Anchored, Self-Assembled Monolayers: A Study of Carboxylate Reactivity and Acid-Base Properties,"Langmuir, 11, 1190-1195 (1995).

9. Collins, R.J., Sukenik, C.N., "Sulfonate-Functionalized, Siloxane-Anchored, Self-Assembled Monolay ers," Langmuir, 11 (1995).

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David L. Wilson
Assistant Professor Biomedical Engineering
CWRU Phone: (216) 368-4099
Fax: (216)368-4969
e-mail: dlw@po.cwru.edu

Education
1975, B.S. Physics, Rice University, Houston, TX.
1977, M.S. Bioengineering, West Virginia Univ., Morgantown, WV.
1985, Ph.D. Electrical Engineering, Penn State University, University Park, PA.

Research Interests
Over the years, my research has spanned biomedical imaging, biophysical modeling and analysis of ionic channels, and molecular imaging. I have applied three-dimensional (3D) image processing and analysis to a variety of biomedical problems including 3D intravascular ultrasound and most recently, biomechanical imaging of the wrist. Many methods such as deformable model and morphological seg mentation techniques apply equally well to cellular imaging. Recently, I invented a morphological restoration method for improving the resolution of atomic force microscopy (AFM) irnages. This new non linear technique is being applied to measurements of fibrinogen and von Willebrand's Factor molecules.

Selected Publications

1. Dalal, P., Kump, K., Eppell, S., Wilson, D.L., "Morphological modeling of AFM imaging with application to fibrinogen," submitted September 1995.

2. Aufrichtig, R., Wilson, D.L., "X-ray fluoroscopy spatiotemporal filtering with object detection," IEEE Trans. Med. Imaging., In press.

3. Wilson, D.L., Kump, K.S., Eppell, S.J., Marchant, R.E., "Morphological restoration of AFM images," Langmuir, 11, 265-272 (1995).

4. Dhawale, P., Wilson, D.L., Hodgson, J.M., "Volumetric intracoronary ultrasound: methods and valida tion," Catheterizahon and Cardiovascular Diagnosis, 33, 296-307 (1994).

5. Dhawale, P., Wilson, D.L., Hodgson, J.M., "Optimal data acquisition for volumetric intracoronary ultra sound," Catheterization and Cardiovascular Diagnosis, 32, 288-299 (1994).

6. Aufrichtig, R., Thomas, C., Xue, P., Wilson, D.L., "A model for perception of pulsed fluoroscopy image sequences," J. Opt. Soc. Am. A, 11, 3167-3176 (1994).

7. Wilson, D.L., Xue, P., Aufrichtig, R., "Perception of fluoroscopy last-image-hold," Med. Phys., 21, 1875 1883 (1994).

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Nicholas P. Ziats, Ph.D.
Assistant Professor Pathology and Biomedical Engineering
CWRU Phone: (216) 368-5176
Fax: (216) 844-8004
e-mail: npz@po.cwru.edu

Education
1976, B.S. Zoology and Microbiology, Ohio University, Athens, Ohio.
1987, Ph.D. Pathology, Case Western Reserve University.

Research Interests
The overall goal of our research is to study the pathobiology of vascular graft failure in humans. We are detemining whether human endothelial cells adhere to and grow on reference or candidate synthetic materials to be used as vascular prostheses. We are particularly interested in mechanisms of incomplete endothelialization of these vascular grafts. Our studies suggest that components of the extracellular matrix (collagens, proteoglycans, coagulation proteins) may directly influence endothelialization on materials. Retrieved human vascular prostheses are also being evaluated for the presence of adhesion proteins, cytokines and growth factors. These studies involve the identification of proteins on material surfaces by immunogold labeling with scanning microscopy and tissue analysis using in situ hybridization for mRNA and immunohistology for protein localization. We are also interested in new materials that promote endothelialization and have evaluated a variety of novel poly(ether urethane ureas) for attachment and growth of endothelial cells, We are attempting to evaluate these materials under known mechanical stress and strain. The role of mechanical stress and strain on cells are being evaluated using a rotating disk system and a FlexerCell~9 strain apparatus. We are particularly interested in the role of stress/strain on cell cell and cell-material interactions. Confocal laser scanning microscopy has also been used to identify the expression of cell adhesion proteins and cytoskeletal organizations of cells cultured under strained or nonstrained conditions. Overall, these combined studies are aimed at determining the mechanism(s) of human vascular graft failure, cell-material interactions and the potential role of extracellular matrix and other proteins in the pathogenesis of vascular diseases.

Selected Publications

1. Ziats, N.P., Anderson, J.M.,"Human vascular endothelial cell attachment and growth inhibition by type V collagen," J. Vasc. Surg., 17, 710-718, 1993.

2. Brunstedt, M.R., Ziats, N.P., Schubert, M., Stack, S., Rose-Caprara, V., Hiltner, P.A,Anderson, J.M.,"Protein adsorption and endothelial cell attachment and proliferation on PAPI-based additive modified poly(ether urethane ureas),"J. Biomed. Mater. Res., 27, 499-510, 1993.

3. Ziats, N.P., Anderson, J.M.,"Endothelial cell culture: evaluation of biomaterials," STP Pharma Sci., 3, 23 30, 1993.

4. Ziats, N.P, andAnderson, J.M.,"Type V collagen and high molecular weight kininogen inhibition of endot helial cell adhesion and growth," J Vasc. Surg., 20, 132-134, 1994.

5. Brunstedt, M.R., Rubin, K.R., Kieswetter, K.M., Sapatnekar, S., Ziats, N.P., Merritt, K., Anderson, I J.M.,"Bacteria/blood/material interactions. 1. Injected and preseeded slime forming Staphylococcus epidermidis in flowing blood with biomaterials,"J. Biomed. Mater. Res., 29, 455-466, 1995.

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