Phase II year
2011
(last award dollars: 2012)
Over 60,000 prosthetic grafts, which are primarily comprised of polyethylene terephthalate (polyester) or expanded polytetrafluoroethylene (ePTFE), are implanted in the United States each year. Unfortunately, these grafts continue to have high failure rates due to secondary complications associated with acute thromboses and incomplete, unregulated cellular proliferation. These complications are only more profound and severe as the diameter of the prosthetic vascular graft decreases (6-8mm internal diameter or ID). To date, there are no small vascular grafts (<5mm ID) that are FDA-approved for clinical use in the United States. Our hypothesis is covalent immobilization of APC onto the functionalized polyester vascular graft surface will prevent surface thrombus formation via renewably inactivating FVa and FVIIIa upon graft implantation. Additionally, surface bound APC would promote adherence of mature and progenitor endothelial cells circulating in the blood to the polyester graft surface through a highly specific, high affinity ligand-receptor binding reaction and signal graft-adherent cells or cells from adjacent endothelium to proliferate and migrate on the surface, thus having a direct effect in controlling cellular proliferation in the adjacent tissue. In surface I, Phase functional groups were created within an existing small-diameter woven polyester graft matrix, (BioFunc) graft functionalized the of properties chemical and physical with characterized. Additionally, the natural anticoagulant Activated Protein C (APC) was covalently immobilized to these surface functional groups, with APC binding optimized (BioFunc-APC significant maintained APC immobilized Surface material). Graft antithrombotic properties as well as promoted increased endothelial cell adhesion to this bioactive graft surface. Lastly, APC was stable on the graft surface over an extended period of time under simulated arterial flow conditions. The goal of this Phase II STTR grant healing and antithrombotic for vivo in graft BioFunc-APC the assess to is characteristics using an arterial grafting model. canine The specific objectives of this Phase II study are to: 1) create functional groups on small diameter (4mm ID) tight woven 2) characterize graft), technology (BioFunc proprietary grafts using polyester physical/chemical properties of BioFunc graft, 3) immobilize APC onto BioFunc graft surface (BioFunc-APC graft), 4) evaluate surface antithrombotic and cell adhesion properties of BioFunc-APC graft, 5) assess in vivo acute and chronic implantation periods using a canine arterial grafting model, and 6) examine macroscopically/microscopically explanted BioFunc-APC grafts. Development of a bioactive polyester vascular graft that would provide localized surface antithrombin properties and stimulate endothelial cell-specific attachment/proliferation would have a significant impact on arterial repair and replacement. These grafts could be utilized in peripheral bypass (specifically below-knee reconstruction) as well as for coronary artery bypass. Thus, the potential annual market value for an "off-the-shelf" bioactive synthetic arterial bypass graft that would be available for medium and small vessel reconstruction could exceed $1.5 billion.
Public Health Relevance: Over 60,000 prosthetic grafts, which are primarily comprised of polyethylene terephthalate (polyester) or expanded polytetrafluoroethylene (ePTFE), are implanted in the United States each year. Unfortunately, these prosthetic arterial grafts continue to have high failure rates due to secondary complications associated with acute thromboses and incomplete, unregulated cellular proliferation. These complications are only more profound and severe as the diameter of the prosthetic vascular graft decreases. To date, there are no small vascular grafts (<5mm I.D.) that are FDA-approved for clinical use in the United States. Development of a novel artificial artery with a surface designed to prevent these types of failures from occurring would have application for complex devices such as artificial arteries, total implantable heart and left ventricular assist devices as well as simple devices such as catheter cuffs. Thus, the potential annual market value for an "off-the-shelf" bioactive synthetic arterial bypass graft that would be available for medium and small vessel reconstruction could exceed $1.5 billion.
Thesaurus Terms: Acute;Adherence;Adherence (Attribute);Affinity;Anticoagulant Agents;Anticoagulant Drugs;Anticoagulants;Antithrombins;Aortocoronary Bypass;Arteries;Assay;Binding;Binding (Molecular Function);Bioassay;Biocompatible;Biologic Assays;Biological Assay;Blood;Body Tissues;Bypass;Caliber;Canine Species;Canis Familiaris;Carotid Arteries;Catheters;Cell Adhesion;Cell Communication And Signaling;Cell Growth In Number;Cell Multiplication;Cell Proliferation;Cell Signaling;Cells;Cellular Adhesion;Cellular Proliferation;Characteristics;Chronic;Clinical;Complex;Coronary Artery Bypass;Coronary Artery Bypass Grafting;Coronary Artery Bypass Surgery;Development;Devices;Diameter;Dogs;Endothelial Cells;Endothelium;Ethene, Tetrafluoro-, Homopolymer;Fda Approved;Fep;Flr;Failure (Biologic Function);Generalized Growth;Goals;Graft Material;Grant;Growth;Healed;Heart;Histologic;Histologically;Immobilization;Implant;Intracellular Communication And Signaling;Knee;Left;Ligands;Mammals, Dogs;Marketing;Modeling;Molecular Interaction;Ptfe;Peripheral;Phase;Polyesters;Polyethylene Terephthalates;Polytef;Polytetrafluoroethylene;Principal Investigator;Proliferating;Property;Property, Loinc Axis 2;Prosthesis;Prosthetic Device;Prosthetics;Protein C (Activated);Proteins;Reaction;Research;Reticuloendothelial System, Blood;Role;Sttr;Secondary To;Signal Transduction;Signal Transduction Systems;Signaling;Simulate;Small Business Technology Transfer Research;Structure;Surface;Surface Properties;Tfe;Technology;Thrombase;Thrombin;Thrombosis;Thrombus;Time;Tissue Growth;Tissues;Transplanted Tissue;United States;Vascular Graft;Artery;Autoprothrombin Iia;Biological Signal Transduction;Blood Thinner;Canine;Carotid Artery;Chemical Property;Coronary Bypass;Design;Designing;Domestic Dog;Economic Impact;Failure;Fibrinogenase;Functional Group;Gene Product;Healing;Immobilization Of Body Part;Implantation;In Vivo;Model;Novel;Ontogeny;Orthopedic Freezing;Phase 2 Study;Physical Property;Prevent;Preventing;Progenitor;Receptor Binding;Reconstruction;Repair;Repaired;Social Role;Surface Property;Thrombopoiesis Inhibitor;Ventricular Assist Device
