Prosthesis (i.e. – artificial body members) – parts thereof – or ai – Arterial prosthesis – Having plural layers
Reexamination Certificate
2001-02-28
2004-06-01
McDermott, Corrine (Department: 3738)
Prosthesis (i.e., artificial body members), parts thereof, or ai
Arterial prosthesis
Having plural layers
C623S001420, C623S001520
Reexamination Certificate
active
06743253
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to biocompatible devices and the methods and materials used to make them. More particularly, the invention relates to synthetic vascular grafts.
Synthetic vascular prostheses have been widely used in clinical medicine as replacements and bypasses for large, medium, and small vessels in human patients. These prostheses are often used when the patient lacks adequate autogenous replacement tissue due to prior chemotherapy, previous harvesting, phlebitis, or other vascular pathologies.
Vascular grafts of medium (6-8 mm) and small (<5 mm) internal diameter are primarily utilized in peripheral regions of the body and appendages. Despite recent advancements in the materials used to make vascular grafts, medium and small diameter grafts continue to have unacceptably high failure rates when used in the clinical setting. The major complications associated with these grafts include: (1) structural and mechanical degradation (Hanson, S. R. In
Cardiovasc. Pathology
157S-165S, Harker, L. A., et al. ed., Elsevier Science Publishing Co. Inc., New York, N.Y. (1993)), (2) acute thrombosis and thromboembolic phenomenon (Fyfe, B., et al.
Cardiovasc. Path
. 2:187 (1993)), and (3) incomplete, unregulated, or inappropriate cellular healing (Kaboda, K., et al.
J. Thorac. Cardiovasc. Surg
. 103:1059 (1992)). Failure of prosthetic arterial grafts can be grouped into three categories: acute, delayed, and late. An acute failure (occurring within hours or days after implantation) is generally the result of reduced blood flow through the luminal surface of the graft, resulting in increased activation of the coagulation cascade with subsequent thrombosis or thromboembolic phenomenon occurring (Hanson, S. R. In
Cardiovasc. Pathology
157S-165S, Harker, L. A., et al. ed., Elsevier Science Publishing Co. Inc., New York, N.Y. (1993)). A delayed failure (occurring within weeks or months after implantation) is generally caused by an incomplete endothelial cell lining of the graft surface, resulting in uncontrolled vascular smooth muscle cell proliferation (LoGerfo, F. W., et al.
Ann. Surg
. 197:479 1983). Late graft failure (occurring within years after implantation) is infrequent and most often due to progression of atherosclerosis in the inflow or outflow vessels.
Expanded polytetrafluoroethylene (ePTFE) is currently one of the most widely used materials for vascular grafts. See, e.g., U.S. Pat. Nos. 4,187,390 and 3,953,566. However, the chemical structure of ePTFE is extremely rigid, thereby creating a mechanical mismatch at the interface between the native artery and the graft. Additionally, surface modification of ePTFE grafts is generally not possible due to the inertness of the polymer.
Polyethylene terephthalate (polyester or Dacron™) vascular grafts, which have better mechanical (i.e. stretching) and handling (i.e. suturing) properties than ePTFE grafts, have had limited use. These grafts have a porous graft matrix that is typically sealed with proteins purified from another species, e.g. porcine, bovine, etc., that are randomly cross-linked by fixative agents such as glutaraldehyde and formaldehyde. These protein-coated surfaces help to “mask” the graft from immune response. However, they have numerous adverse effects in vivo, including platelet adhesion and activation with the release of growth factors and pro-thrombotic molecules, and are rapidly desorbed, potentially re-exposing the biomaterial surface.
Due to the problems associated with conventional synthetic vascular grafts, they are generally unsuitable for smaller diameter vascular reconstructions. Thus, there remains a need to develop biocompatible synthetic vascular prostheses that have physical and chemical properties that more closely approximate those of autogenous blood vessels. In particular, there is a need to develop vascular grafts suitable for use in medium and small diameter arterial reconstructions.
SUMMARY OF THE INVENTION
The present invention features a polyether or polyether/carbonate based urethane polymer that contains functional groups (e.g. carboxylic acid groups) which are capable of serving as anchor sites for protein binding. The polymer is prepared using a process that includes the following two steps: (1) forming a diisocyanate terminated prepolymer, based on a polyether or polyether/carbonate glycol that has a molecular weight between 200-3,000 Da (preferably about 1000 Da), and a diisocyanate having the general structure OCN—R′—NCO, wherein R′ is a hydrocarbon that may include aromatic or non-aromatic structures; and (2) chain extension using a dihydroxy carboxylic acid, for example, 2,2-bis(hydroxymethyl)-propionic acid (DHMPA).
The invention also features a biocompatible device that has been sealed with the polyether or polyether/carbonate based urethane polymer. The biocompatible device can be, for example, a polyethylene terephthalate (polyester or Dacron™) vascular graft or other polymeric base material. The surface properties of the graft can be modified with biologically active proteins in order to emulate certain natural properties of native vessels, thereby improving graft patency and healing. For instance, antithrombin (recombinant hirudin) or other anti-clotting agents, thrombolytic agents (e.g. streptokinase, urokinase, tPA, pro-urokinase, etc.), and mitogenic agents (e.g. vascular endothelial growth factor) or other growth promoting substances, or inhibitors (e.g. &ggr;-interferon) can be linked to the surface of the graft.
In another aspect, the invention provides a technique for sealing a vascular graft, such as a polyethylene terephthalate vascular graft, with polyurethane using an inward/luminal perfusion system. The perfusion system includes a flow chamber which has inflow and outflow fixtures and a hollow inner mandrel. The system also includes a Y-fitting that is connected to the flow chamber and a peristaltic pump via hollow plastic tubing. The Y-fitting is also connected to a container holding a polyurethane sealant solution.
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Kadoba, K. et al., “Experimental Comparison of Albumin-sealed and Gelatin-sealed Knitted Dacron Conduits, Porosity Control, Handling, Sealant Resorption, and Healing,”J. Thorac. Cardiovasc. Surg.103:1059-1067 (1992).
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Dempsey Donald J.
Logerfo Frank W.
Phaneuf Matthew D.
Quist William C.
BioMod Surfaces
Clark Paul T.
Clark & Elbing LLP
Matthews William H
McDermott Corrine
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