Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2000-05-31
2003-01-14
Weber, Jon P. (Department: 1651)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C514S002600, C623S001490
Reexamination Certificate
active
06506398
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to improved medical device and methods for using same. More particularly, the present invention relates to a vascular graft implant comprising vascular endothelial growth factor (VEGF) and/or platelet derived growth factor (PDGF) for enhanced site-specific angiogenesis and methods thereof.
BACKGROUND OF THE INVENTION
The basic function of an arterial blood vessel is for transportation of blood from the heart to organs and tissues of the body. When a blood vessel is diseased or becomes dysfunctional, a vascular graft is usually employed for implantation to replace or assist the diseased or dysfunctional blood vessel. The vascular grafts include autologous blood vessel, homograft, cryo-preserved blood vessel, grafts made of synthetic material such as expanded polytetrafluoroethylene (e-PTFE) or polyester (trade name Dacron), and grafts made of biological material, such as bovine internal mammal artery, human umbilical vein, or pericardium.
A special sub-group that has dysfunctional blood vessels belongs to diabetic patients. Diabetes mellitus is characterized by a broad array of physiologic and anatomic abnormalities, for example, altered glucose disposition, hypertension, retinopathy, abnormal platelet activity, aberrations involving medium and small sized vessels, and other problems. Diabetics may depend on insulin for the prevention of ketoacidosis. Developed atrophic ulcer and infected alterations of the foot as a result of complications of diabetes mellitus may require foot amputation. The current treatment may include drug therapy, for example, U.S. Pat. No. 5,871,769 to Fleming et al. discloses methods for the prevention and/or treatment of diabetes mellitus using magnesium gluconate. However, a biocompatible vascular graft may be implanted to enhance blood circulation and eventually extremity salvage. A vascular graft having enhanced angiogenesis capability or having angiogenesis factors may promote peripheral revascularization or neovascularization for blood perfusion so as to save the diseased foot from amputation. The process of angiogenesis (new capillary formation) is stimulated by angiogenesis factors.
The vascular graft or prosthesis made of synthetic materials is usually porous, compliant, strong, and biocompatible. The micropores of a synthetic prosthesis are believed to facilitate tissue/cells ingrowth from the host so as to accelerate the healing process. It is also suggested that the host cells tend to encapsulate a foreign substrate if the host tissue does not achieve cell infiltration into the substrate. In clinical practices, partially clotted blood, collagen, gelatin or other gelatinous material may be coated upon/into the micropores so that blood leakage during the initial phase of implantation is minimized. U.S. Pat. No. 5,851,230 discloses a vascular graft with a collagen sealant, and the patent is incorporated herein by reference.
The vascular prosthesis made of biological material contains collagen as its major component. A biological prosthesis is usually crosslinked to reduce the antigenicity, enhance its antithrombogenicity, and/or improve the durability. Typical crosslinking agents include glutaraldehyde, formalin, dialdehyde starch, polyepoxy compounds or the like. U.S. Pat. No. 4,082,507 discloses a treatment method with glutaraldehyde, dialdehyde starch and formalin. U.S. Pat. No. 4,806,595 discloses a treatment method with polyepoxy compounds and/or heparin. The implantation with a polyepoxy compounds treated graft usually exhibit much tissue regeneration and capillary proliferation, and may account for some degree of angiogenesis. Both patents are incorporated herein by reference.
When a vascular graft is placed in a human body, the inner walls of the graft may become lined with endothelial cells, which possess antithrombotic properties for preventing blood clotting and deposition of blood thrombus on the inner walls. In actual clinical situations, however, lining by the endothelial cells is usually extremely delayed, and in most cases, only the area of the anastomosis of the vascular graft becomes covered with endothelial cells while remote locations away from the anastomoses are not covered. Accordingly, thrombus continues to deposit on the inner walls where endothelialization is void. Though endothelial seeding or sodding method has been recently developed to assist the endothelialization process, the seeded/sodded cells may separate from the inner wall of a vascular graft and be washed away by the blood stream. For example, U.S. Pat. No. 4,820,626 discloses a method of treating a synthetic or naturally occurring surface with microvascular endothelial cells. One of the major drawbacks is the extra step of collecting autologous endothelial cells, enzymatic digestion by collagenase, centrifugal filtration, and seeding prior to implantation of the graft.
Furthermore, U.S. Pat. No. 5,785,965 discloses a process for sodding modified cells onto a vascular prosthesis for implantation, wherein endothelial cells derived from subcutaneous adipose tissue are genetically modified to express the endothelial cell specific angiogenic factor VEGF. The method accelerates endothelialization on the luminal surface of the vessel. However, during the early stage of transplantation, the sodded cells may separate from the inner wall of a vascular graft and be washed away by the blood stream. It was reported that when endothelial seeding is applied to grafts installed in the canine infrarenal aorta, surface thromboresistance improves significantly over controls only after the seeded grafts have healed for approximately 4 weeks. In the above discussed endothelialization processes, only autologous endothelial cells may be used because of concerns on immunological response. In almost any cell transplantation procedure, immunological response is always a concern.
Noishiki et al. in U.S. Pat. No. 5,387,236 discloses a vascular prosthesis by depositing fragments of biological tissues such as vascular tissues, connective tissues, fat tissues and muscular tissues; and cells such as vascular endothelial cells, smooth muscle cells and fibroblast cells within the wall of a vascular prosthesis. Though the patent discloses a method for effectively depositing cells/tissues into the interstices of a vascular prosthesis, Noishiki et al. does not disclose a method of incorporating vascular endothelial growth factor or platelet derived growth factor to promote angiogenesis and to facilitate in situ proliferation of endothelial cells and/or neovascularization inside the walls of an implanted vascular prosthesis.
The angiogenesis process is believed to begin with the degradation of the basement members by proteases secreted from endothelial cells activated by mitogens such as vascular endothelial growth factor and basic fibroblast growth factor (bFGF). The cells migrate and proliferate, leading to the formation of solid endothelial cell sprouts into the stromal space, then, vascular loops are formed and capillary tubes develop with formation of tight junctions and deposition of new basement membrane. Recent studies have applied vascular endothelial growth factor to expedite and/or augment collateral artery development in animal models of myocardial and hindlimb ischemia. The relationship between growth factors, stem cells and cell progenitors has been documented (Burgess, A and Nicola N.,
Growth Factors and Stem Cells
, Chapter 1, published by Academic Press 1983).
Vascular endothelial growth factor (VEGF) is mitogenic for vascular endothelial cells and consequently is useful in promoting neovascularization (angiogenesis) and reendothelialization. Angiogenesis means the growth of new capillary blood vessels. Angiogenesis is a multi-step process involving capillary endothelial cell proliferation, migration and tissue penetration. VEGF is a growth factor having a cell-specific mitogenic activity. It would be desirable to employ a wound healing substrate incorporating a mitogenic factor having mitogenic activity that is
Quijano Rodolfo C.
Tu Hosheng
LandOfFree
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