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Title:  Device for treating diabetes and methods thereof

United States Patent:  6,506,398

Issued:  January 14, 2003

Inventors:  Tu; Hosheng (2151 Palermo, Tustin, CA 92782); Quijano; Rodolfo C. (27451 Lost Trail La., Laguna Hills, CA 92653)

Appl. No.:  583296

Filed:  May 31, 2000

Abstract

A vascular graft comprising Vascular Endothelial Growth Factor (VEGF) and/or Platelet Derived Growth Factor (PDGF) for enhanced site-specific angiogenesis and methods thereof are disclosed. At least one VEGF, PDGF or angiogenesis factor is incorporated into the vascular graft to facilitate enhanced angiogenesis so as the cells are stimulated to migrate to environments having higher concentration of growth factors and start mitosis.

SUMMARY OF THE INVENTION

In general, it is an object of the present invention to provide a method for preparing a vascular graft having site-specific angiogenesis factor, preferably by incorporating vascular endothelial growth factor and/or platelet derived growth factor onto the vascular graft. The vascular graft of the present invention may be used to bypass or repair a part of the diseased/dysfunctional blood vessel. It is a further object of the present invention to provide a vascular graft having site-specific angiogenesis factors comprising incorporating at least one vascular endothelial growth factor, or at least one platelet derived growth factor, or other angiogenesis factor, and combination thereof onto the medical device.

In one preferred embodiment, the vascular graft having site-specific angiogenesis factor comprises at least one vascular endothelial growth factor. Vascular endothelial growth factor, which is also known as vascular permeability factor, is a secreted angiogenic mitogen whose target cell specificity appears to be restricted to vascular endothelial cells. The "angiogenesis factor" of the present invention refers to any compound, substrate, material, specie, factor, or element that stimulates or promotes angiogenesis activity. The angiogenesis factor may comprise one of the following: vascular endothelial growth factor, platelet derived growth factor, tissue treatment factor, and the like. The "vascular endothelial growth factor" in this invention refers broadly to any and all the members of the vascular endothelial growth factor family, which may comprise polynucleotides, polypeptides encoded by such polynucleotides that facilitate angiogenesis, and the like. U.S. Pat. No. 6,040,157 discloses general characteristics and specific properties of vascular endothelial growth factor and is incorporated herein by reference. VEGF has four different forms of 121, 165, 189 and 206 amino acids due to alternative splicing, which are designated as VEGF121, VEGF165, VEGF189, and VEGF206, respectively.

VEGF121 and VEGF165 are soluble that can be incorporated onto the vascular graft of the present invention. In one embodiment, VEGF121 and/or VEGF165 are mixed with a substrate, such as collagen, heparinized collagen, crosslinked collagen, crosslinked heparinized collagen, blood clot, drug, or the like, prior to be incorporated onto the vascular graft. In another embodiment, the method for incorporating the vascular endothelial growth factor comprises a step of impregnating the growth factor onto the vascular graft. In a further preferred embodiment, the step further comprises applying pressure to force impregnating the vascular endothelial growth factor into the vascular graft, preferably from the inner side or the blood-contacting side of the vascular graft.

VEGF189 and VEGF206 are bound to heparin containing proteoglycans in the cell surface. Therefore, a heparinized medical material, such as the one disclosed by Noishiki et al. (U.S. Pat. Nos. 4,806,595 and 5,387,236), has the capability of incorporating the desired vascular endothelial growth factor by binding VEGF189 and/or VEGF206 for site-specific angiogenesis. Both patents are included herein by reference. The vascular endothelial growth factor of the present invention may be selected from the group consisting of VEGF, VEGF 2, bFGF, VEGF121, VEGF165, VEGF189, and VEGF206.

The "platelet derived growth factor" in this invention may cover broadly PDAF (platelet derived angiogenesis factor), PDGF (platelet derived growth factor), TGF-B (transforming growth factor beta), PDEGF (platelet derived epidermal growth factor), PDWHF (platelet derived wound healing formula), and the like. The platelet derived growth factor of the present invention may also comprise any substrate that contains at least one of the above-referred PDAF, PDGF, TGF-B, PDEGF or PDWHF that possess angiogenesis activity, wherein said substrate may comprise blood clot or blood components. U.S. Pat. No. 5,599,558 to Gordinier et al. discloses general properties and constituents of platelet derived growth factor, and the patent is incorporated herein by reference.

The "tissue treatment factor" in this invention may refer to any chemical, substrate, material, and solution that may treat a tissue to render the tissue more angiogenic or have more angiogenesis propensity. A tissue treated by a polyepoxy compound or combinations of polyepoxy compounds, as disclosed in U.S. Pat. No. 4,806,595 has angiogenesibility. A vascular graft incorporating tissue treatment factor would render the medical device with enhanced angiogenesis. The entire content of the patent is incorporated herein by reference.

In accordance with the preferred embodiment of the present invention, the vascular graft may be selected from the group consisting of autologous graft, homograft, biological graft, synthetic graft, composite graft or the like. Furthermore, the biological graft or conduit is selected from the group consisting of internal mammary artery, umbilical vein, urethra, pericardium, jagular vein, genetically altered blood vessel, and combinations thereof. The vascular graft may be either heparinized or crosslinked, wherein an agent for crosslinking the vascular graft may be selected from the group consisting of glutaraldehyde, formalin, dialdehyde starch, polyepoxy compounds, and the like. The vascular graft of the present invention comprises site-specific angiogenesis factor adapted for enhancing angiogenesis.

In a still preferred embodiment, a method for treating diabetic foot of a patient comprising implanting a vascular graft for enhancing blood perfusion, wherein said vascular graft comprises site-specific angiogenesis factor. The angiogenesis factor may be selected from the group consisting of VEGF, VEGF 2, bFGF, VEGF121, VEGF165, VEGF189, VEGF206, PDGF, PDAF, TGF-B, PDEGF, PDWHF, polyepoxy compounds, and combination thereof

Furthermore, a process for implanting a vascular graft having site-specific angiogenesis factor comprises (a) preparing an implantation site; (b) positioning the vascular graft at the implantation site; and (c) implanting the vascular graft. After the graft is in place, the endothelial cells and cells progenitors deposit site-specifically on the device for expedited angiogenesis and mitosis. The vascular graft for the implantation process may comprise at least one vascular endothelial growth factor or platelet derived growth factor, wherein the vascular graft may be selected from the group consisting of autologous graft, homograft, biological graft, synthetic graft, and composite graft.

Claim 1 of 6 Claims

What is claimed is:

1. A composite vascular graft having a site-specific angiogenesis factor for enhanced angiogenesis comprising:

a vascular graft; and

a tubular conduit wrapped onto said vascular graft, wherein said tubular conduit is incorporated with an angiogenesis factor.
 


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