Methods for implanting cells

Prosthesis (i.e. – artificial body members) – parts thereof – or ai – Arterial prosthesis – Having pores

Reexamination Certificate

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C623S001400, C623S001410, C600S036000, C424S422000

Reexamination Certificate

active

06352555

ABSTRACT:

BACKGROUND OF THE INVENTION
The invention relates to methods for implanting cells onto prosthetic materials, as well as methods for generating such implantable cells.
Despite prevention efforts, atherosclerotic disease remains a major cause of morbidity and mortality. Treatments for atherosclerotic disease range from medical management to interventional therapies, such as angioplasty, atherectomy, and bypass grafting. Bypass grafting with synthetic grafts has received much attention and has been used to treat many patients. Unfortunately, small caliber vascular grafts (i.e., grafts with inner diameters of less than 6 mm) generally have high failure rates, due largely to the thrombogenicity of the grafts. Thrombus deposits can form on the inner walls of the grafts, resulting in occlusions. In addition, intimal hyperplasia can occur, further contributing to the failure of small caliber grafts.
Several strategies for improving the success rates of these grafts have been developed. One such strategy is to increase the rate at which the graft becomes endothelialized, as endothelial cells have natural anti-thrombogenic properties that contribute to long-term graft patency. Moreover, it is believed that the presence of endothelial cells inhibits the development of neointimal hyperplasia at anastomotic regions. Endothelialization, which involves the migration of endothelial cells from adjacent tissue onto the luminal surface, can occur spontaneously when a graft is placed in a recipient. Unfortunately, endothelialization occurs to only a limited degree when prosthetic grafts are placed in human recipients, and the limited endothelialization that does occur takes place slowly.
To promote the rapid formation of an endothelial lining, endothelial cells can be seeded or sodded onto a graft before the graft is placed in the recipient. When the graft is placed in the recipient and exposed to physiologic blood flow, however, these cells are often washed away.
SUMMARY OF THE INVENTION
In general, the invention features a method for implanting cells onto a prosthesis; the method includes the steps of: (a) providing a prosthesis including a porous tube, where at least 25% of the pores on the inner surface of the tube have diameters of more than about 40 &mgr;m, at least 25% of the pores on the outer surface of the tube have diameters of less than about 30 &mgr;m, and the tube includes a substantially continuous layer of a biocompatible material; (b) contacting the prosthesis with a suspension of cells; and (c) providing a pressure differential between the inner surface and the outer surface, whereby the cells are retained in the pores of the inner surface. An example of a prosthesis that can be used is a vascular graft. The invention also features a sodded prosthesis formed by this method.
Preferably, at least 50% of the pores on the inner surface of the tube have diameters of more than about 40 &mgr;m, and at least 50% of the pores on the outer surface of the tube have diameters of less than about 30 &mgr;m. More preferably, at least 70%, or at least 90%, of the pores on the inner surface of the tube have diameters of more than about 40 &mgr;m, and at least 70%, or at least 90%, of the pores on the outer surface of the tube have diameters of less than about 30 &mgr;m.
In other preferred methods, at least 25% of the pores on the inner surface have diameters of more than about 50 &mgr;m, and more preferably have diameters of about 60 &mgr;m; in addition, at least 25% of the pores on the outer surface have diameters of less than about 20 &mgr;m, and more preferably have diameters of less than about 15 &mgr;m. More preferably, at least 50%, 70%, or 90% of the pores on the inner surface have diameters of more than about 50 &mgr;m, and more preferably have diameters of about 60 &mgr;m; in addition, at least 50%, 70%, or 90% of the pores on the outer surface have diameters of less than about 20 &mgr;m, and more preferably have diameters of less than about 15 &mgr;m.
Preferably, the pores on the inner surface and the pores on the outer surface are connected by gradually tapered openings.
In a related aspect, the invention features a method for implanting cells onto a prosthesis; the method includes the steps of: (a) providing a prosthesis including a porous tube, where the diameters of at least 25% of the pores on the inner surface of the tube are larger than the diameter of a human cell, such that human cells fit within the pores, the diameters of at least 25% of the pores on the outer surface of the tube are smaller than the diameter of a human cell, such that cells do not pass through the pores, and the tube includes a substantially continuous layer of a biocompatible material; (b) contacting the prosthesis with a suspension of cells; and (c) providing a pressure differential between the inner surface and the outer surface, whereby the cells are retained in the pores of the inner surface.
Preferably, the pores on the inner surface and the pores on the outer surface are connected by gradually tapered openings. In addition, the diameters of at least 50%, 70%, or 90% of the pores on the inner surface of the tube are preferably larger than the diameter of a human cell, and the diameters of at least 50%, 70%, or 90% of the pores on the outer surface of the tube are preferably smaller than the diameter of a human cell. The invention also features a sodded prosthesis formed by this method.
In another related aspect, the invention features a sodded vascular graft including a porous tube, where at least 25% of the pores on the inner surface of the tube have diameters of more than about 40 &mgr;m, at least 25% of the pores on the outer surface of the tube have diameters of less than about 30 &mgr;m, and the tube includes a substantially continuous layer of a biocompatible material; the graft has cells embedded in the pores of the inner surface. Preferably, the pores on the inner surface and the pores on the outer surface are connected by gradually tapered openings. In preferred grafts, at least 50%, 70%, or 90% of the pores on the inner surface of the tube have diameters of more than about 40 &mgr;m, and at least 50%, 70%, or 90% of the pores on the outer surface of the tube have diameters of less than about 30 &mgr;m.
In yet another related aspect, the invention features a sodded vascular graft including a porous tube, where the diameters of at least 25% of the pores on the inner surface of the tube are larger than the diameter of a human cell, the diameters of at least 25% of the pores on the outer surface of the tube are smaller than the diameter of a human cell, such that cells do not pass through the pores, and the tube includes a substantially continuous layer of a biocompatible material; the graft has cells embedded in the pores of the inner surface. Preferably, the pores on the inner surface and the pores on the outer surface are connected by gradually tapered openings. In preferred grafts, the diameters of at least 50%, 70%, or 90% of the pores on the inner surface of the tube are larger than the diameter of a human cell, and the diameters of at least 50%, 70%, or 90% of the pores on the outer surface of the tube are smaller than the diameter of a human cell.
In a final aspect, the invention features a method for obtaining an endothelial cell culture from a blood sample, the method involving: (a) obtaining a sample of mononuclear cells from a blood sample; and (b) culturing the sample of mononuclear cells, without further cell separation, on a cell adhesive polymer-coated solid support in the presence of endothelial growth factors.
In preferred embodiments, the blood sample is from a mammal (for example, a human) and the product of step (b) is an autologous endothelial cell sample; the blood sample is a peripheral blood sample; the mononuclear cells are obtained from the blood sample by centrifugation; the cell adhesive polymer is fibronectin; the solid support is a tissue culture plate; the endothelial growth factors include VEGF, bFGF, IGF, or any combination thereof; and the endothelial cell cul

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