Patent US6328762B1 successfully refreshed from Google Patents.
US6328762B1
Expired / Lapsed
US
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Prosthetic grafts
Assignee: Zimmer Orthobiologics Inc
•
Filing: 1999-04-27
•
Granted: 2001-12-11
•
Expires: 2019-04-27
Abstract
Abstract An improved prosthetic graft for the bypass, replacement or repair of vessels and organs that are in contact with blood flow is disclosed. The prosthetic graft includes a porous prosthetic implant and adherent cells adhered to the outer surface of the implant. The adherent cells are transfected with at least one recombinant nucleic acid molecule encoding at least one protein that enhances patency of the graft. The prosthetic graft has a long-term patency and success rate that is superior to other previously described prosthetic grafts designed for such use. Also disclosed are methods of making and using such a graft.
Inventors
- 👤 Diane Lee Anderson
- 👤 John Paul Ranieri
- 👤 Maurizio Capogrossi Colognesi
- 👤 Marco Scoccianti
- 👤 Antonio Facchiano
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-07 16:11
CPC Classifications
A; A61; A61L; A61L27/00; A61L27/36; A61L27/38; A61L27/3804; A61K; A61K48/00; A61K48/0075; A61L27/3839; A61L27/3843; A61L27/50; A61L27/507; C; C07; C07K; C07K14/00; C07K14/435; C07K14/52; C12; C12N; C12N5/00; C12N5/06; C12N5/0602; C12N5/0652; C12N5/0656; A61F; A61F2/00; A61F2/02; A61F2/04; A61F2/06; A61F2/062; A61K35/00; A61K35/12; A61K2035/126; C12N2510/00; C12N2510/02; C12N2799/00; C12N2799/02; C12N2799/021; C12N2799/022; C12N2799/04
Claims Analysis
Total Claims: 66
Claim 1
Independent Claim
140 words
A prosthetic graft for containment of blood flow in vivo, comprising: (a) a porous prosthetic implant for containing blood in vivo, said prosthetic implant having an outer surface that is not in contact with blood flow in vivo and an inner surface that is in contact with blood flow in vivo, said inner surface defining an interior space for containment of blood flow; and, (b) adherent cells adhered to the outer surface of said porous prosthetic implant, wherein said adherent cells are transfected with at least one recombinant nucleic acid molecule operatively linked to a transcription control sequence, said recombinant nucleic acid molecule encoding a protein wherein at least a portion of said protein, upon secretion from said cells, perfuses through pores of said prosthetic implant to said inner surface of said prosthetic implant, enhancing patency of said prosthetic implant.
Claim 2
Dependent Claim
140 words
A prosthetic graft for containment of blood flow in vivo, comprising: (a) a porous prosthetic implant for containing blood in vivo, said prosthetic implant having an outer surface that is not in contact with blood flow in vivo and an inner surface that is in contact with blood flow in vivo, said inner surface defining an interior space for containment of blood flow; and, (b) adherent cells adhered to the outer surface of said porous prosthetic implant, wherein said adherent cells are transfected with at least one recombinant nucleic acid molecule operatively linked to a transcription control sequence, said recombinant nucleic acid molecule encoding a protein wherein at least a portion of said protein, upon secretion from said cells, perfuses through pores of said prosthetic implant to said inner surface of said prosthetic implant, enhancing patency of said prosthetic implant.
Claim 3
Dependent Claim
33 words
The prosthetic graft of claim 1 , wherein said prosthetic implant is selected from the group consisting of, a prosthetic vessel, an artificial heart, a left ventricle assist device, and a dialysis shunt.
Claim 4
Dependent Claim
45 words
The prosthetic graft of claim 1 , wherein said cells are selected from the group consisting of fibroblasts, mesenchymal stem cells, bone marrow stem cells, embryonal stem cells, adipocytes, keratinocytes, vascular smooth muscle cells, platelets, and cells which have been genetically engineered to be adherent.
Claim 5
Dependent Claim
12 words
The prosthetic graft of claim 1 , wherein said cells are fibroblasts.
Claim 6
Dependent Claim
78 words
The prosthetic graft of claim 1 , wherein said protein is selected from the group consisting of a protein that enhances angiogenesis in the vascular bed downstream of the prosthetic graft, a protein that enhances angiogenesis transmurally and into the interior space of the prosthetic implant to endothelialize the inner surface of the prosthetic implant, a protein that inhibits thrombosis, a protein that causes thrombolysis, a protein that inhibits smooth muscle migration and/or proliferation, and a vasodilator protein.
Claim 7
Dependent Claim
13 words
The prosthetic graft of claim 5 , wherein said vasodilator protein is prostacyclin.
Claim 8
Dependent Claim
66 words
The prosthetic graft of claim 1 , wherein said protein is selected from the group consisting of vascular endothelial growth factor (VEGF), platelet-induced growth factor (PIGF), transforming growth factor β1 (TGFβ1), acidic fibroblast growth factor (aFGF), basic fibroblast growth factor (bFGF), transforming growth factor α (TGFα), epidermal growth factor, osteonectin, angiopoietin 1 (Ang1), Ang2, insulin-like growth factor (IGF), platelet-derived growth factor AA (PDGF-AA), PDGF-AB and PDGF-BB.
Claim 9
Dependent Claim
30 words
The prosthetic graft of claim 1 , wherein said protein is selected from the group consisting of tissue plasminogen activator (TPA), streptokinase, hirudin V, αv-βIII, and urokinase plasminogen activator (uPA).
Claim 10
Dependent Claim
16 words
The prosthetic graft of claim 1 , wherein said protein is nitric oxide synthase (NO synthase).
Claim 11
Dependent Claim
45 words
The prosthetic graft of claim 1 , wherein said prosthetic implant is constructed of a material selected from the group consisting of highly resilient polyester, expanded polytetrafluorethylene (ePTFE), high porosity ePTFE, non-immunogenic xenogeneic tissue, porous silicon rubber, porous polyurethane, porous degradable polymer, and porous copolymers.
Claim 12
Dependent Claim
13 words
The prosthetic graft of claim 1 , wherein said prosthetic implant is non-immunogenic.
Claim 13
Dependent Claim
13 words
The prosthetic graft of claim 1 , wherein said prosthetic implant is non-calcific.
Claim 14
Dependent Claim
17 words
The prosthetic graft of claim 1 , wherein said prosthetic implant is a small bore prosthetic vessel.
Claim 15
Dependent Claim
21 words
The prosthetic graft of claim 13 , wherein the inner diameter of said prosthetic vessel is less than about 6 mm.
Claim 16
Dependent Claim
17 words
The prosthetic graft of claim 1 , wherein said prosthetic implant is a medium bore prosthetic vessel.
Claim 17
Dependent Claim
17 words
The prosthetic graft of claim 1 , wherein said prosthetic implant is a large bore prosthetic vessel.
Claim 18
Dependent Claim
24 words
The prosthetic graft of claim 1 , wherein said prosthetic implant has a pore size of from about 0.1 μm to about 500 μm.
Claim 19
Dependent Claim
24 words
The prosthetic graft of claim 1 , wherein said prosthetic implant has a pore size of from about 0.2 μm to about 100 μm.
Claim 20
Dependent Claim
28 words
The prosthetic graft of claim 1 , wherein said transcription control sequence is selected from the group consisting of retroviral transcription control sequences and mammalian transcription control sequences.
Claim 21
Dependent Claim
18 words
The prosthetic graft of claim 1 , wherein said transcription control sequence comprises a promoter that is inducible.
Claim 22
Dependent Claim
29 words
The prosthetic graft of claim 20 , wherein said promoter is inducible in vivo by administration to a recipient of said graft of a compound that induces said promoter.
Claim 23
Dependent Claim
25 words
The prosthetic graft of claim 21 , wherein said compound is selected from the group consisting of an antibiotic, a hormone, and a transcription factor.
Claim 24
Dependent Claim
94 words
A vascular graft, comprising: (a) a porous prosthetic vessel having a perivascular surface and a lumenal surface; and (b) adherent cells adhered to the perivascular surface of said porous prosthetic vessel, wherein said adherent cells are transfected with at least one recombinant nucleic acid molecule operatively linked to a transcription control sequence, said recombinant nucleic acid molecule encoding a protein wherein at least a portion of said protein, upon secretion from said cells, perfuses through pores of said prosthetic vessel to said lumenal surface of said prosthetic vessel, enhancing patency of said prosthetic vessel.
Claim 25
Dependent Claim
94 words
A vascular graft, comprising: (a) a porous prosthetic vessel having a perivascular surface and a lumenal surface; and (b) adherent cells adhered to the perivascular surface of said porous prosthetic vessel, wherein said adherent cells are transfected with at least one recombinant nucleic acid molecule operatively linked to a transcription control sequence, said recombinant nucleic acid molecule encoding a protein wherein at least a portion of said protein, upon secretion from said cells, perfuses through pores of said prosthetic vessel to said lumenal surface of said prosthetic vessel, enhancing patency of said prosthetic vessel.
Claim 26
Dependent Claim
122 words
A prosthetic graft for containment of blood flow in vivo, comprising: (a) a porous prosthetic implant for containing blood in vivo, said prosthetic implant having an outer surface that is not in contact with blood flow in vivo and an inner surface that is in contact with blood flow in vivo, said inner surface defining an interior space for containment of blood flow; and, (b) adherent cells adhered to the outer surface of said porous prosthetic implant, wherein said adherent cells express and secrete at least one protein wherein at least a portion of said protein, upon secretion from said cells, perfuses through pores of said prosthetic implant to said inner surface of said prosthetic implant, enhancing patency of said prosthetic implant.
Claim 27
Dependent Claim
122 words
A prosthetic graft for containment of blood flow in vivo, comprising: (a) a porous prosthetic implant for containing blood in vivo, said prosthetic implant having an outer surface that is not in contact with blood flow in vivo and an inner surface that is in contact with blood flow in vivo, said inner surface defining an interior space for containment of blood flow; and, (b) adherent cells adhered to the outer surface of said porous prosthetic implant, wherein said adherent cells express and secrete at least one protein wherein at least a portion of said protein, upon secretion from said cells, perfuses through pores of said prosthetic implant to said inner surface of said prosthetic implant, enhancing patency of said prosthetic implant.
Claim 28
Dependent Claim
22 words
The prosthetic graft of claim 24 , wherein said adherent cells are endothelial cells that have been genetically modified to be adherent.
Claim 29
Independent Claim
121 words
A method for producing a prosthetic graft, comprising applying adherent cells to a porous prosthetic implant for containing blood in vivo, wherein said prosthetic implant has an outer surface and an inner surface that defines an interior space for containment of blood flow; wherein said adherent cells are applied to said outer surface of said prosthetic implant; and, wherein said adherent cells are transformed with at least one recombinant nucleic acid molecule operatively linked to a transcription control sequence, said recombinant nucleic acid molecule encoding a protein wherein at least a portion of said protein, upon secretion from said cells, perfuses through pores of said prosthetic implant to said inner surface of said prosthetic implant, enhancing patency of said prosthetic implant.
Claim 30
Independent Claim
121 words
A method for producing a prosthetic graft, comprising applying adherent cells to a porous prosthetic implant for containing blood in vivo, wherein said prosthetic implant has an outer surface and an inner surface that defines an interior space for containment of blood flow; wherein said adherent cells are applied to said outer surface of said prosthetic implant; and, wherein said adherent cells are transformed with at least one recombinant nucleic acid molecule operatively linked to a transcription control sequence, said recombinant nucleic acid molecule encoding a protein wherein at least a portion of said protein, upon secretion from said cells, perfuses through pores of said prosthetic implant to said inner surface of said prosthetic implant, enhancing patency of said prosthetic implant.
Claim 31
Dependent Claim
20 words
The method of claim 26 , wherein said method enhances naturally occurring endothelialization of the inner surface of said implant.
Claim 32
Dependent Claim
14 words
The method of claim 26 , wherein said method inhibits thrombosis in said implant.
Claim 33
Dependent Claim
21 words
The method of claim 26 , wherein said method enhances formation of a neointima in the inner surface of said implant.
Claim 34
Dependent Claim
17 words
The method of claim 26 , wherein said prosthetic implant is an arterial or venous prosthetic vessel.
Claim 35
Dependent Claim
29 words
The method of claim 30 , wherein said step of applying comprises seeding the outer surface of the vessel uniformly in both radial and longitudinal directions on the vessel.
Claim 36
Dependent Claim
19 words
The method of claim 26 , wherein said step of applying is performed by a programmable mechanical graft rotator.
Claim 37
Dependent Claim
24 words
The method of claim 26 , wherein said graft is incubated after said step of applying for about 5 minutes to about 14 days.
Claim 38
Dependent Claim
44 words
The method of claim 26 , wherein said cells are selected from the group consisting of fibroblasts, mesenchymal stem cells, bone marrow stem cells, embryonal stem cells, adipocytes, keratinocytes, vascular smooth muscle cells, platelets, and cells which have been genetically engineered to be adherent.
Claim 39
Dependent Claim
11 words
The method of claim 26 , wherein said cells are fibroblasts.
Claim 40
Dependent Claim
79 words
The method of claim 26 , wherein said protein is selected from the group consisting of a protein that enhances angiogenesis in the vascular bed downstream of the prosthetic graft, a protein that enhances angiogenesis transmurally and into the interior space of the prosthetic implant so as to endothelialize the inner surface of the prosthetic implant, a protein that inhibits thrombosis, a protein that causes thrombolysis, a protein that inhibits smooth muscle migration and/or proliferation, and a vasodilator protein.
Claim 41
Dependent Claim
12 words
The method of claim 36 , wherein said vasodilator protein is prostacyclin.
Claim 42
Dependent Claim
65 words
The method of claim 26 , wherein said protein is selected from the group consisting of vascular endothelial growth factor (VEGF), platelet-induced growth factor (PIGF), transforming growth factor β1 (TGFβ1), acidic fibroblast growth factor (aFGF), basic fibroblast growth factor (bFGF), transforming growth factor α (TGFα), epidermal growth factor, osteonectin, angiopoietin 1 (Ang1), Ang2, insulin-like growth factor (IGF), platelet-derived growth factor AA (PDGF-AA), PDGF-AB and PDGF-BB.
Claim 43
Dependent Claim
29 words
The method of claim 26 , wherein said protein is selected from the group consisting of tissue plasminogen activator (TPA), streptokinase, hirudin V, αv-βIII, and urokinase plasminogen activator (uPA).
Claim 44
Dependent Claim
15 words
The method of claim 26 , wherein said protein is nitric oxide synthase (NO synthase).
Claim 45
Dependent Claim
44 words
The method of claim 26 , wherein said prosthetic implant is constructed of a material selected from the group consisting of highly resilient polyester, expanded polytetrafluorethylene (ePTFE), high porosity ePTFE, non-immunogenic xenogeneic tissue, porous silicon rubber, porous polyurethane, porous degradable polymer, and porous copolymers.
Claim 46
Independent Claim
132 words
A method of implantation of a prosthetic graft for containment of blood flow, comprising implanting a prosthetic graft into a patient, said prosthetic graft comprising: (a) a porous prosthetic implant for containing blood in vivo, said prosthetic implant having an outer surface and an inner surface defining an interior space for containment of blood flow; and, (b) adherent cells adhered to the outer surface of said porous prosthetic implant, wherein said adherent cells are transfected with at least one recombinant nucleic acid molecule operatively linked to a transcription control sequence, said recombinant nucleic acid molecule encoding a protein wherein at least a portion of said protein, upon secretion from said cells, perfuses through pores of said prosthetic implant to said inner surface of said prosthetic implant, enhancing patency of said prosthetic implant.
Claim 47
Independent Claim
132 words
A method of implantation of a prosthetic graft for containment of blood flow, comprising implanting a prosthetic graft into a patient, said prosthetic graft comprising: (a) a porous prosthetic implant for containing blood in vivo, said prosthetic implant having an outer surface and an inner surface defining an interior space for containment of blood flow; and, (b) adherent cells adhered to the outer surface of said porous prosthetic implant, wherein said adherent cells are transfected with at least one recombinant nucleic acid molecule operatively linked to a transcription control sequence, said recombinant nucleic acid molecule encoding a protein wherein at least a portion of said protein, upon secretion from said cells, perfuses through pores of said prosthetic implant to said inner surface of said prosthetic implant, enhancing patency of said prosthetic implant.
Claim 48
Dependent Claim
14 words
The method of claim 42 , wherein said cells are autologous to said patient.
Claim 49
Dependent Claim
27 words
The method of claim 42 , wherein said cells are from a cell selected from the group consisting of undifferentiated stem cell lines and embryonal cell lines.
Claim 50
Dependent Claim
25 words
The method of claim 42 , further comprising inducing said cells to express said protein in vivo, after implantation of said graft into a patient.
Claim 51
Dependent Claim
18 words
The method of claim 42 , wherein said prosthetic graft is used as an arterial or venous replacement.
Claim 52
Dependent Claim
19 words
The method of claim 42 , wherein said method enhances endothelialization of the inner surface of the prosthetic implant.
Claim 53
Dependent Claim
14 words
The method of claim 42 , wherein said method inhibits thrombosis in the implant.
Claim 54
Dependent Claim
29 words
The method of claim 48 , wherein said method inhibits thrombosis of the inner surface of the prosthetic implant due to smooth muscle migration and/or proliferation in the implant.
Claim 55
Dependent Claim
22 words
The method of claim 42 , wherein said method enhances formation of a neointima in the inner surface of said prosthetic implant.
Claim 56
Dependent Claim
16 words
The method of claim 42 , wherein said prosthetic implant is a small bore prosthetic vessel.
Claim 57
Dependent Claim
20 words
The method of claim 51 , wherein the inner diameter of said prosthetic vessel is less than about 6 mm.
Claim 58
Dependent Claim
16 words
The method of claim 42 , wherein said prosthetic implant is a medium bore prosthetic vessel.
Claim 59
Dependent Claim
16 words
The method of claim 42 , wherein said prosthetic implant is a large bore prosthetic vessel.
Claim 60
Dependent Claim
23 words
The method of claim 42 , wherein said prosthetic implant has a pore size of from about 0.1 μm to about 500 μm.
Claim 61
Dependent Claim
23 words
The method of claim 42 , wherein said prosthetic implant has a pore size of from about 0.2 μm to about 100 μm.
Claim 62
Independent Claim
140 words
A method for implantation of a prosthetic graft for containing blood flow in a patient, comprising: (a) harvesting fibroblast cells from a patient in need of a prosthetic graft for containing blood flow; (b) transfecting said fibroblast cells with an isolated nucleic acid molecule encoding a protein that enhances patency of said graft; (c) applying said transfected fibroblast cells onto a surface of a prosthetic implant configured for containing blood flow in vivo for a time sufficient to allow said fibroblast cells to adhere to said surface to form a prosthetic graft, wherein said surface is not in contact with blood flow in vivo, wherein at least a portion of said protein, upon secretion from said cells, perfuses through pores of said prosthetic graft to a surface in contact with blood flow; (d) implanting said prosthetic graft into said patient.
Claim 63
Independent Claim
140 words
A method for implantation of a prosthetic graft for containing blood flow in a patient, comprising: (a) harvesting fibroblast cells from a patient in need of a prosthetic graft for containing blood flow; (b) transfecting said fibroblast cells with an isolated nucleic acid molecule encoding a protein that enhances patency of said graft; (c) applying said transfected fibroblast cells onto a surface of a prosthetic implant configured for containing blood flow in vivo for a time sufficient to allow said fibroblast cells to adhere to said surface to form a prosthetic graft, wherein said surface is not in contact with blood flow in vivo, wherein at least a portion of said protein, upon secretion from said cells, perfuses through pores of said prosthetic graft to a surface in contact with blood flow; (d) implanting said prosthetic graft into said patient.
Claim 64
Dependent Claim
26 words
The method of claim 57 , further comprising inducing said fibroblast cells to express said protein in vivo, after implantation of said graft into a patient.
Claim 65
Independent Claim
114 words
A method of enhancing endothelialization of a vascular graft, comprising applying adherent cells to a porous prosthetic vessel having a perivascular surface and a lumenal surface, wherein said adherent cells are adhered to the perivascular surface of the prosthetic vessel; and wherein said adherent cells are transfected with at least one recombinant nucleic acid molecule operatively linked to a transcription control sequence, said recombinant nucleic acid molecule encoding a protein that enhances endothelialization of said prosthetic vessel; whereby said protein is expressed and secreted by said adherent cells and perfuses through pores in said prosthetic vessel to the lumenal surface of said prosthetic vessel to enhance endothelialization of said graft at said lumenal surface.
Claim 66
Independent Claim
114 words
A method of enhancing endothelialization of a vascular graft, comprising applying adherent cells to a porous prosthetic vessel having a perivascular surface and a lumenal surface, wherein said adherent cells are adhered to the perivascular surface of the prosthetic vessel; and wherein said adherent cells are transfected with at least one recombinant nucleic acid molecule operatively linked to a transcription control sequence, said recombinant nucleic acid molecule encoding a protein that enhances endothelialization of said prosthetic vessel; whereby said protein is expressed and secreted by said adherent cells and perfuses through pores in said prosthetic vessel to the lumenal surface of said prosthetic vessel to enhance endothelialization of said graft at said lumenal surface.
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