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Prosthetic Grafts

a technology of prosthetic grafts and grafts, which is applied in the field of prosthetic grafts, can solve the problems of incomplete graft occlusion, synthetic or biosynthetic small vascular grafts, non-synthetic or biological, etc., and achieve the effects of enhancing angiogenesis, and enhancing patency in the prosthetic gra

Inactive Publication Date: 2007-04-19
ANDERSON DIANE LEE +4
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention relates to a prosthetic graft for containment of blood flow in vivo. The graft includes a porous prosthetic implant and adherent cells adhered to the outer surface of the implant. The adherent cells are transformed with at least one recombinant nucleic acid molecule operatively linked to a transcription control sequence, the recombinant nucleic acid molecule encoding a protein that enhances patency of the prosthetic implant. The graft can be used as a blood vessel, an artificial heart, a left ventricle assist device, or a dialysis shunt. The graft promotes endothelialization of the inner surface of the implant, inhibits thrombosis, and inhibits smooth muscle migration and proliferation. The adherent cells can be fibroblasts, mesenchymal stem cells, bone marrow stem cells, or other adherent cells. The graft can be produced using a method that involves applying adherent cells to the outer surface of the implant.

Problems solved by technology

Research over the past several decades has yet to produce a synthetic or biosynthetic small bore vascular graft which can approach the patency rates of autologous vessels.
Platelet adhesion and activation at the lumenal surface of the graft are much more likely to result in complete graft occlusion.
Currently, non-synthetic or biological small bore grafts are routinely used as an arterial replacement since nothing has proven to perform nearly as well as the autologous saphenous vein or internal mammary artery, which are the conventional biological materials used as a small diameter vascular graft.
The harvesting surgery increases the total operating time and can also lead to complications and discomfort.
Furthermore, a small percentage of patients do not have autologous vessels suitable for, harvesting.
In some cases, the vessels are not available due to previous surgery, while in other cases, the vessel may be too small or varicose.
Even larger bore vessel and organ prosthetic grafts, however, suffer from complications associated with smooth muscle proliferation, compliance mismatch with native vessels, and poor endothelialization due to blood shear stresses and mechanical damage.
However, a completely non-fouling surface has yet to be discovered and many now view the quest for such a material as unrealistic.
Although a small number of grafts seeded lumenally with endothelial cells have been implanted clinically outside of the United States, and improved patencies over non-seeded grafts have been observed, this approach has generally enjoyed mixed success, and the concept still faces many challenges.
The harvesting surgical procedure not only increases prosthetic implant preparation time, but can also lead to complications and discomfort for the patient.
Second, retention of the cells on the graft surface after implantation has been an issue.
Although there is some evidence that methods such as conditioning may improve cell retention, all of these methods add yet another level of complexity to the seeding process and it is still not clear that significantly improved cellular retention can be achieved.

Method used

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Examples

Experimental program
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Effect test

example 1

[0097] The following example describes the production of a prosthetic graft according to the present invention.

Primary Cell Culture:

[0098] Primary Rabbit Aortic Fibroblasts (RAF) were obtained from young male White New Zealand rabbits. The aorta was explanted, the vessel was then longitudinally opened and the endothelium was removed by gently rubbing the lumenal surface with a scraper. After this step, the vessel was cut into small pieces, it was placed in a 60 mm dish containing 2 ml of Trypsin and kept at 37° C. in a 5% CO2 incubator for 60 minutes. After this incubation, the vessel was removed and placed in 60 mm dishes with 0.5 ml of DMEM supplemented with 10% FBS containing 2 mM L-glutamine and 100 UI / mL Pen / Strep. After overnight incubation, 1.5 ml of culture medium was added. RAFs were cultured with DMEM with 10% FBS, 2 mM L-glutamine and 100 UI / mL Pen / Strep in a humidified 5% CO2 atmosphere at 37° C. Proliferating cells were used between passage 3 and 8 and were used for ...

example 2

[0103] The following example demonstrates that a prosthetic graft of the present invention produces the recombinant protein both inside and outside of the graft under static in vitro culture conditions.

[0104] Production and secretion of VEGF under static in vitro conditions was measured from the PhotoFix graft seeded perivascularly with rabbit aortic fibroblasts infected with AdV cmv VEGF as described in Example 1. Briefly, the seeded PhotoFix was mounted within a closed circuit placed in a chamber and connected to a peristaltic pump. Five ml of medium in static condition were placed inside the PhotoFix, while 300 ml of medium was placed in the incubation chamber outside the PhotoFix. The chamber was incubated under static conditions under shear stress in a humidified 5% CO2 atmosphere at 37° C. At the end of incubation, external and internal medium was recovered (the internal medium was collected through a plastic outlet mounted on the circuit) and stored at −20° C. for the ELISA ...

example 3

[0107] The following example demonstrates that a prosthetic graft of the present invention produces the recombinant protein both inside and outside of the graft under shear stress in vitro culture conditions.

[0108] Release of VEGF under dynamic condition-shear stress of 1.5 dyn / cm2 during in vitro conditions was measured from the PhotoFix graft seeded perivascularly with rabbit aortic fibroblasts infected with AdV cmv VEGF as described in Example 1. Briefly, as described in Example 2 above, the seeded graft was mounted within a closed circuit placed in a chamber and connected to a peristaltic pump. For the dynamic condition assays, 15 ml of medium were placed inside the PhotoFix and 300 ml of medium was placed in the incubation chamber outside the PhotoFix. The chamber was incubated in a humidified 5% CO2 atmosphere at 37° C. under dynamic conditions of shear stress by circulating the medium through the circuit at a velocity of 1.5 dyn / cm2 as indicated. The medium was collected and...

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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.

Description

FIELD OF THE INVENTION [0001] The present invention relates to prosthetic grafts which are used to contain blood flow in vivo. BACKGROUND OF THE INVENTION [0002] Diseases of the major circulatory and renal organs and vessels have created a need for prosthetic grafts to bypass, repair and / or replace the function of the diseased organs and vessels. Such grafts should ideally be non-immunogenic, non-calcific, and readily capable of recreating or reestablishing the natural blood contact interface of the organ or vessel to be replaced or repaired. Complications that have inhibited the widespread use of prosthetic grafts in organs and vessels in contact with blood include: (1) intimal hyperplasia, whereby smooth muscle cell and myofibroblast proliferation and extracellular matrix accumulation cause thickening of the intima in the graft and in the adjoining vessels, and ultimately lead to failure of the graft; and, (2) occlusion of the graft, whereby platelet adhesion and activation at the...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A01N63/00A61K48/00A61F2/06A61K35/12A61L27/38A61L27/50C12N5/02C12N5/077
CPCA61F2/06A61F2/062A61K48/00A61K48/0075A61K2035/126A61L27/38A61L27/3804A61L27/3843A61L27/507C07K14/52C12N5/0656C12N2510/02C12N2799/022C12N2799/04
Inventor ANDERSON, DIANE LEERANIERI, JOHN PAULCOLOGNESI, MAURIZIO CAPOGROSSISCOCCIANTI, MARCOFACCHIANO, ANTONIO
Owner ANDERSON DIANE LEE
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