Controlled and Localized Release of Retinoids to Improve Neointimal Hyperplasia

Inactive Publication Date: 2010-02-11
VESSELTEK BIOMEDICAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0008]Controlled release vascular implants, such as vascular grafts, stents, gels, and wraps, comprising a biocompatible polymer and all trans retinoic acid (ATRA), or its derivatives, can be used to treat, prevent, or inhibit thrombosis and neointimal hyperplasia which may otherwise be induced by prosthetic impla

Problems solved by technology

Persons with PAD often have impaired function and quality of life, regardless of symptoms.
While the patency for infrainguinal vein grafts remains approximately 70% at 5 years, vein is not available in approximately one-third of patients due to intrinsic venous disease or prior vein harvesting.
However, the primary patency rates for infrapopliteal ePTFE bypass grafts are dismal.
Problems associated with using prosthetic grafts are so severe that cardiac surgeons do not use

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Example

Example 1

Poly(1,8 octanediol-co-citrate) (POC) Pre-Polymer Synthesis

[0059]Equimolar amounts of citric acid and 1,8-octanediol are melted together at 160° C. while stirring for 15 minutes The temperature can be subsequently decreased to 140° C. and the mixture stirred for 1 hour. The pre-polymer can then be purified by dissolution in ethanol followed by precipitation in water and freeze-dried. For surface modification of an ePTFE graft, POC pre-polymer is dissolved in ethanol or 1,3-dioxolane to a concentration of 10% (w / v). See, for example, Yang J, Webb A R, Pickerill S J, Hageman G, Ameer G A. Synthesis and evaluation of poly(diol citrate) biodegradable elastomers. Biomaterials 2006 March; 27(9):1889-98; and Yang J, Webb A R, Ameer G A. Novel citric acid-based biodegradable elastomers for tissue engineering. Adv Mater 2004; 16(6):511-6, each of which are hereby incorporated by reference in their entirety).

[0060]The mechanical properties of the preceding elastomer can be modulated ...

Example

Example 2

In Vitro Evaluation of Clotting and Inflammatory Characteristics of POC

[0062]Re-calcification clotting assays were performed to assess the clotting kinetics of POC relative to tissue culture polystyrene and PLGA. Briefly, test and control polymer samples in 96-well plates were incubated in acid citrate dextrose (ACD) anticoagulated human or pig platelet poor plasma (PPP). Immediately prior to absorbance measurement, CaCl2 (0.025 M) was added to each well to initiate clotting. The absorbance of each well was monitored every 30 seconds for 30 minutes at 405 nm. The rate of clot formation is consistently lower for plasma exposed to POC when compared to the other materials (slope of linear region=0.088±0.027, 0.089±0.013, and 0.025±0.019 A.U. / min, for TCP, PLGA, and POC, respectively). This finding may be explained by the presence of the hydroxyl, carboxyl, and potentially chelating citric acid functional groups within the POC.

[0063]For assessment of inflammatory potential, a s...

Example

Example 3

Modification of ePTFE Grafts with POC

[0064]Prior to modification, standard-wall non-stretch ePTFE grafts were cleaned by first soaking under sonication in absolute ethanol, acetone, and vacuum drying. The lumen of ePTFE grafts were modified by mechanically coating a layer of POC through a spin-shearing method. Briefly, a 5 mm diameter glass rod was dipped into 10% POC pre-polymer (pre-POC, Example 1) solution in 1,4-dioxane and inserted horizontally into the motor of a mechanical stirrer. The pre-POC-coated glass rod was spun clockwise at 300 rpm for 2 minutes and a 6 cm-long piece of ePTFE graft was placed concentrically over the spinning rod. The lumen of the graft was sheared against the spinning rod for 2 minutes by manually rotating the graft counterclockwise. The above procedure was considered to be 1 coating. To change the amount of POC deposited onto the graft (and, therefore, the coating thickness), the above procedure was repeated 3 and 6 times (defined as 3 and 6...

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Abstract

Controlled release vascular implants, such as vascular grafts, stents, wraps, and gels comprising a biocompatible polymer and all trans retinoic acid (ATRA), or its derivatives, can be used to treat, prevent, or inhibit thrombosis and/or neointimal hyperplasia which may otherwise be induced by prosthetic implantation. In particular, the implants herein can inhibit smooth muscle cell proliferation, neointimal hyperplasia, and upregulate antithrombotic genes and nitric oxide production in the vasculature. Further, the implants are capable of delivering controlled and predictable localized concentrations of ATRA.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of the filing date of U.S. Provisional Application Ser. No. 61 / 077,949 filed 3 Jul. 2008, which is hereby incorporated by reference in its entirety.FIELD OF THE INVENTION[0002]The present disclosure relates to vascular implants incorporating all trans-retinoic acid or its derivatives reduce thrombosis and / or neointimal hyperplasia following surgical implantation.BACKGROUND OF THE INVENTION[0003]Atherosclerosis is prevalent in all developed nations and is the leading cause of death and disability in the United States. A debilitating and disabling sequela of atherosclerosis is peripheral arterial disease (PAD). Persons with PAD often have impaired function and quality of life, regardless of symptoms. For those with severe PAD, often lower extremity bypass grafting remains the only option for limb salvage.[0004]The gold standard conduit for infrainguinal bypass grafting is autologous vein. While the patenc...

Claims

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Application Information

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IPC IPC(8): A61F2/06
CPCA61L27/34A61L27/507A61L27/54A61L31/10A61L31/16A61L2300/416A61L2420/06A61L2430/36A61L31/08A61L33/04A61L2300/602A61L2300/606A61L2300/626A61L2300/428A61P7/02A61L27/18A61L31/06A61L2300/42
Inventor AMEER, GUILLERMO A.KIBBE, MELINAWEBB, ANTONIO
Owner VESSELTEK BIOMEDICAL
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