Controlled and Localized Release of Retinoids to Improve Neointimal Hyperplasia

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...

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 implantation. In particular, the implants described 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.

[0009]In one aspect, the present disclosure provides methods for reducing or preventing the occurrence of neointimal hyperplasia and / or thrombosis following implantation of a vascular implant, said method comprising, contacting a vascular implant with all-trans retinoic acid (ATRA); and implanting the vascular implant in a patient in need of thereof, wherein the vascular implant comprises a biocompatible polymeric matrix; and the vascular implant releases a therapeutically effective amount of ATRA sufficient to inhibit or prevent neointimal hyperplasia when implanted in the patient.

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 them for coronary artery bypass grafting (CABG).

Although ePTFE grafts are the current standard for prosthetic infrainguinal bypass grafting, they can be thrombogenic, especially when used in small diameter below-knee revascularization procedures.

Stenosis due to neointimal hyperplasia remains a challenge to their long-term efficacy.

However, the possible formation of antiplatelet antibodies and the associated heparin-induced thrombocytopenia can result in deadly outcomes.