This is a proposal to create a biologically active prosthetic arterial graft (PG) incorporating gene silencing and gene overexpression in an antithrombotic and pro-angiogenic surface. The research team is unique in its cohesiveness and breadth of expertise including nanotechnology, polymers, gene therapy, vascular biology, and surgery, all with an established focus on vascular grafts. This project builds on our long-standing work where we have 1) characterized the lesion of anastomotic neointimal hyperplasia (AIH) downstream of the prosthetic graft, 2) established the role of blood flow-surface interaction in AIH pathogenesis, 3) determined the unique gene signature associated with AIH development, including identification of high profile pathogenic and protective targets, 4) documented delivery of siRNA from a prosthetic surface to knockdown pathogenic genes in vascular smooth muscle cells, 5 ) documented adeno associated virus (AAV) mediated delivery of atheroprotective genes to the vascular wall and through the prosthetic surface to endothelial cells and, 6) demonstrated the advantages of a cryogel coating as a delivery system for antithrombotic and pro-angiogenic molecules and gene therapy. Based on this knowledge and achievements, we propose an optimized approach to create a highly functional and adaptable flow surface. We will build a composite PG comprising three components: A) A `backbone' graft composed of standard polyethyleneterephthalate (PET), B) An anti-thrombotic (heparin) gel with improved cell attachment properties (RGD) to be applied to the graft prior to cryogelation, and C) Biologic therapeutic agents to be incorporated in the cryogel-PG prior to surgery, which would create a high capacity multifunctional bioactive flow surface. Using gene therapy technologies, biologics with anti-inflammatory and atheroprotective properties that have been fully validated by our group will be incorporated to synthesize the composite PG. Our goal is to optimize the composite PG for delivery of drugs and biologics from the flow surface into the PG microenvironment. This would target the circulating cells invading the pseudo intima, decreasing contact activation and platelet aggregation. Additionally, this will modulate endothelial and smooth muscle cells of the native artery at the anastomosis site as to prevent their phenotypic switch that fuels AIH. In a rabbit model we will implant the composite PG with the bioactive gel applied intraluminally and/or extraluminally. We will then gauge efficacy of drug delivery, and determine its effect on PG molecular signature and AIH. This is a stepwise study bringing to bear the necessary and broad range of expertise on the effective application of a multifunctional bioactive prosthetic arterial graft to improve outcome. This work will also serve as proof of concept to instill bioactivity and adapt biomaterials for therapeutic purposes such as endografts, hernia repair, and wound coverage.

Public Health Relevance

This is a proposal to create an improved arterial prosthetic graft to treat cardiovascular disease. A new gel will be applied to the graft biomaterial, which has a high capacity to carry and deliver agents that prevent clotting, silence the expression of tissue genes that cause blockage of existing graft materials, and increase expression of genes that prevent blockage. It will greatly improve the treatment of atherosclerosis in the heart and circulation system, and more general benefits will come from using biomaterials for control gene delivery for other purposes such as tissue repair.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL021796-33
Application #
9876954
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Lundberg, Martha
Project Start
1987-07-01
Project End
2021-01-31
Budget Start
2020-02-01
Budget End
2021-01-31
Support Year
33
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
Nabzdyk, Christoph S; Pradhan-Nabzdyk, Leena; LoGerfo, Frank W (2017) RNAi therapy to the wall of arteries and veins: anatomical, physiologic, and pharmacological considerations. J Transl Med 15:164
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