Date of Award

2015

Document Type

Open Access Dissertation

Degree Name

Doctor of Philosophy in Biomedical Engineering (PhD)

Administrative Home Department

Department of Biomedical Engineering

Advisor 1

Megan C. Frost

Advisor 2

Jeremy Goldman

Committee Member 1

Rupak Rajachar

Committee Member 2

Bruce P. Lee

Committee Member 3

Jaroslaw Drelich

Abstract

Small diameter (< 6 mm) vascular grafts suffer from serious deleterious effects not encountered with their larger diameter relatives, leading to premature graft failure through restenosis. Platelet activation, inflammation, and smooth muscle cell proliferation are leading contributors to thrombosis and neointimal hyperplasia, both contributors to the progression of restenosis. It may be possible to suppress negative biological responses to vascular implants through the modification of surface properties and incorporation of drug release into blood contacting materials. In this work, bioengineering approaches are presented to improve the biocompatibility of small diameter vascular grafts.

We demonstrate a novel engineering approach for incorporating natural, decollagenized elastin matrices into PEU 1074A reinforced vascular grafts through spray-coating and electrospinning processes in a manner that retains elastin’s excellent blood contacting properties. A vascular construct with excellent mechanical and surgical handling properties demonstrating the suppression of neointimal hyperplasia is presented after 21 days in vivo.

Nitric oxide (NO) has been investigated over the past several decades due to its platelet, inflammation, and smooth muscle cell suppressing effects; and if appropriately delivered, could positively mediate the contributors to restenosis. Here, we characterize a novel macrocyclic NO donor developed by linking S-nitroso-N-acetyl-D-penicillamine (SNAP) directly to 1,4,8,11-tetraazacyclotetradecane (cyclam). Here, we present characterization data for SNAP-Cyclam and demonstrate stable, long term NO release at physiologically relevant levels for more than 90 days when incorporated into poly(˪-lactic acid) films.

Transition metals, such as copper and iron, are known to initiate NO production from S-nitrosothiols. It is reported in this work that additional transition metal ions; Co2+, Ni2+, and Zn2+, which have not been reported to generate NO from RSNOs have the capacity to generate NO from the S-nitrosothiol, S-nitroso-N-acetyl-D-penicillamine. In vivo data alludes to the possibility that Zn2+ may be able to generate NO from endogenous donors and provide beneficial effects.

These three novel developments form the basis for the potential construction of clinically relevant small diameter vascular grafts capable of suppressing the deleterious effects, namely thrombosis and neointimal hyperplasia, commonly encountered in current small diameter vascular grafts.

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