Date of Award

January 2014

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Christopher K. Breuer

Subject Area(s)

Medicine, Biomedical engineering

Abstract

Autologous tissue engineered vascular grafts (TEVGs) are limited by graft stenosis. Small diameter TEVGs implanted as unseeded scaffolds are prone to failure by occlusive luminal proliferation of smooth muscle cells derived from endothelial precursors within a critical period of two weeks. The development, validation, and application novel platform for controlling TEVG performance by local delivery of peptide and/or small molecule therapeutic agents from the TEVG scaffold is presented with insights into the autologous TEVG biology and development.

We hypothesized that inhibition of TGF-βR1 by local delivery of SB-431542, a competitive inhibitor of ALK5/TGFβR1 signaling, is superior to systemic administration of SB-431542 in the prevention of EndMT-mediated neointimal hyperplastic stenosis of a TEVG during the critical period for graft failure in a mouse model. Specific aims included the development of a multiplexed hybrid drug release platform for delivery of small molecule and/or protein species from a TEVG scaffold; validation of the clinical utility of local versus systemic delivery of SB-431542 in the prevention of TEVG neointimal hyperplastic stenosis in a small animal model; and exploration of TGF-β1 signaling in EndMT and TEVG neointimal hyperplastic stenosis.

Local delivery of SB-431542 or recombinant human TGF-β1 prevented stenosis of a small diameter TEVG. Optimization of the local delivery platform achieved maximum therapeutic efficacy with lower costs than systemic therapy. TGF-β1 signaling is central to endothelial-mesenchymal transition in TEVG dysfunction. Translation of this technology for vascular interventional therapy the hypoplastic left heart syndrome has the potential to improve clinical outcomes.

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