Date of Award

2012

Degree Type

Thesis

Department

Chemical and Biomedical Engineering

First Advisor

Ramamurthi, Anand

Subject Headings

Transforming growth factors-beta, Nanoparticles, Vascular smooth muscle, Abdominal aneurysm, Abdominal aorta, TGF-ß1, PLGA nanoparticles, smooth muscle cells, elastogenic induction

Abstract

Abdominal aortic aneurysms (AAAs) typically manifest as localized wall weakening and dilation of the infrarenal aorta, which grows gradually, and ultimately leads to fatal rupture. It is caused due to overexpression of proteolytic enzymes (matrix metalloproteases or MMPs) resulting into disruption of tissue structure, especially elastic matrix, which cannot be regenerated by adult vascular cells. On account of post-operative complications associated with their surgical repair, there is a critical need for developing non-surgical strategies for slowing and even regressing AAA growth. Recent studies in our laboratory have demonstrated that 1 ng/mL of transforming growth factor-β1 (TGF-β1) enhances regenerative repair by stimulating elastogenesis in healthy and aneurysmal rat aortic smooth muscle cell (SMC) cultures. The purpose of this study is to develop and characterize a nanoparticulate delivery system for localized, controlled and sustained delivery of TGF-β1 to AAA tissue, for the elastogenic induction of SMCs. Accordingly, in this study, we have developed TGF-β1 loaded poly (lactic-co-glycolic acid) PLGA nanoparticles using double-emulsion/solvent evaporation method. The NPs exhibited sustained release of TGF-β1 over a period of at least 21 days in an in vitro aqueous system. The released TGF-β1 from NPs inhibited the proliferation of mink lung epithelial cells, which confirmed the bio-functionality of TGF-β protein post-encapsulation. Additionally, our IF studies demonstrated better fiber formation and orientation of elastin in TGF-β1 NP treated cultures, which was potentially due to up-regulated expression of structural proteins like collagen and fibrillin-1 in TGF-β1 treated cultures, as demonstrated by quantitative and qualitative studies. Our studies also demonstrated up-regulated levels of lysyl oxidase (LOX), protein enzyme responsible for cross-linking elastin molecules into fibers in smooth muscle cell (SMC) extracellular matrix. However, quantitative analysis of

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