Artificial and natural biomaterials in the form of tubular grafts and patches are frequently used for surgical treatment of vascular diseases in adults and children. While these biomaterials restore the required basic mechanical functions, they fail to fully integrate into the biological milieu to which they are subjected and fail due to atherosclerosis, thrombosis, infections, degeneration and calcification. Moreover, they fail to grow when implanted in a pediatric patient. Overall, the clinical reality is that traditional artificial prosthetic devices cannot fully replace organs, autograft tissue is not typically available, and allograft tissue is in high demand but short supply. Since cardiovascular diseases are a serious health concern we believe that this study is highly relevant to public health. Therefore, our long-term objective is to develop """"""""off the shelf, functional tissue-engineered vascular grafts and patches for vascular surgery, thus ultimately impacting thousands of patients. Our approach is based on development of acellular scaffolds derived from blood vessels that encourage repopulation by host cells and facilitate remodeling after implantation, while maintaining adequate mechanical functions. Due to their very dense matrix, decellularized blood vessels are not fully conducive to cell repopulation and unless scaffolds are stabilized, degeneration and calcification may occur upon implantation. Our pure elastin scaffolds obtained by removal of the collagen component (in addition to cell removal), are more porous than decellularized arteries and are more readily repopulated and remodeled in vivo, as compared to decellularized arteries.
In Specific Aim 1. We will prepare and fully characterize pure elastin scaffolds obtained from porcine arteries and treat with penta-galloyl glucose (PGG), an elastin- stabilizing phenolic tannin, for management of enzyme-mediated biodegradation and inhibition of calcification. As criteria for stabilization we will test resistance to metalloproteinases (MMPs) using gravimetry, ELISA and ultrastructural analysis. Mechanical properties of stabilized elastin including stress- strain, compliance, burst pressure and residual strain (recoil) will also be evaluated. Stabilized elastin scaffolds will be then treated with basic fibroblast growth factor (bFGF) for enhanced repopulation and neovascularization, and bFGF-binding stability will be assayed by in vitro leaching studies.
In Specific Aim 2. stabilized, bioactive elastin scaffolds will be implanted subdermally in rats for initial evaluation of biocompatibility and host reactions and selection of optimal PGG concentration. Tubular elastin constructs, treated with PGG and bFGF, will be seeded with autologous endothelial cells for thrombosis resistance and used as interposition vascular grafts in a circulatory rabbit model and their properties, including patency, remodeling, inflammation, immunological reactivity and thrombogenicity, will be evaluated. Properties of engineered elastin scaffolds will be consistently compared to those of decellularized artery controls. ? ? ?
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