Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Biomedical Engineering

Supervisor

Kibret Mequanint

Abstract

Therapeutic angiogenesis relies on the delivery of exogenous growth factors to stimulate neovessel formation. However, systemic administration of angiogenic factors results in rapid clearance from the site of interest due to their short biological half-life. In this work, we are reporting controlled delivery of a ‘cocktail’ of growth factors, an angiogenic factor −fibroblast growth factor-2 (FGF2), and an arteriogenic factor −fibroblast growth factor-9 (FGF9), from biodegradable poly(ester amide) (PEA) electrospun fibers towards targeting neovascular formation and maturation. FGF2 and FGF9 were dual loaded into PEA fibers using a mixed blend and emulsion electrospinning technique. Matrigel tube formation and Boyden chamber assays were used to evaluate neovessel formation in vitro. Chick chorioallantoic membrane (CAM) model coupled with power Doppler ultrasound imaging, and ischemic hindlimb mouse model were employed to assess the in vivo angiogenic capacity of the delivery system. Co-released FGF2 and FGF9 from dual loaded PEA fibers enhanced endothelial cell tube formation, directed-migration of smooth muscle cells towards PDGF-BB, and tube stabilization in vitro. The 3D power Doppler volumes of the CAM displayed enhanced localized angiogenesis underneath the fibrous mats with enhanced blood perfusion and flow. Histological analysis of the ischemic tibialis anterior muscle revealed increased percentage of mural cell-covered microvessels in mice treated with FGF9-loaded PEA fibers than those treated with unloaded fibers. This supports the premise that controlled delivery of fibroblast growth factors from biodegradable PEA electrospun fibers can provide means for minimally invasive revascularization of ischemic tissues as a novel approach for treatment of ischemic vascular disease.

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