Date of Award

12-2014

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Legacy Department

Bioengineering

Advisor

Simionescu, Agneta

Committee Member

Visconti, Richard P

Committee Member

LaBerge, Martine

Committee Member

Wright, Christopher C

Abstract

Myocardial infarction (MI) affects nearly 600,000 individuals each year, and the resulting damage initiates a pathophysiological progression towards congestive heart failure (CHF). A shortage of donor organs precludes heart transplantation as a practical solution, and neither surgical intervention nor stem cell therapy have yielded consistent and sufficiently positive results in clinical investigation. To prevent CHF, prospective therapies must target the cause of the maladaptive cardiac remodeling which precedes it--the nonfunctional, dyskinetic infarct scar--and aim to replace it with functional cardiac muscle. Tissue engineering holds promise for the development of novel therapies to either halt or reverse post-MI cardiac remodeling. However, early efforts to implant thick (> 100 µm), functional, tissue-engineered grafts have failed in animal models because such grafts lack the vascularization, among other features, necessary for long term survival. Therefore, the primary goal of this research was to develop a tissue-engineering approach to fulfill the need for thick, fully vascularized, and functional myocardial grafts to replace infarct scar tissue and prevent or reverse development of CHF in affected patients. First, myocardial flap scaffolds based on decellularized (DCELLed) porcine left-ventricular myocardium and its associated coronary arteries and veins were generated and characterized. All scaffolds displayed a fully intact and patent vasculature to the level of capillaries, were devoid of cellular proteins, contained only residual DNA, retained collagen, elastin, and basal laminar components, exhibited excellent mechanical properties, and were compatible towards seeded cells. To evaluate the host response to the scaffold material in a xenogeneic scenario, scaffold samples were implanted subdermally in rats. Long-term, macrophages at the implant site were observed to shift in polarization from an inflammatory to a more constructive, remodeling phenotype. In a subsequent series of studies, these scaffolds were seeded with human adipose derived stem cells (hADSC) and exposed to stimuli reflective of the cardiac environment using a custom-designed platform. Seeded constructs were subjected to various combinations of mechanical, electrical, and pharmacological stimuli with the objective of directing the differentiation of hADSC into a cardiomyocyte phenotype en route to resembling functional myocardial tissue. Finally, the feasibility of infarct scar surgical replacement with myocardial scaffold-based grafts was evaluated in a porcine model. A surgical anastomosis of the scaffold's vessels to the host's vasculature demonstrated complete perfusion of the scaffold. Hemostasis was achieved with no major bleeding events, and no complications were encountered. It is expected that this research will have a positive impact upon efforts to treat a growing population of patients suffering from complications of MI. It will not only enable clinicians to prevent or reverse the progression towards CHF--saving lives and improving the quality of life for recipients of this therapy--but also contribute to the advancement of the cardiac tissue engineering field

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Surgery Commons

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