Document Type

Dissertation

Degree

Doctor of Philosophy (PhD)

Major/Program

Biomedical Engineering

First Advisor's Name

Sharan Ramaswamy

First Advisor's Committee Title

Committee Chair

Second Advisor's Name

Arvind Agarwal

Second Advisor's Committee Title

Committee Member

Third Advisor's Name

Steven Bibevski

Third Advisor's Committee Title

Committee Member

Fourth Advisor's Name

Joshua D. Hutcheson

Fourth Advisor's Committee Title

Committee Member

Fifth Advisor's Name

Nikolaos M. Tsoukias

Fifth Advisor's Committee Title

Committee Member

Keywords

bioscaffold valve, mechanically conditioned stem cells, critical mitral valve disease, 2ply PSIS, porcine small intestinal submucosa, in vivo growth potential, ECM robust-PSIS, non-human primate model, residual PSIS, mitigate chronic inflammation

Date of Defense

11-13-2020

Abstract

Congenital heart disease, which includes heart valve defects, are the most common type of birth abnormality in the US. Infants with critical congenital valve disease have no established treatment-measure other than compassionate care options, owing to an absence of prosthetic valves in small sizes and their inability to support somatic growth. A regenerable valve would be appealing since these barriers could be overcome; it can potentially provide for growth, self-repair, infection resistance and be a permanent approach for replacing defective heart valves.

Porcine small intestinal submucosa (PSIS) bioscaffold was used to create valvular constructs with the possibility to grow overtime. PSIS bio-scaffolds consisting of two different yarn-twist configurations (2ply and 4ply) were assessed for mechanical properties to determine which scaffold would withstand fatigue loading in a similar manner to the native heart valves. It was found that fatigued 2ply PSIS exhibited higher yield stress (p

Next, a pilot study was investigated for implanting 2ply hand-made PSIS mitral valves into juvenile baboons (n=3) to assess their functionality and somatic growth longitudinally. Bioscaffold mitral heart valve function was assessed via echocardiography, while somatic growth was evaluated with a novel parameter, normalized aspect growth ratio (NAGR), where ideal growth is 1, and via histological analysis after the valves were explanted. Our results showed trivial to mild regurgitation up to 17-months post-implantation demonstrating proper functionality of the PSIS mitral valves. The NAGR was found to be roughly 1 within the first 2-4 months, showing ideal growth. The PSIS mitral valve explants were found to develop extracellular matrix (ECM) proteins of collagen, elastin, proteoglycans and fibrin at all explant time points (3-, 11- and 20- months). Overall, the PSIS mitral valves functioned well and regenerated the proper ECM components over their implantation durations. However, sudden valve failure (at 3-, 11- and 20-months post-bioscaffold mitral valve implantation) occurred in all 3 subjects.

As a possible means to circumvent valve failure, PSIS tubular mitral bioscaffold valves were subsequently seeded in vitro with bone marrow stem cells and exposed to fluid-induced shear stress patterns in a perfusion bioreactor. The cells secreted a thin layer of ECM, which potentially could help mitigate chronic inflammatory responses, an underlying reason for the valve failure that was observed with the raw PSIS bioscaffolds. It was found that our flow-conditioned valve could produce ECM proteins significantly higher (pde novo ECM that was secreted and the valvular phenotype that resulted from the flow-based mechanical conditioning of allogeneic stem cells-seeded, bioscaffold mitral valves have the potential to accelerate in vivo valve tissue formation. We thus expect these flow-conditioned valves to have longer-term function post-implantation compared to what was possible with the bioscaffold valves-alone.

Identifier

FIDC009539

Previously Published In

Gonzalez, B., et al. (2018). "Recapitulation of human bio-scaffold mitral valve growth in the baboon model." Circulation 138(Suppl_1): A11348-A11348.

Gonzalez, B. A., et al. (2020). "Physiologically Relevant Fluid-Induced Oscillatory Shear Stress Stimulation of Mesenchymal Stem Cells Enhances the Engineered Valve Matrix Phenotype." Frontiers in cardiovascular medicine 7.

Gonzalez, B. A., et al. (2020). "Porcine small intestinal submucosa mitral valve material responses support acute somatic growth." Tissue Engineering Part A 26(9-10): 475-489.

Gonzalez, B. A., Gonzalez Perez, M., Mirza, A., Scholl, F., Bibevski, S., Wagner, K. R., ... & Casares, M. (2020). Extracellular Matrix Quantification of Fully Regenerated Neochorade After Bio-scaffold Mitral Valve Implantation in a Juvenile Non-human Primate Model. Circulation, 142(Suppl_3), A14888-A14888.

Available for download on Tuesday, November 02, 2021

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