Date of Award

8-2007

Document Type

Thesis

Degree Name

Master of Science (MS)

Legacy Department

Bioengineering

Advisor

Vyavahare, Naren R

Committee Member

Simionescu , Dan T

Committee Member

Nagatomi , Jiro

Abstract

Currently, bioprosthetic heart valves are crosslinked with glutaraldehyde to prevent tissue degradation and to reduce tissue antigenicity. Glutaraldehyde forms stable crosslinks with collagen via a Schiff base reaction of the aldehyde with an amine group of the hydroxylysine/lysine in collagen. However, within a decade of implantation, 20-30% of these bioprostheses will become dysfunctional and over 50% will fail due to degeneration within 12-15 years post-operatively.
Gylcosaminoglycans, a major constituent of valvular tissue, play an important role in maintaining a hydrated environment necessary for absorbing compressive loads, modulating shear stresses, and resisting tissue buckling. One of the disadvantages of glutaraldehyde crosslinking is its incomplete stabilization of GAGs, which lack the amine functionalities necessary for fixation by aldehyde addition. Previous studies have reported a greater depth of buckling in glutaraldehyde crosslinked aortic valves, one of the major causes of failure in these bioprostheses. Buckling occurs at sites of sharp bending, producing large stresses that can eventually lead to mechanical fatigue and consequent valvular degeneration. Local structural collapse occurs at these areas of tissue buckling to minimize compressive stresses, which subsequently causes a reduction in tissue length.
Previous studies have reported the loss of GAGs in glutaraldehyde crosslinked porcine cusps during fixation, storage, in vitro fatigue experimentation, and in vivo subdermal implantation due to enzyme-mediated GAG degradation. Additionally, GAG loss has been observed in failed porcine bioprosthetic heart valves following clinical use.
Therefore, to evaluate the potential role of GAGs in reduction of buckling in bioprosthetic heart valves, we used two 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) based crosslinking chemistries that link GAG carboxyl groups to the amine groups of proteins. Neomycin trisulfate, a hyaluronidase inhibitor, was employed to effectively stabilize the GAGs and subsequently prevent its enzymatic degradation. Previously, stabilization of valvular GAGs using neomycin trisulfate, a GAG-enzyme inhibitor, coupled with carbodiimide fixation chemistry was found to resist in vitro and in vivo enzymatic degradation of GAGs. Thus, using the above-mentioned GAG-targeted fixation strategies, we demonstrate that the retention of valvular GAGs reduces the extent of buckling in bioprosthetic heart valves, which may subsequently improve the durability of these bioprostheses.

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