Date of Award
Doctor of Philosophy (PhD)
LABERGE , MARTINE
RAMAMURTHI , ANAND
SIMIONESCU , DAN
Approximately 85,000 heart valve replacement surgeries are performed every year in United States and about 300,000 surgeries worldwide. It is estimated that half of them are mechanical valve replacements and the other half bioprosthetic valve replacements. The use of bioprosthetic heart valves is slowly increasing. Bioprosthetic heart valves are made from porcine aortic valves or bovine pericardium. Commercially these bioprostheses are currently crosslinked using glutaraldehyde (GLUT) to prevent tissue degradation and reduce tissue antigenicity. GLUT crosslinks these bioprostheses by stabilizing the collagen present in the tissue via a Schiff base reaction of the aldehyde with the hydroxylysine / lysine residues of collagen. However, Glut crosslinked BHVs fail due to structural dysfunction or calcification and need second replacements. 10 years after surgery, 20-30% of these valves become dysfunctional, and more than 50% of them fail between 12 - 15 years postoperatively.
GLUT is known to be a good fixative for the collagenous component of the heart valves. However, GLUT is known to cause cytotoxicity and it is one of the causes of calcification of BHVs. Several alternative fixatives have been researched for BHV stabilization. Physical methods of crosslinking include ultraviolet irradiation and dye mediated photo-oxidation (PhotoFix®, Carbomedics, Austin, TX). Alternative chemical fixatives include stabilization using epoxy compounds, diphenylphosphorylazide, acyl azides, cyanamide, diisocyanates, diglycidyl ether, polyethylene glycol (PEG), carbodiimide (Ultifix®, Medtronic, Minneapolis, MN), diamine bridges, triglycidylamine, sodium metaperiodate, reuterin and genepin. They have shown significantly lower calcification of BHVs, however none of the above mentioned crosslinker is proven successful in long-term clinical studies. Glutaraldehyde is still the only major crosslinker used for clinically used BHVs.
Glycosaminoglycans (GAGs) and elastin the other two major components of heart valves apart from collagen are not stabilized by GLUT fixation. It has been shown that GAGs are lost during harvesting, fixation, storage, in vitro cyclic fatigue and after in vivo animal implantation. Clinically explanted BHVs also show GAG depletion. GAGs are an important component of the valves and they maintain a hydrated environment in the valves and help in absorbing compressive and shear stresses acting on the valve and resisting local tissue buckling. It has been hypothesized that loss of these important matrix elements might result in the accelerated degeneration of BHVs. Furthermore, fixation of these components in the valves may help in the better biomechanics of the valves and also improve in vivo durability of the valves. Better extracellular matrix (ECM) stabilization to prevent degeneration will determine the long-term success and durability of these valves.
Crosslikers such as carbodiimide, triglycidylamine, and sodium metaperiodate were tried as GAG-targeted fixatives; however, they were unable to completely inhibit the enzyme mediated degradation of GAGs. The focus of this study is on using neomycin trisulfate, a hyaluronidase inhibitor, along with GAG-targeted fixative carbodiimide for stabilizing the GAGs present in the valves. Systematic approach is used in our studies to determine the tissue GAG content, resistance to enzymatic GAG degradation, collagen and elastin stability, in vitro cyclic fatigue, in vivo calcification, effect on biomechanical properties of valves as well as combination with anti-calcification treatments to prevent both degeneration and calcification. We show that neomycin based chemistry significantly stabilize GAGs in the BHVs against GAG degrading enzymes and such fixation would improve long-term durability of the prosthesis.
Raghavan, Devanathan, "ECM STABILIZATION STRATEGIES FOR BIOPROSTHETIC HEART VALVES FOR IMPROVED DURABILITY" (2008). All Dissertations. 320.