Date of Award
Master of Science (MS)
Vyavahare, Naren R
LaBerge , Marine
Nagatomi , Jiro
Bioprosthetic heart valves (BHVs) fail within 12-15 years of implantation due to limited durability. This limits their application to elderly population. Younger patients with contraindications for long-term anticoagulant therapy necessary for mechanical heart valves may also receive BHVs. Investigation into improving valve durability can lead to longer implant life, increased quality of life for patients receiving BHVs, and a broadened patient demographic.
Current BHVs are chemically treated with glutaraldehyde (GLUT) to stabilize collagen via chemical crosslinking and to reduce tissue antigenicity. GLUT fails to adequately stabilize elastin and glycosaminoglycans (GAGs), essential extracellular matrix components for valve function and durability. Degradation of elastin also increases elastin-oriented calcification. Previous use of neomycin and carbodiimide crosslinking has improved GAG stability. Similarly, use of pentagalloyl glucose (PGG), a plant polyphenol, has previously improved elastin stability in aortic wall and abdominal aortic aneurysm. We have focused on long term GAG stability using neomycin and carbodiimide crosslinking to replace GLUT, and the use of neomycin and PGG along with GLUT to stabilize elastin.
The first study shows improved long term GAG stability when tissue treated with neomycin and carbodiimide crosslinking is stored for ten months or implanted subdermally in rats for up to 15 weeks. The second study evaluated stabilization of all extracellular matrix components against enzymatic degradation in an in vivo model, mechanical properties, and calcification potential and extracellular matrix stability in a rat subdermal model. This study demonstrated a marked increase in extracellular matrix stability when compared to GLUT control. Further, the changes we saw to mechanical properties can be attributed to specific crosslinking modalities. Neomycin, PGG and GLUT crosslinked tissue also demonstrated increased calcification potential in a rat subdermal model when compared to GLUT controls.
In these studies we present two viable heart valve fixation techniques. One replaces GLUT with carbodiimide based chemistry, to stabilize GAGs and remove negative effects caused by GLUT. The other adds neomycin and PGG to GLUT to stabilize elastin and GAGs in bioprosthetic heart valve leaflets. By stabilizing these components, in vivo tissue and valve mechanics may improve, accompanied by an increase in valve durability.
Tripi, Daniel, "STABILIZATION OF EXTRACELLULAR MATRIX COMPONENTS IN BIOPROSTHETIC HEART VALVES USING NEOMYCIN AND PENTAGALLOYL GLUCOSE ENHANCED CROSSLINKING" (2012). All Theses. 1439.