Neomycin and carbodiimide crosslinking as an alternative to glutaraldehyde for enhanced durability of bioprosthetic heart valves

Abstract

Glutaraldehyde cross-linked porcine aortic valves, referred to as bioprosthetic heart valves (BHVs), are often used in heart valve replacements. Glutaraldehyde does not stabilize glycosaminoglycans (GAGs) and they are lost during preparation, in vivo implantation, cyclic fatigue, and storage. We report that binding of neomycin, a hyaluronidase inhibitor, to the tissues with carbodiimide cross-linking improves GAG retention without reducing collagen and elastin stability. It also led to improved biomechanical properties. Neomycin carbodiimide cross-linking did not significantly reduce calcification in a rat subdermal implantation model when they were stored in formaldehyde after cross-linking. Removal of formaldehyde storage significantly reduced calcification.

A novel crosslinking method for improved tear resistance and biocompatibility of tissue based biomaterials

“…This protective ability for neomycin towards GAGs has been previously demonstrated in our laboratory in which tissues treated with neomycin combined with glutaraldehyde reduced GAG loss during enzymatic treatment and this retention in GAGs reduced the tissue’s propensity to buckle compared to glutaraldehyde only treated tissue [11]. Furthermore, tissues treated with neomycin and carbodiimide chemistry has previously been demonstrated to prevent GAG loss during enzymatic treatment and this retention has shown similar biomechanics to GLUT valves [36]. However, neomycin treatment was unable to stabilize elastin, another important component of the ECM [6, 11].…”

“…Glutaraldehyde only actively crosslinks collagen and leaves other key ECM components such as GAGs and elastin unstabilized in the overall tissue composite [24]. Elastin and GAGs that play crucial roles in the biomechanics of the native heart valve tissue are left open to proteolytic degradation by both host and endogenous enzymes as well as constant mechanical fatiguing of the tissue [6, 9, 16, 18, 35, 36]. Slow depletion of these ECM components compounded with constant cyclic loading may lead to microtears after valve implantation.…”

“…If this backbone is stabilized, GAGases are unable to hydrolyze proteoglycans thus increasing the retention of GAGs in the ECM. By using neomycin in conjunction with a crosslinker that utilizes amine groups for crosslinking such as glutaraldehyde or carbodiimide, neomycin can be incorporated into the crosslinking scheme sustained protective effect to prevent GAG loss [6, 11, 16, 35, 36]. This protective ability for neomycin towards GAGs has been previously demonstrated in our laboratory in which tissues treated with neomycin combined with glutaraldehyde reduced GAG loss during enzymatic treatment and this retention in GAGs reduced the tissue’s propensity to buckle compared to glutaraldehyde only treated tissue [11].…”

Reinforced Pericardium as a Hybrid Material for Cardiovascular Applications

“…17 Despite the discrepancies in origin of the deterioration, a strong correlation between GA-treated tissue and increased calcification suggests that the chemical fixation of the tissue further inhibits the appropriate remodeling.…”

Movement Effects on the Flow Physics and Nutrient Delivery in Engineered Valvular Tissues

“…The primary appeal of TEHVs lies in their potential to integrate and grow with the patient, but in addition, TEHVs could potentially overcome current valve replacement barriers such as hemolysis, immune rejection, calcification, anticoagulation therapies and the need for multiple invasive surgeries (Chen et al, 2013;Hmiel, 2012;Leong et al, 2013;Munnelly et al, 2012;Nora et al, 2012;Syedain, 2009a).…”