Factors which affect the calcification of tissue‐derived bioprostheses

Abstract

Mineralization of implanted bioprostheses poses a major clinical problem. Crosslinking of collagenous matrices, a process used to render tissues relatively inert and nonbiodegradable, seems to encourage calcification. Residual, noncovalently bound glutaraldehyde, as well as glutaraldehyde crosslinks which can be degraded with time, seem to play a role in this connection.Our findings demonstrate the need to carefully remove noncovalently or labile-associated glutaraldehyde by thorough rinsing or neutralization before implantation. Components of a valve prosthesis such as cusps and aortic wall, which are known to vary in their proportions of collagen, elastin, and noncollagenous proteins and to calcify to different extents, can both be prevented from calcifying if treated with a biphosphonate before implantation. Calcification can also be reduced by selective enzymatic removal of noncollagenous materials. In addition to the age of rats, animals usually used to evaluate calcification, the strain of animal can markedly affect the response. The Fischer-344 rat, a highly inbred animal, will not calcify exhaustively rinsed implants. Our findings suggest that multifactorial approaches may have to be combined to generate the most ideal bioprostheses. These should include careful removal of noncovalently bound glutaraldehyde, neutralization of the nonbifunctionally reacted residues, removal of lipids and noncollagenous proteins (and possibly the more antigenic nonhelical collagen telopeptides), as well as inclusion of agents such as biphosphonates, which by interfering with crystal growth prevent the accumulation of mineral in the interstices of the tissue.

Elastin as a biomaterial for tissue engineering

“…bioprosthetic heart valves and aortic homografts). Besides crosslinked cellular debris, elastin and collagen may serve as nucleation sites for mineralisation, independent of cellular components [100][101][102]. Calcifi cation may be genetically controlled by molecules that actively inhibit calcifi cation and may occur passively when these inhibitors are absent [103].…”

Periodate-mediated glycosaminoglycan stabilization in bioprosthetic heart valves

“…In addition, the devitalized nature of BPHVs after glutaraldehyde treatment prevents any cellmediated remodeling of the extracellular matrix (ECM) that would otherwise maintain GAG concentrations. 1,5 The implications of this have been demonstrated in clinically retrieved BPHVs derived from glutaraldehyde-crosslinked porcine aortic cusps, which exhibit decreased levels of GAG molecules. 4 Reduction in cuspal GAG concentrations has also been shown in rheumatic and aged valves, both of which are highly prone to failure.…”

Natural and Prosthetic Heart Valve Calcification: Morphology and Chemical Composition Characterization

“…In the case of bioprosthetic valves, usually made from porcine and bovine heart tissues, besides the already mentioned factors, calcification is also related to the valve treatment before implantation (4)(5)(6)(7). The stabilization of tissues by glutaraldehyde promotes cell death, and it has been demonstrated that its activity persists for many months, slowly liberating active glutaraldehyde monomers, causing the death of host fibrocytes and macrophages that come into contact with the toxic valve material (1).…”