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 biphosphohates, which by interfering with crystal growth prevent the accumulation of mineral in the interstices of the tissue.

Neomycin fixation followed by ethanol pretreatment leads to reduced buckling and inhibition of calcification in bioprosthetic valves

“…This high ratio suggests that calcification did not show poorly crystalline hydroxyapatite generally seen in BHV calcification in these groups. It has been suggested that reduction of free aldehydes by sodium borohydride in glutaraldehyde crosslinked tissues reduces calcification38 but we did not see any difference in the present study. Many of the previous studies included other neutralizing agents such as glutamic acid or L ‐lysine in addition to NaBH 4 that may have affected calcification 39.…”

Effects of periodate and chondroitin 4-sulfate on proteoglycan stabilization of ostrich pericardium. Inhibition of calcification in subcutaneous implants in rats

“…The most extended commercial chemical modification of biological tissues is GA crosslinking; however, this treatment is one of the major causes for clinical failure of bioprosthetic tissues combined with deposition of proteins and lipids and mechanical stress. Several authors have demonstrated that GA treatment induces an structural deterioration of collagen molecules and promotes GAGs extraction, both processes being probably linked to an increased calcification [7,26].…”

Biological Calcification

“…Calcification of degenerative type does, in fact, affect over 50% of glutaraldehyde-treated porcine aortic valves implanted in young patients, and from 5-10% of those implanted in adults, 5-10 years after implantation . In addition, because bioprosthetic valves are fixed with glutaraldehyde to improve their durability and make them less biodegradable, a number of studies have been carried out to detect the role this type of fixation may have in promoting valve calcification (Grabenwoger et al 1996;Nimni et al 1997), its effects on intracellular calcium and phosphate concentration (Kim et al 1999;Kim 2001), and the changes it may induce in the molecular tissue configuration (Girardot et al 1995). Obviously, this potentially highly dangerous process has repeatedly been studied to determine the role of the host metabolism, the effect of the mechanical forces involved and -the question most pertinent to the aims of this book -which of the valve components is locally responsible for the calcification process.…”