Riboflavin photo‐cross‐linking method for improving elastin stability and reducing calcification in bioprosthetic heart valves

Abstract

Background:Glutaraldehyde cross-linked bioprosthetic heart valves might fail due to progressive degradation and calcification. Methods:In this study, we developed a new BHVs preparation strategy named as "HPA/TRA/FMN" that utilized 3,4-hydroxyphenylpropionic acid (HPA)/tyramine (TRA) conjugated pericardium and riboflavin 5'-monophosphate (FMN) initiated photo-cross-linking method. HPA/TRA-pericardium conjugation would provide extra phenol groups for FMN initiated photo-cross-linking. Results:The feeding ratio of riboflavin 5'-monophosphate was optimized. The collagenase and elastase enzymatic degradation in vitro, biomechanics, calcification, elastin stability in vivo, and macrophage marker CD68 were characterized. We demonstrated that riboflavin photo-cross-linked pericardiums had great collagen and elastin stability, improved mechanical properties, better resistance for calcification, and less CD68 positive macrophages in rat subdermal implantation study. Conclusions:This new riboflavin photo-cross-linking strategy would be a promising method to make BHVs which have better elastin stability, less calcification, and reduced inflammatory response. K E Y W O R D Sbioprosthetic heart valves, calcification, elastin stabilization, photo-cross-linking, riboflavin

Prosthetic heart valves for transcatheter aortic valve replacement

“…[29] However, the toxic aldehyde residues can affect the activity of phospholipids, enabling the binding of calcium ions. [30] To relieve the calcification degree of biological valves, many natural crosslinkers such as riboflavin, [31,32] tannic acid [33][34][35] and tea polyphenol [36] have been excavated, which reveal lower cytotoxicity and better biocompatibility.…”

Nitric Oxide Generation and Endothelial Progenitor Cells Recruitment for Improving Hemocompatibility and Accelerating Endothelialization of Tissue Engineering Heart Valve

“…[ 19,20 ] Thus, excellent mechanical properties exert as a fundamental requirement during the development of valve scaffolds as scaffolds with poor mechanical properties would undergo rapid wear‐and‐tear and result in deterioration and calcification. In the past, various cross‐linking agents had been used to improve scaffold mechanical strength including carbodiimide, [ 21 ] riboflavin, [ 22 ] procyanidins, [ 23 ] curcumin [ 24 ] and so on. However, while GLUT will result in inevitable calcification, universally agreed alternative cross‐linkers outperforming GLUT remained lacking.…”

Recent progress in functional modification and crosslinking of bioprosthetic heart valves

“…Biomacromolecules modified with tyramine and its analogs could undergo cross-coupling reactions between the grated phenolic groups through riboflavin-mediated photo-crosslinking [ 124 , 125 ]. Lei et al [ 98 ] reported that coupling reactions ( Figure 3A ) between phenol groups on tyrosine and p-hydroxyphenylpropionic acid grafted BHVs were initiated under the catalysis of riboflavin and ultraviolet light to achieve the crosslinking of BHVs. This crosslinking strategy for BHVs allowed for greater utilization of reactive groups (amine and carboxyl groups) on BHVs compared with the conventional glutaraldehyde crosslinking method [ 98 ].…”

“…Lei et al [ 98 ] reported that coupling reactions ( Figure 3A ) between phenol groups on tyrosine and p-hydroxyphenylpropionic acid grafted BHVs were initiated under the catalysis of riboflavin and ultraviolet light to achieve the crosslinking of BHVs. This crosslinking strategy for BHVs allowed for greater utilization of reactive groups (amine and carboxyl groups) on BHVs compared with the conventional glutaraldehyde crosslinking method [ 98 ]. Elastin on BHVs’ matrix was effectively stabilized to avoid the elastin degradation-induced calcification [ 98 ].…”