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The aging population and the development of transcatheter aortic valve replacement (TAVR) technology largely expand the usage of bioprosthetic heart valves (BHVs) in patients. Almost all of the commercial BHVs are treated with glutaraldehyde (GA). However, the GA-treated BHVs display the drawbacks such as extracellular matrix (ECM) degradation, cytotoxicity, immune response, and calcification. In this study, radical polymerization reaction, a powerful tool commonly used in preparing polymers and hydrogels, has been developed to fix decellularized ECM instead of GA treatment. Porcine pericardium (PP) is taken as an example of ECM for BHVs fabrication to investigate the impact of radical polymerization on the tissue properties. The radical polymerization method better stabilizes collagen and elastin of PP than GA treatment and produces a soft biomaterial more like the native heart valve. Furthermore, radical polymerization cross-linked PP exhibits excellent cytocompatibility. After implanted subcutaneously in rats for 30 days, radical polymerization cross-linked PP shows better elastin stability, mitigated immune response, and reduced calcification than GA-PP. All these results suggest that radical polymerization is an ideal cross-linking method for BHVs or tissue engineering heart valve scaffolds and it also has the potential for creating a variety of ECM–polymer hybrid biomaterials in the future.

Hydrogel/porcine pericardium hybrid provides a more biocompatible biomaterial for the pre-mounted TAVI valve.

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The lifetime of bioprosthetic heart valves (BHVs) is limited by the mechanical damage and calcification. The major components of BHVs are collagen and elastin. Collagen could be well protected by glutaraldehyde (GLUT) crosslinking, while elastin is not stabilized and has a high risk of degradation, which could lead to the calcification of BHVs. We aimed to develop methods for stabilizing elastin and decreasing calcification. We investigated the combined tannic acid (TA) or epigallocatechin gallate (EGCG) with ferric chloride to stabilize elastin and prevent calcification. We found that the amount of TA/EGCG bound to elastin was in a time-dependent pattern and this reaction showed better efficiency in acidic condition and ethanol-water mixed solvents. Moreover, Fe could compete with Ca to bind to polyphenol, which could reduce the calcium deposition on BHVs. Cytotoxicity test showed that all extracts from different treatments had similar cell viabilities (85-100%). Through the combined treatments of polyphenol and ferric chloride, the pericardium had a better resistance to elastase degradation and more excellent anticalcification performance.

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

Abstract