A New Type of Bioprosthetic Heart Valve: Synergistic Modification with Anticoagulant Polysaccharides and Anti-inflammatory Drugs

Valvular heart disease (VHD) poses a significant threat to human health, and the transcatheter heart valve replacement (THVR) is the best treatment for severe VHD. Currently, the glutaraldehyde cross-linked commercial bioprosthetic heart valves (BHVs) remain the first choice for THVR. However, the cross-linking by glutaraldehyde exhibits several drawbacks, including calcification, inflammatory reactions, and difficult endothelialization, which limits the longevity and applicability of BHVs. In this study, λ-carrageenan with anticoagulant function was modified by carboxymethylation into carboxymethyl λ-carrageenan (CM-λC); subsequently, CM-λC was used as a cross-linking agent to stabilize decellularized bovine pericardial tissue through amide bonds formed by a 1-(3-(Dimethylamino)propyl)-3-ethylcarbodiimide/N-Hydroxysuccinimide (EDC/NHS)-catalyzed reaction between the amino functional groups within pericardium and the carboxyl group located on CM-λC. Lastly, the inclusion complex (CD/Rutin) (formed by encapsulating the rutin molecule through the hydrophobic cavity of the mono-(6-ethylenediamine-6-deoxy)-β-cyclodextrin) was immobilized onto above BHVs materials (λCar-BP) through the amidation reaction. The treated sample exhibited mechanical properties and collagen stability similar to those of GA-BP, except for improved flexibility. Because of the presence of sulfonic acid groups and absence of aldehyde group as well as the Rutin release from CD/Rutin immobilized onto BHVs, the hemocompatibility, anti-inflammatory, HUVEC-cytocompatibility, and anticalcification properties, of the CM-λC-fixed BP modified with CD/Rutin was significantly better than that of GA-BP. In summary, this nonaldehyde-based natural polysaccharide cross-linking strategy utilizing the combination of CM-λC and CD/Rutin provides a novel solution to obtain BHVs with durable and stable anticoagulant, anticalcification, and anti-inflammatory properties, and has a wide range of potential applications in improving the various properties of BHVs.