A versatile drug-controlled release polymer brush hybrid non-glutaraldehyde bioprosthetic heart valves with enhanced anti-inflammatory, anticoagulant and anti-calcification properties, and superior mechanical performance.

Transcatheter heart valve replacement (THVR) is a novel treatment modality for severe heart valves diseases and has become the main method for the treatment of heart valve diseases in recent years. However, the lifespan of the commercial glutaraldehyde cross-linked bioprosthetic heart valves (BHVs) used in THVR can only serve for 10-15 years, and the essential reason for the failure of the valve leaflet material is due to these problems such as calcification, coagulation, and inflammation caused by glutaraldehyde cross-linking. Herein, a kind of novel non-glutaraldehyde cross-linking agent bromo-bicyclic-oxazolidine (OX-Br) has been designed and synthesized with both crosslinking ability and in-situ atom transfer radical polymerization (ATRP) function. Then OX-Br treated porcine pericardium (OX-Br-PP) are stepwise modified with co-polymer brushes of reactive oxygen species (ROS) response anti-inflammatory drug conjugated block and anti-adhesion polyzwitterion polymer block through the in-situ ATRP reaction to obtain the functional BHV material MPQ@OX-PP. Along with the great mechanical properties and anti-enzymatic degradation ability similar to glutaraldehyde-crosslinked porcine pericardium (Glut-PP), good biocompatibility, improved anti-inflammatory effect, robust anti-coagulant ability and superior anti-calcification property have been verified for MPQ@OX-PP by a series of in vitro and in vivo investigations, indicating the excellent application potential as a multifunctional heart valve cross-linking agent for OX-Br. Meanwhile, the strategy of synergistic effect with in situ generations of reactive oxygen species-responsive anti-inflammatory drug blocks and anti-adhesion polymer brushes can effectively meet the requirement of multifaceted performance of bioprosthetic heart valves and provide a valuable reference for other blood contacting materials and functional implantable materials with great comprehensive performance.

A functionalized biological heart valve by double bond crosslinking with enhanced biocompatibility and antithrombogenicity.

With the advancement of minimally invasive interventional therapy, biological heart valves (BHVs) have been extensively used in clinics. However, BHVs are generally prone to degeneration within 10-15 years after implantation due to defects including cytotoxicity, immune response, calcification and thrombosis, which are closely related to glutaraldehyde-crosslinking. In this work, we prepared a functionalized BHV through the in situ polymerization of methacrylated porcine pericardium and 2-hydroxyethyl methacrylate to avoid and overcome the defects of glutaraldehyde-crosslinked BHVs. The functionalized BHV was proven to be stable against enzymatic degradation and compatible towards HUVECs. After implantation in rats subcutaneously, a significantly mitigated immune response and reduced calcification were observed in the functionalized BHV. With the grafting of hydrophilic 2-hydroxyethyl methacrylate polymers, the antithrombogenicity of BHV was markedly enhanced by resisting the unfavorable adhesion of blood components. Moreover, the hydrodynamics of the functionalized BHV totally conformed to ISO 5840-3 under a wide range of simulated physiological conditions. These results indicate that the functionalized BHV with enhanced biocompatibility, anticalcification property and antithrombogenicity exhibited a low risk of degeneration and should be explored for further application.

Preclinical study of a self-expanding pulmonary valve for the treatment of pulmonary valve disease.

In the past decade, balloon-expandable percutaneous pulmonary valves have been developed and applied in clinical practice. However, all the existing products of pulmonary artery interventional valves in the market have a straight structure design, and they require a preset support frame and balloon expansion. This shape design of the valve limits the application range. In addition, the age of the population with pulmonary artery disease is generally low, and the existing products cannot meet the needs of anti-calcification properties and valve material durability. In this study, through optimization of the support frame and leaflet design, a self-expanding pulmonary valve product with a double bell-shaped frame was designed to improve the match of the valve and the implantation site. A loading and deployment study showed that the biomaterial of the valve was not damaged after being compressed. Pulsatile flow and fatigue in vitro tests showed that the fabricated pulmonary valve met the hydrodynamic requirements after 2 × 108 accelerated fatigue cycles. The safety and efficacy of the pulmonary valve product were demonstrated in studies of pulmonary valve implantation in 11 pigs. Angiography and echocardiography showed that the pulmonary valves were implanted in a good position, and they had normal closure and acceptable valvular regurgitation. The 180 days' implantation results showed that the calcium content was 0.31-1.39 mg/g in the anti-calcification treatment group, which was significantly lower than that in the control valve without anti-calcification treatment (16.69 mg/g). Our new interventional pulmonary valve product was ready for clinical trials and product registration.