Recent progress in functional modification and crosslinking of bioprosthetic heart valves

Valvular heart disease(VHD),clinically manifested as stenosis and regurgitation of native heart valve,is one of the most prevalent cardiovascular diseases with high mortality.Heart valve replacement surgery has been recognized as golden standard for the treatment of VHD.Owing to the clinical application of transcatheter heart valve replacement technic and the excellent hemodynamic performance of bioprosthetic heart valves(BHVs),implantation of BHVs has been increasing over recent years and gradually became the preferred choice for the treatment of VHD.However,BHVs might fail within 10-15 years due to structural valvular degeneration(SVD),which was greatly associated with drawbacks of glutaraldehyde crosslinked BHVs,including cytotoxicity,calcification,component degradation,mechanical failure,thrombosis and immune response.To prolong the service life of BHVs,much effort has been devoted to overcoming the drawbacks of BHVs and reducing the risk of SVD.In this review,we summarized and analyzed the research and progress on:(i)modification strategies based on glutaraldehyde crosslinked BHVs and(ii)nonglutaraldehyde crosslinking strategies for BHVs.

A strategy for mechanically integrating robust hydrogeltissue hybrid to promote the anti-calcification and endothelialization of bioprosthetic heart valve

Bioprosthetic heart valve(BHV)replacement has been the predo-minant treatment for severe heart valve diseases over decades.Most clinically available BHVs are crosslinked by glutaraldehyde(GLUT),while the high toxicity of residual GLUT could initiate calcification,severe thrombosis,and delayed endothelializa-tion.Here,we construed a mechanically integrating robust hydrogel-tissue hybrid to improve the performance of BHVs.In particular,recombinant humanized coilagen type Ⅲ(rhCOLⅢ),which was precisely customized with anti-coagulant and pro-endothelialization bioactivity,was first incorporated into the polyvinyl alcohol(PVA)-based hydrogel via hydrogen bond interactions.Then,tannic acid was introduced to enhance the mechanicalperfo of PVA-based hvdrogel and interfacial bonding between the hydrogel layer and bio-derived tissue due to the strong affinity for a wide range of substrates.In vitro and in vivo experimental results confirmed that the GLUT-crosslinked BHVs modified by the robust PVA-based hydrogel embedded rhCOLII and TA possessed long-term anti-coagulant,accelerated endothelialization,mild inflammatory response and anti-calcification properties.Therefore,our mechanically integrating robust hydrogel-tissue hybrid strategy showed the potential to enhance the service function and prolong the service life of the BHVs after implantation.

Functional non-glutaraldehyde treated porcine pericardium for anti-coagulation,anti-calcification,and endothelial proliferation bioprosthetic heart valves

In the last decade,the number of transcatheter heart valve replacement for severe heart valve disease has increased exponentially.Although the bioprosthetic artificial heart valve(BHV)has similar fluid dynamics performance to the original heart valve compared with mechanical heart valve so that there is no need to take long-term anticoagulant drugs to prevent thromboembolism,transcatheter BHV replacement are still at risk for thrombosis during the first few months according to the clinical data.However,the use of antithrombotic drugs can also increase the risk of bleeding.Therefore,it is particularly important to improve the anticoagulant properties for the BHV itself.In this work,a kind of non-glutaraldehyde cross-linked BHV material with excellent antithrombotic ability has been prepared from carboxylated oxazolidine treated porcine pericardium(consisting of collagen,elastin and glycoprotein)with the further graft of the anticoagulant heparin sodium via hydrophilic modified chitosan.Along with the similar mechanical properties and collagen stability comparable to the glutaraldehyde cross-linked porcine pericardium(PP),these functional non-glutaraldehyde cross-linked PPs exhibit better biocompatibility,promoted endothelial proliferation and superior anti-calcification ability.More importantly,excellent anticoagulant activity can be observed in the hematological experiments in vivo and in vitro.In summary,these excellent performances make these functional non-glutaraldehyde cross-linked PPs great potentialities in the BHV applications.

A NEW TYPE OF BIOPROSTHETIC HEART VALVE

Jin Lei,a professor at Fu Wai Hospital,Chinese Academy of Medical Sciences,invented a new method of chemical

Crosslinking of Bovine Pericardia Using Procyanidins

The aim of this study was to evaluate the crosslinking effect of a naturally crosslinking reagent-procyanidins （PA）-on the materials of bioprosthetic heart valves. After fixing bovine pericardial tissues by procyanidins, crosslikng characteristics, mechanical properties, in vitro enzymatic degradation resistance, the hydrophilicity and hemolysis tests were examined. The results showed that the fixation of biological tissue with glutaraldehyde （GA） or procyanidins increased its denaturation temperature, the surface hydrophilieity and mechanical properties as well as in vitro enzymatic degradation resistance. There were no significant differences in denaturation temperature, mechanical properties, the hydrophilicity and the in vitro enzymatic degradation between the glutaraldehyde and procyanidins fixed tissues. However, the ultimate tensile strength of the procyanidins fixed tissues was significantly superior to the glutaraldehyde fixed tissues. The hemolysis tests showed that hemolysis rate of the proeyanidins fixed tissues was lower than that of the glutaraldehyde fixed tissues. This study shows that procyanidins can crosslink which bovine pericardiaa effectively without toxicity. Our results suggest that this method might be a useful approach for the preparation of bioprosthetic heart valve.

Polyphenol based hybrid nano-aggregates modified collagen fibers of biological valve leaflets to achieve enhanced mechanical,anticoagulation and anti-calcification properties

Glutaraldehyde(Glut)-crosslinked porcine pericardium and bovine pericardium are mainly consisted of collagen and widely used for the preparation of heterogenous bioprosthetic heart valves(BHV),which play an important role in the replacement therapy of severe valvular heart disease,while their durability is limited by degeneration due to calcification,thrombus,endothelialization difficulty and prosthetic valve endocarditis.Herein,we develop a novel BHV,namely,TPly-BP,based on natural tannic acid and polylysine to improve the durability of Glut crosslinked bovine pericardium(Glut-BP).Impressively,tannic acid and polylysine could form nanoaggregates via multiple hydrogen bonds and covalent bonds,and the introduction of nanoaggregates not only improved the mechanical properties and collagen stability but also endowed TPIy-BP with good biocompatibility and hemocompatibility.Compared to Glut-BP,TPIy-BP showed significantly reduced cytotoxicity,improved endothelial cell adhesion,a low hemolysis ratio and obviously reduced platelet adhesion.Importantly,TPly-BP exhibited great antibacterial and in vivo anti-calcification ability,which was expected to improve the in vivo durability of BHVs.These results suggested that TPly-BP would be a potential candidate for BHV.

Polyphenol based hybrid nano-aggregates modified collagen fibers of biological valve leaflets to achieve enhanced mechanical,anticoagulation and anti-calcification properties

Glutaraldehyde(Glut)-crosslinked porcine pericardium and bovine pericardium are mainly consisted of collagen and widely used for the preparation of heterogenous bioprosthetic heart valves(BHV),which play an important role in the replacement therapy of severe valvular heart disease,while their durability is limited by degeneration due to calcification,thrombus,endothelialization difficulty and prosthetic valve endocarditis.Herein,we develop a novel BHV,namely,TPly-BP,based on natural tannic acid and polylysine to improve the durability of Glut crosslinked bovine pericardium(Glut-BP).Impressively,tannic acid and polylysine could form nanoaggregates via multiple hydrogen bonds and covalent bonds,and the introduction of nanoaggregates not only improved the mechanical properties and collagen stability but also endowed TPly-BP with good biocompatibility and hemocompatibility.Compared to Glut-BP,TPly-BP showed significantly reduced cytotoxicity,improved endothelial cell adhesion,a low hemolysis ratio and obviously reduced platelet adhesion.Importantly,TPly-BP exhibited great antibacterial and in vivo anti-calcification ability,which was expected to improve the in vivo durability of BHVs.These results suggested that TPly-BP would be a potential candidate for BHV.