Immobilization of heparin on decellularized kidney scaffold to construct microenvironment for antithrombosis and inducing reendothelialization

In recent years, rapid development of tissue engineering technology provides possibilities for the construction of artificial tissues or organs. In construction of engineered kidneys, researchers used native decellularized extracellular matrix(ECM) as the scaffolds to recellularization. However, thrombosis has been a great issue that hinders the progress of transplantation in vivo. In this study, heparin was immobilized to the collagen part of decellularized scaffold with collagen-binding peptide(CBP). Through the anticoagulant and endothelial cell reperfusion experiments, it can be demonstrated that the heparinized scaffolds absorbed less platelets and red blood cells which can effectively reduce the formation of thrombosis. Moreover, it is conducive to longterm adhesion of endothelial cells which is important for the formation of subsequent vascularization. Taken together, our results reveal that the whole kidney can be modified by CBP-heparin composite to reduce the thrombosis and provide the better conditions for neovascularization.

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.

Anti-thrombotic effect of W007B,a newly synthesized compound,in vitro and in vivo

In the present study, we investigated anti-thrombotic effects of W007B, a water-soluble derivative of honokiol, with different models both in vitro and in vivo. Rat platelet aggregation was induced by adenosine diphosphate （ADP）, thrombin, arachidonic acid （AA） and collagen in vitro. The anti-thrombotic effects were evaluated with the arterio-venous shunt model, electrode-stimulated carotid thrombosis model in rats and ADP-induced acute pulmonary embolic model in mice. The bleeding time in vivo was examined with tail incision in mice. W007B inhibited ADP-, thrombin-, collagen- and AA-induced platelet aggregation in a concentration-dependent manner, with an ICs0 value of 899.5 μM, 212.9 μM, 266.0 μM and 52.5 μM, respectively. In vivo, W007B （2-10 mg/kg, ig） significantly reduced the thrombus weight in the model of arterio-venous shunt. Besides, W007B could effectively prolong the occlusion time in the electrode-stimulated carotid thrombosis model. Moreover, in the ADP-induced acute pulmonary embolism model in mice, 2.8-14 mg/kg of W007B significantly reduced the death of mice. In conclusion, W007B is effective on platelet aggregation, and it is most sensitive on AA-induced aggregation. W007B has potent anti-thrombotic effect on different arterial thrombosis models. It may be an orally active candidate of anti-thrombotic agents.

Discovery of novel aspartate derivatives as highly potent and selective FXIa inhibitors

As a coagulation factor in the intrinsic coagulation pathway,factor XIa(FXIa)is an effective and safe target for the development of antithrombotic drugs.Many small-molecule FXIa inhibitors have been discovered,some of which are being evaluated in clinical trials.However,none of them have been approved.In the present study,a highly selective potent FXIa inhibitor with poor solubility reported in our previous work was selected as a lead compound to be further modified to improve FXIa potency and physicochemical properties.The structure-based drug design and structure-activity relationship study led to the discovery of LY8,LY17,and LY25,which demonstrated enhanced FXIa potency and maintained excellent selectivity.In addition,LY8 exhibited significantly improved aqueous solubility,suggesting that it could be a promising compound to be further evaluated.