Construction Of Vascularized Conductive Elastic Myocardial Patch And Its Effect On The Repair Of Injured Myocardium

BackgroundCardiovascular diseases are the leading cause of death worldwide,higher than cancer and other diseases.Myocardial infarction(MI)is caused by the sudden blockage of the coronary artery,which leads to myocardial ischemia,necrosis,and heart failure.The current treatment methods of traditional drugs and interventions are unable to reverse MI and the deterioration of cardiac function.Conductive and elastic scaffold-based engineered cardiac patches have the potential to construct a regenerative microenvironment and repair MI in vivo.However,the pure conductive elastic engineered heart patch rarely forms a substantial connection with the host heart,and can not achieve effective perfusion in the myocardial infarction area.The pre-vascularization of conductive elastic cardiac patches could be an effective strategy for building a substantial connection between the patch and the infarcted heart to promote the reperfusion of the infarcted area.However,vascularization in vitro and in vivo of engineered tissues have been a long-term challenge for tissue engineering research,and vascularized heart patches based on conductive elastic scaffold materials have not yet been optimized and have few published studies.Therefore,pre-vascularized engineered cardiac patches can act as a promising material for MI repair.ObjectiveReduced holey graphene oxide/polypyrrole-based hybrid was produced and pre-vascularized engineered cardiac patches with biomimetic electrical and mechanical properties were constructed,and the repair effect of the vascularized conductive elastic heart patch on MI was explored,the possible MI repair mechanism of pre-vascularized engineered cardiac patches was discussed.Method1.holey graphene oxide(hGO)nanosheets and polypyrrole(pPy)nanoparticles were prepared.Reduced holey graphene oxide/polypyrrole-poly-(hydroxyethyl methacrylate)cryogel—p(HEMA)-rhGO/pPy cryogel(HrhGP)with biomimetic electrical and mechanical properties was constructed.The prepared materials were characterized.and the biocompatibility of HrhGPs was evaluated.2.A pre-vascularized HrhGP was constructed using coronary artery casting templates produced using traditional gross anatomy casting technology.Rat aortic endothelial cells were cultured inside and outside the HrhGP channels to produce fully vascularized HrhGP(v-HrhGP).Vascular sprouts and anastomoses were observed.A fully vascularized engineered cardiac patch(v-HrhGP ECP)was formed by which cardiomyocytes were seeded in v-HrhGP under dynamic culture conditions.The effects of different ECPs on cardiomyocyte maturation and functionalization were evaluated in vitro.3.The v-HrhGP ECP was transplanted onto infarcted hearts to determine its effect on MI repair in vivo.4.Whole-transcriptome RNA-seq was used to explore the potential mechanisms by which the conductive microenvironment and dynamic culture conditions influenced cardiomyocytes’ functionalization.And we explore the possible mechanism of v-HrhGP ECP in MI repair.Result1.Prepared HrhGP0.5(hGO/pPy=1:0.5;hGO:1mg mL-1,pPy:0.5 mg mL-1)exhibited mechanical and electrical properties similar to native myocardium,and exhibited good biocompatibility.2.The engineered vessels in HrhGP0.5 with vascular channels had good hemocompatibility.v-HrhGP0.5 can promote vascular sprouting and self-assembled vascular formation under dynamic culture conditions,and promote engineered vascular remodeling.v-HrhGP0.5 ECP facilitates cardiomyocytes’ functionalization and synchronous contraction.3.After transplantation for 4 weeks,the cardiac function of the infarcted heart was improved obviously and the infarcted area was reduced in the v-HrhGP0.5 ECP group.The v-HrhGP0.5 ECP repaired infarcted myocardium through building functional vascular anastomoses with infarcted hearts,and rebuilding the electrical integration from healthy myocardium to infarcted myocardium.4.Whole-transcriptome RNA-seq results showed that the effective MI repair of v-HrhGP0.5 ECP may be related to the activation of pathways related to cardiomyocytes’ maturation and functionalization.ConclusionWe developed a novel multi-functional engineered cardiac patch with integrated conductivity,elasticity,and full vascularization.And in vitro and in vivo results indicated that it may have a good application prospect in the repair of injured cardiac.