Construction of a small-caliber tissue-engineered blood vessel using icariin-loaded β-cyclodextrin sulfate for in situ anticoagulation and endothelialization

The rapid endothelialization of tissue-engineered blood vessels(TEBVs) can effectively prevent thrombosis and inhibit intimal hyperplasia. The traditional Chinese medicine ingredient icariin is highly promising for the treatment of cardiovascular diseases.β-cyclodextrin sulfate is a type of hollow molecule that has good biocompatibility and anticoagulation properties and exhibits a sustained release of icariin. We studied whether icariin-loaded β-cyclodextrin sulfate can promote the endothelialization of TEBVs. The experimental results showed that icariin could significantly promote the proliferation and migration of endothelial progenitor cells; at the same time, icariin could promote the migration of rat vascular endothelial cells(RAVECs). Subsequently,we used an electrostatic force to modify the surface of the TEBVs with icariin-loaded β-cyclodextrin sulfate, and these vessels were implanted into the rat common carotid artery. After 3 months, micro-CT results showed that the TEBVs modified using icariin-loaded β-cyclodextrin sulfate had a greater patency rate. Scanning electron microscopy(SEM) and CD31 immunofluorescence results showed a better degree of endothelialization. Taken together, icariin-loaded β-cyclodextrin sulfate can achieve anticoagulation and rapid endothelialization of TEBVs to ensure their long-term patency.

Engineering hiPSC-CM and hiPSC-EC laden 3D nanofibrous splenic hydrogel for improving cardiac function through revascularization and remuscularization in infarcted heart

Cell therapy has been a promising strategy for cardiac repair after myocardial infarction(MI),but a poor ischemic environment and low cell delivery efficiency remain significant challenges.The spleen serves as a hematopoietic stem cell niche and secretes cardioprotective factors after MI,but it is unclear whether it could be used for human pluripotent stem cell(hiPSC)cultivation and provide a proper microenvironment for cell grafts against the ischemic environment.Herein,we developed a splenic extracellular matrix derived thermoresponsive hydrogel(SpGel).Proteomics analysis indicated that SpGel is enriched with proteins known to modulate the Wnt signaling pathway,cell-substrate adhesion,cardiac muscle contraction and oxidation-reduction processes.In vitro studies demonstrated that hiPSCs could be efficiently induced into endothelial cells(iECs)and cardiomyocytes(iCMs)with enhanced function on SpGel.The cytoprotective effect of SpGel on iECs/iCMs against oxidative stress damage was also proven.Furthermore,in vivo studies revealed that iEC/iCM-laden SpGel improved cardiac function and inhibited cardiac fibrosis of infarcted hearts by improving cell survival,revascularization and remuscularization.In conclusion,we successfully established a novel platform for the efficient generation and delivery of autologous cell grafts,which could be a promising clinical therapeutic strategy for cardiac repair and regeneration after MI.

Programmable dual responsive system reconstructing nerve interaction with small-diameter tissue-engineered vascular grafts and inhibiting intimal hyperplasia in diabetes

Small-diameter tissue-engineered vascular grafts(sdTEVGs)with hyperglycemia resistance have not been constructed.The intimal hyperplasia caused by hyperglycemia remains problem to hinder the patency of sdTEVGs.Here,inspired by bionic regulation of nerve on vascular,we found the released neural exosomes could inhibit the abnormal phenotype transformation of vascular smooth muscle cells(VSMCs).The transformation was a prime culprit causing the intimal hyperplasia of sdTEVGs.To address this concern,sdTEVGs were modified with an on-demand programmable dual-responsive system of ultrathin hydrogels.An external primary Reactive Oxygen Species(ROS)-responsive Netrin-1 system was initially triggered by local inflammation to induce nerve remolding of the sdTEVGs overcoming the difficulty of nerve regeneration under hyperglycemia.Then,the internal secondary ATP-responsive DENND1A(guanine nucleotide exchange factor)system was turned on by the neurotransmitter ATP from the immigrated nerve fibers to stimulate effective release of neural exosomes.The results showed nerve fibers grow into the sdTEVGs in diabetic rats 30 days after transplantation.At day 90,the abnormal VSMCs phenotype was not detected in the sdTEVGs,which maintained long-time patency without intima hyperplasia.Our study provides new insights to construct vascular grafts resisting hyperglycemia damage.