Cross-linking agents are frequently used to restore corneal properties after decellularization,and it is especially important to select an appropriate method to avoid excessive cross-linking.In addition,how to promote...Cross-linking agents are frequently used to restore corneal properties after decellularization,and it is especially important to select an appropriate method to avoid excessive cross-linking.In addition,how to promote wound healing and how to improve scar formation require further investigation.To ensure the safety and efficacy of animal-derived products,we designed bioartificial corneas(BACs)according to the criteria for Class III medical devices.Our BACs do not require cross-linking agents and increase mechanical strength via self-cross-linking of aldehyde-modified hyaluronic acid(AHA)and carboxymethyl chitosan(CMC)on the surface of decellularized porcine corneas(DPCs).The results showed that the BACs had good biocompatibility and transparency,and the modification enhanced their antibacterial and anti-inflammatory properties in vitro.Preclinical animal studies showed that the BACs can rapidly regenerate the epithelium and restore vision within a month.After 3 months,the BACs were gradually filled with epithelial,stromal,and neuronal cells,and after 6 months,their transparency and histology were almost normal.In addition,side effects such as corneal neovascularization,conjunctival hyperemia,and ciliary body hyperemia rarely occur in vivo.Therefore,these BACs show promise for clinical application for the treatment of infectious corneal ulcers and as a temporary covering for corneal perforations to achieve the more time.展开更多
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 th...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.展开更多
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 hemat...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.展开更多
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,in...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.展开更多
基金National Science Fund for Distinguished Young Scholars(No.31625011)the National Key Research and Development Program(No.2016YFC1101100).
文摘Cross-linking agents are frequently used to restore corneal properties after decellularization,and it is especially important to select an appropriate method to avoid excessive cross-linking.In addition,how to promote wound healing and how to improve scar formation require further investigation.To ensure the safety and efficacy of animal-derived products,we designed bioartificial corneas(BACs)according to the criteria for Class III medical devices.Our BACs do not require cross-linking agents and increase mechanical strength via self-cross-linking of aldehyde-modified hyaluronic acid(AHA)and carboxymethyl chitosan(CMC)on the surface of decellularized porcine corneas(DPCs).The results showed that the BACs had good biocompatibility and transparency,and the modification enhanced their antibacterial and anti-inflammatory properties in vitro.Preclinical animal studies showed that the BACs can rapidly regenerate the epithelium and restore vision within a month.After 3 months,the BACs were gradually filled with epithelial,stromal,and neuronal cells,and after 6 months,their transparency and histology were almost normal.In addition,side effects such as corneal neovascularization,conjunctival hyperemia,and ciliary body hyperemia rarely occur in vivo.Therefore,these BACs show promise for clinical application for the treatment of infectious corneal ulcers and as a temporary covering for corneal perforations to achieve the more time.
基金supported by the National Science Fund for Distinguished Young Scholars (31625011)the National Key Research and Development Program (2016YFC1101100)+1 种基金the National Key Research and Development Plan Young Scientists Program (2017YFA0106000)the Young Elite Scientists Sponsorship Program by Cast (YESS20160180)
文摘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.
基金This work was supported by the Key projects of the National Natural Science Foundation of China(No.81830055)National Science Fund for Distinguished Young Scholars(No.31625011)+1 种基金the National Key Research and Development Program(No.2016YFC1101100)the National Science Fund for Outstanding Young Scholars(No.31822021).
文摘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.
基金We would like to thank Xing Shen and Yaqing Tang in the Innovative Drug Research Center of Chongqing University and Jing Zhou in the Department of Physiology,Basic Medical College,Peking University,for their support with the work.Thank Zhang San from Shiyanjia Lab(www.shiyanjia.com)for the modulus analysis.This work was supported by the National Key Research and Development Plan Young Scientists Program(No:2017YFA0106000)The National Science Fund for Outstanding Young Scholars(No.31822021)+1 种基金the National Science Foundation of China(No:31771057)and The National Key Research and Development Plan(No:2016YFC1101100).
文摘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.