Research On Preparation Of Polyzwitterion-Based Hydrogels And Their Application For Allevation Of Myocardial Infarction

Myocardial infarction(MI)is an acute ischemic cardiovascular disease caused by coronary artery occlusion,which is the main cause of death around the world.After MI occurs,the propagation of electrical pulses in the damaged myocardium is interrupted,causing problem in synchronous beating.To address this problem,in this thesis,an injectable zwitterionic hydrogel was designed to utilize the ionic conductivity to alleviate the blockage of electrical impulse signal conduction in the demaged myocardium.Firstly,a zwitterionic macromonomer PCB-OAA was designed and prepared.The thiol-acrylate Michael addition reaction occurred between PCB-OAA and dithiothreitol(DTT)to generate an injectable PCB-OAA hydrogel,and the intrinsic conductivity provided by positive and negative ions in PCB-OAA hydrogel was quivalent to that of natural myocardium.Subsequently,owing to the antioxidant capacity of free DTT and tethered-DTT residues,the PCB-OAA hydrogel could scavenge active oxygen.The PCB-OAA hydrogel exhibited a protective effect on cells under the oxidative stress microenvironment that hydrogen peroxide simulated,which could improve cell survival rate.After being injected into the infarcted myocardium of MI rats,the zwitterionic PCB-OAA hydrogel could effectively improve the microenvironment,alleviating high oxidative stress,significantly inhibitting the inflammatory response,down-regulating MI markers and homocysteine,and enhancing the level of antioxidant markers.The experimental outcomes revealed that the PCBOAA hydrogel could effectively improve ventricular function,reduce the fibrosis level of MI and facilitate neovascularization.Another notable feature of zwitterions is the ability to resist non-specific protein adsorption and resist adhesion of cells,so stem cells encapsulated in zwitterionic hydrogel can maintain the pluripotency,thus prolong the time of paracrine effects and is beneficial to improve MI.Based on that,the zwitterionic macromonomer PCB-OAA mixed with rat bone marrow mesenchymal stem cells(r BMSCs)and thiol-modified polyethylene glycol(HS-PEG-SH)were loaded into a microfluidic system to obtain r BMSCs-bearing microgels(r BMSCs@microgels).The r BMSCs were uniformly distributed in the microgel and maintained good survival state for a long time.The r BMSCs in PCB-PEG microgels exhibited a highly compact morphology in a superhydrophilic microenvironment,which was benefical for maintaining the stemness.At the same time,the r BMSCs were encapsulated in the low-oxygen microenvironment induced by microgels,thus enhancing the expressions of proangiogenic factors and anti-inflammatory cytokines in the r BMSCs@microgels,which were analysed by ELISA.To increase the retention of r BMSCs@microgels in the infarcted area,tyraminemodified hyaluronic acid(HA-Tyr)was mixed with the r BMSCs@microgels,and then hydrogen peroxide/horseradish peroxidase was used to calalyze the inter-pheonal coupling reaction between HA-Try and puerarin to form an injectable hydrogel(HATyr-PUE).Loading puerarin endowed the HA-Tyr-PUE hydrogel with an excellent antioxidant ability to scavenge active oxygen.Injecting HA-Tyr-PUE hydrogel loaded with r BMSCs@microgels(HA-Tyr-PUE@r BMSCs@microgels)into the infarcted area of MI rats could significantly reduce the inflammatory response,decrease cell apoptosis,and relieve the oxidative stress induced by excessive reactive oxygen species.Animal experimental results demonstrated that the HA-Tyr-PUE@r BMSCs@microgels could favorably regulate the microenvironment of infarcted area,reduce fibrosis,increase ventricular wall thickness and promote neovascularization,thus significantly restoring cardiac function and ventricular structure.