Controlled Delivery System Of Injectable Hydrogel With Nanoparticles For Myocardial Infarction Repair

Myocardial infarction is one of the leading causes of global death. Due to ischemia andhypoxia, myocardial cells suffered irreversible damage, accompanied by the degradation ofextracellular matrix, causing myocardial cell loss and cardiac function, and eventually lead toheart failure. Adult myocardial cells, terminally differentiated cells, lack ability ofproliferation.Exogenous cells including embryonic stem cells and bone marrow cells are widely used topromote the function recovery of cardiac tissue. However, this strategy faces many challenges:for example, embryonic stem cells faces ethical issues and problems of immune rejection; bonemarrow mesenchymal stem cells may cause myocardial calcification although without ethicsand immune rejection; iPS, which showed the strongest promise of solving these problems,however, exhibited thepotentialofinducing strong immunerejection. Recent studies showthat,under specific stimulate condition, adult myocardial cells will enter mitosis split state. Thediscovery provides a new strategy for the treatment of myocardial infarction by promoting theheart own cardiac cell proliferation. The program has a good advantage, and that there is noethics and immune rejection problems, but also to strengthen the integration of new cells withtheoriginalmyocardialtissue,to avoidtheoccurrenceofarrhythmia.BIO (6-bromoindirubin-3-oxime) is a small molecule compounds with the ability ofpromoting cardiomyocyte proliferation and IGF (insulin-like growth factor) could promoteangiogenesis, both are essential for cardinal repair. In the present study, a novel strategyinducing both myocardialcell proliferation and angiogenesis through sustained deliveryof BIOand IGF in situ is proposed. Therefore, new myocardial cells are complemented as well asimprove the blood supply of the cardiac tissue, and ultimately the heart functions are restored.The system is composed of injectable hydrogels and nanospheres encapsulating both BIO andIGFwhich can becross-linked to hydrogel. Firstly, thein vitroreleasing behavior wasevaluatedby UV method, then a three-dimensional cultured primary rat cardiomyocytes model was usedfor simulating in vivo releasing and the myocardial cells proliferation effect. Secondly, the invivo releasing behavior was studied by a smallanimal in vivo imaging system. Thirdly,SDratswith old myocardial infarction model was fabricated and the cardiomyocyte proliferation,angiogenesis, cardiac function were investigated by injecting thesysteminto the infarction area.Our results demonstrated that the system exhibited long term slow-releasing in vitro andsignificantly promoted the proliferation of cardiomyocytes in three dimensional culture states.The system could be releasedin vivo sustained for nine days while less than2days for control.Finally, co-delivery of BIO and IGF significantly induced cardiomyocyte proliferation,angiogenesis,therebyimproving cardiacfunction.