Study On Repairing Myocardial Infarction With3Dimensional Heart-Like Tissue And Alginate Hydrogels In Rat Model

Myocardial infarction (MI) is necrosis of heart muscle due to local obstruct of heart vessel. MI and related heart diseases are the highest death rate around world because of the limited ability of regeneration and insufficient of the donors for heart transplantation. Currently, the therapy strategies for MI include heart reperfusion, relief pain, anti-arrhythmia, anti-shock, complication treatment and so on. The development of intervene therapy make many patients with MI alive. But clinic still can not treat the cardiac failure after MI due to the loss of cardiac cell and extracellular matrix degradation during cardiac ventricle reconstruction, the thining of ventricular wall, the reduced mechanics property of ventricular wall, which, can make heart function descent or heart failure. Therefore, novel strategy for treat MI is crucial needed. Variety of study showed that tissue engineering method, that fabricat artificial heart with live cell and biologic scaffold, could significantly improve heart function after MI, which provided a new way for MI therapy. However this therapy program is in the period of animal experiment. In present study, two strategies including3D heart sissue fabrication in vitro and in-situ heart tissue tissue using alginate polymer were used to repair the injury of MI respectively.Alginate is a giant molecule material with polysaccharide. Because of excellent biocompatibility and anticoagulant property, it is used widely in the tissue engineering and heart tissue engineering, especially as a frame material in bone tissue and heart tissue. Due to the cell loss during the pahtlogical process of MI and difficulty of constrction of heart tissue with highly cell density, a micoencapsulation technology was used to fabricate3D heart tissue in vitro. First, the use of different proportions of collagen developed sodium alginate/collagen composite microcapsules, and barium ions replace calcium ions to prepare composite microcapsules, the composite microcapsules cell compatibility has been significantly improved, suitable for primary rat cardiomyocytes attachment and proliferation. Two dimensional cultured myocardial cells are typically weaker proliferative capacity, but also are easy to lose the characteristics of cardiomyocytes. However, encapsulated within the microcapsules myocardial cells can be sustained in a proliferative state, and without passaging, and maintaining the characteristics of a typical myocardial cells. Therefore, the composite microcapsules technology has a unique advantage to maintain the continued proliferation of neonatal rat cardiomyocytes. The results show the proliferation of cardiac cells in the microbeads and formation of interconnected multilayer heart-like tissues, the presence of well-organized and dense cell structures, the presence of intercalated discs and spaced Z lines, and the spontaneous synchronized contractility of EHT grafts (at a rate of20–30beats min-1after two weeks., the fabricated myocardial tissue were implanted in a myocardial infarction rat model to further verify in vivo activity of the fabricated myocardial tissue. The three-dimensional fabricated myocardial tissue can significantly improve the ejection fraction of the heart after six weeks implantation due to enhanced angiogenesis in infarct location.Myocardial extracellular matrix loss initiated by MI is another critical reason for abbrent heart function. Promising results were observed in both acute and chronic rat MI models, that were treated with calcium ion cross-linked alginate hydrogels in situ combined with growth factors or grafted with bioactive peptides arginine–glycine–aspartate (RGD). Although CICAH is a promising hydrogel for cardiac infarction treatment, the polymer has its drawbacks. However, alginate hydrogels cross-linked with ions have disadvantages including an uncontrollable degradation rate, insufficient mechanical strength and poor cell affinity. In present study, covalent cross-linked hydrogel was fabricated with partial oxidated alginate by cross-linking an aldehyde group with the free amino groups in the gelatin. Chemical crosslinked injectable alginate hydrogel and ion crosslinked hydrogel comparative study of the properties of covalently crosslinked gel system, degradation of performance and cell affinity significantly better than calcium ion crosslinked hydrogel, thereby generally improve the recovery of myocardial function, the mechanical properties of the gel to106Pa, the solidification time can be regulated in30-40min, the porosity rate of50%, in vitro, and in vivo degradation rate of speed, plant into a rat model of myocardial infarction, heart function was enhanced. Histological studies that injectable gel for chemical crosslinking increased left ventricular wall thickness in the body, promote angiogenesis, and can inhibit the activity of matrix metalloproteinases MMP-2and MMP-9.In summary, to address the basic problems of myocardial cells loss and extracellular matrix damage during myocardial infarction, microencapsulated sodium alginate hydrogel3D technology was fabricated and injectable chemical cross-linked gel was designed for the extracellular matrix loss. Both stratagies significantly improved cardiac function in rat myocardial infarction model. These stratagies provide a new avenue for myocardial infarction treatment.