Novel tissue engineering strategies for cardiac repair after a myocardial infarction

Resumo

Irreversible heart damage produced after a myocardial infarction (MI) represents the main cause of heart failure and death worldwide. Nowadays, the most effective clinical approach after a MI is timely reperfusion, based on the reopening of the occluded coronary artery and restoration of blood flow. In parallel to its benefits, this strategy encounters a severe tissue response that results in serious damage, accounting for 50% of the final infarct size. Moreover, survivors of a MI are at increased risk of recurrent infarctions, morbid events and rehospitalisations that are costly to treat. In most cases, these patients undergo progressive cardiac deterioration, which affects their quality of life and severely threatens their lives in the long-term. Several approaches have been developed aimed at reducing reperfusion injury by the administration of cardioprotective drugs. However, their efficacy has been limited due to the short half-life of the drugs when administered in biological environments, and to off-target side effects. At the same time, a variety of stem cells has been injected in the heart in recent years with the objective of stimulating myocardial repair. Nevertheless, cell survival and retention in the heart has been very low, which has hampered therapeutic success. In this study, we proposed the implementation of tissue engineering and drug delivery systems to improve the cardiac delivery of cardioprotective drugs and stem cells and therefore enhance therapeutic outcomes. In our first approach, poly(lactic-co-glycolic acid) microparticles were explored as delivery vehicles for adipose-derived stem cells and cardiomyocytes derived from induced pluripotent stem cells. Cardiac administration of both cell types in combination with microparticles dramatically increased cell survival and retention in the ischemic myocardium, which translated into a marked increase in cardiac repair. Encouraged by the hypothesis that injected cells exerted a reparative effect by the secretion of paracrine factors, in our second strategy we optimized the isolation of extracellular vesicles secreted by cardiac progenitor cells. Different cell culture conditions and isolation techniques were compared. Finally, extracellular vesicles were incorporated in a novel injectable alginate-collagen hydrogel designed for cardiac administration. Lastly, the biodistribution and efficacy of adenosine, a cardioprotective drug, covalently linked to squalene and encapsulated in nanoparticles, was analysed in an ischemia/reperfusion MI model after intravenous administration. It was observed that squalene-adenosine nanoparticles accumulated in the infarcted myocardium and protected the heart from reperfusion injury. To conclude, research conducted in this thesis provides evidence of the therapeutic benefits of drug delivery systems to enhance cardiac repair and achieve cardioprotection after a MI.