Preparation of biomimetic hydrogels for cellular recruitment to induce myocardial regeneration

According to the World Health Organization, cardiovascular diseases are the major cause worldwide of mortality and morbidity, taking approximately 17.9 million lives each year. Current therapies are focused on protecting the heart from the progression of the disease rather than inducing myocardial regeneration and facilitating self-repair. Nevertheless, many strategies for therapeutic regeneration are being developed in order to achieve long-term functional stabilization and improvement in the heart function. One of these involves the use of injectable hydrogels as carriers of nanoparticles or bioactive molecules aiming to restore the cardiomyocytes functionality. Alginate-based hydrogels have reached clinical trials in cardiac applications because of their high biocompatibility and promising results by improving cardiac tissue remodelling. However, alginate presents some drawbacks such as its low degradability in vivo because of the absence of alginate-degrading enzymes in mammals and the reduced cell adhesion because of the lack of cell-interacting regions on its structure. In this project, an alginate derivative was formulated in order to obtain a novel oxidized alginate-based hydrogel (ADA hydrogel). Degree of oxidation and yield of reaction were studied for two different samples of ADA. FTIR analysis underlined the formation of free reactive aldehyde groups that can bind covalently to molecules that contain amino groups, such as proteins or small peptides. Afterwards, ADA was crosslinked with gelatin with different weight ratios (70/30 and 50/50) to obtain an injectable, and most important, biodegradable and bioactive hydrogel because of the faster degradation rate and free reactive aldehyde groups of ADA. Nevertheless, results obtained led to the need of further research and for future work. Literature was revised to overcome the two main limits of the applied research approach. In the first place, an improved protocol for oxidizing alginate was described, aiming to an increased reproducibility of the process by changes in the reagents, such as the use of sodium alginate with medium viscosity grade instead of low viscosity grade, because of its greater strength and swelling properties, and changes in the sodium metaperiodate/sodium alginate ratio, according to the desired degree of oxidation, based in a theoretical analysis. In the second place, it was proposed an alternative strategy for ADA crosslinking with calcium alginate, aiming to increase the hydrogel stability. Finally, diverse techniques were presented for ADA hydrogel functionalization with a cardioprotective peptide, Thymosin β4, in order to activate resident cells and recruiting them to initiate a self-repair process.