Design and characterization of an injectable hydrogels for cellular reprogramming

During Myocardial infarction (MI), cardiomyocytes (CMs) irreversible death occurs, leading to the formation of a non-contractile fibrotic scar. To date, heart transplantation remains the only effective clinical therapy to restore heart function. An alternative promising strategy is the use of injectable hydrogels as minimally invasive systems for the release of bioactive agents for cardiac repair. In situ release of specific micro-RNAs (miRNAs) has been previously found to trigger direct reprogramming of human cardiac fibroblasts (CFs) into CMs, favoring heart regeneration. Alginate-based injectable hydrogels are widely used in biomedical applications thanks to their promising results in supporting cardiac regeneration. However, alginate (ALG) presents some limitations such as low degradability in vivo and poor cell adhesion. Partial oxidation of ALG chains can overcome these drawbacks, leading to the formation of alginate dialdehyde (ADA). Specifically, through Schiff-base reaction, ADA can form covalent bonds with bioactive molecules containing amino groups, such as gelatin (GEL). In this thesis project, an injectable ADA-GEL crosslinked hydrogel was designed for in situ controlled delivery of miRNAs-loaded nanoparticles (NPs), to mechanically sustain damaged myocardium and promote heart regeneration. The goal was to select an ADA-GEL hydrogel composition with biomimetic stiffness and injectable properties. The work is part of BIORECAR ERC project (contract nr: 772168, www.biorecar.polito.it).