Bioinspired chitosan cardiac patches: assemblies with the secretome of Mesenchymal Stem Cells for cardiac tissue regeneration – MYOCHITO

Several studies in the literature have shown that the beneficial effects on cardiac muscle regeneration caused by cell injection come mainly from the effects induced by cell secretions. These secretions, called secretomes, contain biologically active molecules («trophic factors«): proteins, hormones, cytokines, vesicles, etc.
In this context, the objective of the MYOCHITO project was to develop a biomaterial enriched with trophic factors capable of allowing the regeneration and functional recovery of cardiac muscle after a myocardial infarction. The biomaterial that was developed was a hydrogel designed in the form of a patch/membrane in order to be positioned and sutured on the injured tissue. In this work, we chose to elaborate the hydrogel patch from a natural polysaccharide, chitosan, a polymer notably known for its numerous biological properties (biodegradability, fungistaticity, bacteriostaticity, healing activity, etc.). Trophic factors were collected from cultures of mesenchymal stromal cells widely used for cardiac regeneration applications.

The project has allowed to develop and define the optimal characteristics of a hydrogel patch enriched in secretome for the targeted cardiac application. This «bio-functionalized« biomaterial was tested on a rat model of chronic myocardial infarction.
The results obtained in this pre-clinical model validate the feasibility of combining a biomaterial with a secretome to promote cardiac regeneration and to improve cardiac function after 30 days of treatment.

From an industrial point of view, the acellular approach removes many of the obstacles to conventional cell therapy by offering a product that is sterilizable, more reproducible, devoid of the risks of immune rejection and easily transportable.
The development of chitosan physical hydrogels enriched with secretome from mesenchymal stromal cells appears to be a promising strategy for the regeneration and functional recovery of cardiac muscle after myocardial infarction. Further study and understanding of the cellular mechanisms that may explain these beneficial effects is now required. For example, it would be interesting to consider a new series of patch implantation to try to better understand what happens the days after biomaterial placement.
The hydrogel patches enriched with secretome constitute a reserve of trophic factors which will be released during the hours, then in a second time during the degradation of the gel. Different approaches can still be tested during the preparation of these biomaterials to try to further enrich the patches in trophic factors.

O. Domengé, H. Ragot, R. Deloux, A. Crépet, G. Revet, S. E. Boitard, A. Simon, N. Mougenot, L. David, T. Delair, A. Montembault+, O. Agbulut+ (+equally contributing authors). Efficacy of epicardial implantation of acellular chitosan hydrogels in ischemic and nonischemic heart failure: impact of the acetylation degree of chitosan. Acta Biomaterialia. 2021, 119, 125-139 (doi: 10.1016/j.actbio.2020.10.045).
Other publications are in progress.

The main objective of this project is to develop new acellular patches that will allow regeneration and functional recovery of the cardiac muscle after acute myocardial infarction. The strategy is to associate polysaccharide hydrogels with the secretome of mesenchymal stem cells and then to evaluate these biomaterials in vitro (cardiomyocyte cultures) and in vivo (rat model of cardiomyopathy).
Thus polysaccharide-based gels will be produced varying in composition and associated or not with the secretome. The retention of various components of the secretome within the gels will be investigated, probably affected by gels composition and their physico-chemical properties. Moreover, the association of oppositely charged polymers to produce hydrogels will allow the modulation of the mechanical and biological properties of the final biomaterials. Rat and canine cardiomyocytes will be cultured in vitro on gels to assess the effect of gel composition or the secretome compounds on the survival, proliferation and functionalities of cardiomyocytes. In vivo evaluation will be carried out in a rat myocardial infarction model to evaluate therapeutic potential of this approach.
Thus, gathering knowledge from these in vitro and in vivo evaluations will allow us to investigate the transposition from rat to canine models in order to prepare a further pre-clinical experiment on dog model.