Abstract
Epicardial placement of mesenchymal stromal cells (MSCs) is a promising strategy for cardiac repair post-myocardial infarction, but requires the design of biomaterials to maximise the retention of donor cells on the heart surface and control their phenotype. To this end, we propose the use of a poly(2-alkyl-2-oxazoline) (POx) derivative, based on 2-ethyl-2-oxazoline and 2-butenyl-2-oxazoline. This POx polymer can be cured rapidly (less than 2 min) via photo-irradiation due to the use of di-cysteine cell degradable peptides. We report that the cell-degradable properties of the resulting POx hydrogels enables the regulation of cell protrusion in corresponding 3D matrices and that this, in turn, regulates the secretory phenotype of MSCs. In particular, the expression of pro-angiogenic genes was upregulated in partially cell-degradable POx hydrogels. Improved angiogenesis was confirmed in an in vitro microfluidic assay. Finally, we confirmed that, owing to the excellent tissue adhesive properties of thiol-ene crosslinked hydrogels, the epicardial placement of MSC-loaded POx hydrogels promoted the recovery of cardiac function and structure with reduced interstitial fibrosis and improved neovascular formation in a rat myocardial infarction model. This report demonstrates that engineered synthetic hydrogels displaying controlled mechanical, cell degradable and bioactive properties are particularly attractive candidates for the epicardial placement of stem cells to promote cardiac repair post myocardial infarction.
Highlights
Myocardial infarction (MI) remains a major cause of death and disability worldwide
The concentration of the POx backbone had a significant impact on the storage modulus, increasing at higher polymer contents, in agreement with other synthetic hydrogels crosslinked via thiol-ene chemistry (Figure 1C) [43]
The design of degradable POx hydrogels is found to be an attractive strategy for the epicardial placement of mesenchymal stromal cells (MSCs)
Summary
Mesenchymal stromal cell (MSC)-based therapy is an emerging treatment for MI. Epicardial placement of MSCs has recently been successful in preclinical studies. This approach achieves higher retention rate of donor cells, compared to other methods, which leads to enhanced myocardial repair and cardiac function post-MI [1]. In order to translate such pre-clinical success into clinically effective strategies, several hurdles remain to be tackled. These include the type and quality of donor MSCs and the design of biomaterials enabling efficient epicardial placement whilst regulating stem cell phenotype [2,3,4,5]
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