A rule-based method for predicting the electrical activation of the heart with cardiac resynchronization therapy from non-invasive clinical data

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Intrapericardial delivery of small extracellular vesicles derived from mesenchymal stromal cells in a thermo-responsive chitosan hydrogel for myocardial repair

Administration of exosomes (or small extracellular vesicles; sEVs) derived from mesenchymal stromal cells (MSCs) promote cardiac repair post-myocardial infarction (MI). The current delivery routes include intravenous, intracoronary and intramyocardial injection; however, these have limitations in the efficacy and clinical affordability, requiring the development of improved technology. We hypothesise that intrapericardial injection will achieve an enhanced delivery of sEVs, as intrapericardial space could serve as their reservoir, protecting them from systemic wash-out and allowing their permeation into the myocardium. We also consider that incorporating sEVs in biocompatible hydrogel will increase sEV-delivery efficacy by facilitating a long-term release. To allow practical intra-pericardial injection, we developed a thermo-responsive chitosan hydrogel, allowing easy infusion through a needle at <34ºC with gelation after injection in vivo. We isolated sEVs from human amniotic membrane MSCs (hAMCs) and confirmed their identification as sEVs in terms of size, morphology, and protein expression. Scratch assays using endothelial cells showed that the addition of sEVs increased the wound closure in a doseresponsive manner. Subsequently, we examined the effect of intrapericardial delivery of sEVs loaded in a thermo-responsive chitosan hydrogel (sEV+hydrogel) in a rat acute MI model. Echocardiography demonstrated that this treatment improved cardiac function and reduced ventricular dilatation compared to the untreated, and intrapericardial injection of hydrogel only or sEVs only. Furthermore, this effect in the intrapericardial delivery of sEV+hydrogel was greater than that of intramyocardial injection of sEVs. Histological assessments showed that intrapericardial delivery of sEV+hydrogel vii reduced infarct size, increased the capillary density, reduced interstitial fibrosis, and attenuated cardiomyocyte hypertrophy in the peri-infarct myocardium. These data suggest that intrapericardial delivery of human amniotic membrane MSC-derived sEVs loaded in a thermo-responsive chitosan hydrogel is feasible and effective for the treatment of MI. Further research is warranted towards the clinical application of this novel therapeutic technology