Transplantation of stem cell spheroid-laden three-dimensional patches with bioadhesives for the treatment of myocardial infarction.

Abstract

Abstract Background Myocardial infarction (MI) is treated with stem cell transplantation using various methods. However, current methods, such as stem cell/spheroids injection, cell sheets, and cardiac patches have some limitations, such as low stem cell engraftment and poor therapeutic effects. Furthermore, these methods cause secondary damage due to injection and suturing to immobilize them in the heart, inducing side effects. Methods We fabricated human adipose-derived stem cell spheroids-laden three-dimensional (3D)-printed patches. The morphology, viability, and paracrine angiogenic effect of spheroids formed within 3D patches were analyzed in in vitro experiments. We synthesized thiolated gelatin and maleimide-conjugated gelatin as the polymers and fabricated a tissue adhesive biosealant using the polymers. The biocompatibility and biodegradability of the biosealant were evaluated using human dermal fibroblasts in vitro and the mouse subcutaneous models in vivo. In addition, the therapeutic effects of stem cell spheroid-laden 3D patches (S_3DP) with biosealant were evaluated using a rat MI model in vivo. Results The spheroids showed increased viability and expression of angiogenic factors compared to two-dimensional cultured cells. Our gelatin-based tissue adhesive biosealants were rapidly formed via a thiol-ene reaction and disulfide bond formation and revealed stronger tissue adhesiveness than commercial fibrin glue. Furthermore, we successfully applied S_3DP using a biosealant in a rat MI model without suturing in vivo, thereby improving cardiac function and reducing fibrosis of the heart. Conclusion We developed S_3DP with gelatin-based tissue adhesive biosealant to treat MI. This 3D patch has dual modules, such as open pockets to directly deliver the spheroids with their paracrine effects and closed pockets to improve the engraft rate by protecting the spheroid from harsh microenvironments. In summary, S_3DP and biosealant have excellent potential as advanced stem cell therapies with a sutureless approach to MI treatment.