In Situ Formation of Proangiogenic Mesenchymal Stem Cell Spheroids in Hyaluronic Acid/Alginate Core/Shell Microcapsules

Mesenchymal-stem-cell (MSC)-based therapies have been recognized as promising strategies for the treatment of various injuries or diseases due to their unique characteristics, such as self-renewal, differentiation potential, and secretion of various bioactive molecules. However, MSC transplantation often results in low efficacy, including a cell viability loss and a low therapeutic activity. Alternatively, MSC spheroids have been studied to improve the viability and therapeutic activity of MSCs. Also, microencapsulation of cells can protect and retain the cells from harsh environments after transplantation. Here, MSC spheroids were formed in hyaluronic acid/alginate (HA@Alg) core-shell microcapsules and employed for neovascularization. A well-defined core-shell structure of HA@Alg microcapsules was produced by optimizing various electrospraying conditions. MSC spheroids could be spontaneously formed in the HA core of the microcapsules after 1 day of incubation. An enhanced secretion of various growth factors was found from MSC spheroids in HA@Alg. In vivo plug assay revealed the significant promotion of angiogenesis by MSC spheroids in HA@Alg compared to that by the controls (i.e., MSCs and MSC spheroids), which is likely due to the better retention of MSC spheroid forms in the microcapsules. Thus, the HA@Alg microcapsules embedding MSC spheroids will be greatly beneficial for various stem cell-based therapies.