Low-fouling granular hydrogel for efficient preparation and delivery of stem cell spheroids towards wound treatment

Stem cell spheroids possess higher viability and up-regulated paracrine function, showing advanced curative effect. However, the barrier of efficient spheroids preparation and application limits spheroids application in clinical. The present study developed an “all-in-one” porous granular hydrogel to not only produce numerous stem cell spheroids, but also apply the spheroids conveniently for wound treatment. Poly (sulfobetaine methacrylate) (PSBMA)-based microgels that cross-linked with disulfide bonds assembled, and further cross-linked by in-situ co-polymerized poly (N-isopropylacrylamide-co-sulfobetaine methacrylate) (P(NIPAM-co-SBMA)) to prepare porous composite granular hydrogel with bulk, shear-thinning, self-healing, hundred micron pores and low-fouling feature. Adipose-derived stem cells (ASCs) seeded into the porous composite granular hydrogel formed numerous spheroids inside the hundred micron pores. The porous composite granular hydrogel carrying produced ASC spheroids were spread onto the wound like creams. Then, PSBMA-based microgels dissolved quickly and spontaneously, forming extensive pores with the size less than 10 μm, which ensured the effective release of growth factors produced by stem cell spheroids into the wound. In vivo evaluation confirmed that ASC spheroids up-regulated the secretion of anti-inflammatory factors and reparative growth factors, effectively inhibited the local inflammatory response of wounds in the early stage of wound, thus accelerating wound healing.