Injectable microcapillary network hydrogels engineered by liquid-liquid phase separation for stem cell transplantation

Injectable hydrogels are promising carriers for cell delivery in regenerative medicine. However, injectable hydrogels composed of crosslinked polymer networks are often non porous and prevent biological communication with host tissues through signals, nutrients, oxygen, and cells, thereby limiting graft survival and tissue integration. Here we report injectable hydrogels with liquid-liquid phase separation-induced microcapillary networks ({micro}CN) as stem cell-delivering scaffolds. The molecular modification of gelatin with hydrogen bonding moieties induced liquid-liquid phase separation when mixed with unmodified gelatin to form {micro}CN structures in the hydrogels. Through spatiotemporally controlled covalent crosslinking and dissolution processes, porous {micro}CN structures were formed in the hydrogels, which can enhance mass transport and cellular activity. The encapsulation of cells with injectable {micro}CN hydrogels improved cellular adhesion, spreading, migration, and proliferation. Transplantation of mesenchymal stem cells with injectable {micro}CN hydrogels enhanced graft survival and recovered hindlimb ischemia by enhancing material-tissue communication with biological signals and cells through {micro}CN. This facile approach may serve as an advanced scaffold for improving stem cell transplantation therapies in regenerative medicine.