Regarding synthetic self-healing materials, as healing reactions occur at the molecular level, bond formation occurs when healing chemicals are nanometer distances apart. However, motility of healing chemicals in materials is quite limited, permitting only passive diffusion, which reduces the chance of bond formation. By contrast, biological-tissues exhibit significant high-performance self-healing, and cadherin-mediated cell−cell adhesion is a key mechanism in the healing process. This is because cells are capable of a certain level of motility and actively migrate to damage sites, thereby achieving cell−cell adhesion with high efficacy. Here, we report biological-tissue-inspired, self-healing hydrogels in which azide-modified living cells are covalently cross-linked with alkyne-modified alginate polymers via bioorthogonal reactions. As a proof-of-concept, we demonstrate their unique self-healing capabilities originating from cadherin-mediated adhesion between cells incorporated into the gels as mobile healing mechanism. This study provides an example of self-healing material incorporating living components into a synthetic material to promote self-healing.

Currently, one of the major tendencies to be adopted for the design of hydrogel scaffolds in tissue engineering include that cells are loaded physically into the pores of 3D hydrogel networks. In this study, a drastic deviation from this tendency is proposed and developed a new type of hydrogel scaffold in which cells are covalently connected to 3D hydrogel networks via bioorthogonal click cross‐linking reactions of azide‐modified cells with alkyne‐modified polymers. The purpose of this study is to directly compare the utility of the covalent cell‐loading approach and the conventional physical cell‐loading approach as hydrogel scaffolds for in vivo tissue engineering. It is found that the proposed covalent cell‐loading approach significantly promotes tissue regeneration and functional recovery in vivo in comparison with the conventional physical cell‐loading approach. This is the first report demonstrating the importance of the covalent cell‐loading approach in tissue engineering. This covalent cell‐loading approach is applicable to a broad spectrum of mammalian cells, including stem cells. The present findings provide a promising new route to generate innovative hydrogel scaffolds for in vivo tissue engineering.

Desferrioxamine (DFO) upregulates HIF-1α and stimulates expression of vascular endothelial growth factor (VEGF), thereby accelerating neovascularization. As DFO acts primarily upon surrounding vein endothelial cells to stimulate angiogenesis, the angiogenic efficacy of DFO could be reduced in severely injured tissues lacking a sufficient number of vein endothelial cells. We hypothesized that combined administration of DFO and vein endothelial cells is a promising tissue engineering approach for promoting neovascularization. In this study, we evaluated the applicability of this approach using injectable, biocompatible, biodegradable nanocomposite gels consisting of poly­(d l-lactide-co-glycolide)-b-polyethylene glycol-b-poly­(d l-lactide-co-glycolide) (PLGA-PEG-PLGA) copolymers and clay nanoparticle LAPONITE. The nanocomposites exhibited irreversible thermo-gelation in the presence of DFO, and the mechanical strength was strongly affected by the amount of DFO. The storage moduli of the gels increased with increasing amount of DFO. These results indicate that the interaction between DFO and LAPONITE works as physical cross-linking points and facilitates the formation of the gel network. The nanocomposite gels achieved sustained slow release of DFO due to interactions between DFO and LAPONITE. Human umbilical vein endothelial cells (HUVECs) cultured on DFO-loaded nanocomposite gels exhibited a higher degree of vascular tube formation than cells cultured on nanocomposite gels without DFO. Moreover, the number of branching points and the diameter of the blood vessels regenerated in the gels significantly increased with increasing DFO amount, indicating that DFO released from the gels facilitates vascular tube-forming capacity. As a proof of concept, we demonstrate that the combined administration of DFO and vein endothelial cells using nanocomposite gels promotes greater angiogenesis than DFO administration alone using the same gels by in vivo experiments, confirming the validity of our hypothesis. Considering the multiple advantages of nanocomposite gels with regard to potential vascularization capacity, certain biocompatibility, biodegradability, and injectable cell- and drug-delivery capacity, we concluded that the nanocomposite gels have potential utility as scaffolding biomaterials for vascularization in tissue engineering applications.

A novel technique to form a thin hydrogel barrier on aberrantly expressed sialic acid residues on cancer cell surfaces was developed.