Hydrogels that are capable of wet adhesion and self-healing can enable major advances in a variety of biomedical applications such as tissue regeneration, wound dressings, wearable/implantable devices, and drug delivery. We hereby developed an innovative but simple strategy to achieve adhesive, self-healing, and highly stretchable double-network hydrogels, which were composed of a primary covalent polyethylene glycol diacrylate (PEGDA) network in combination with a noncovalent network of highly diffusive, giant PEG chains. The adhesion to substrates including tissue matrices was instant and repeatable due to the diffusive PEG chains that can spontaneously penetrate and entangle with the substrate network. Combining the intrinsic biocompatibility of PEG and rational design for tuning the hydrogel network properties, we exemplarily demonstrated that this hydrogel can be used as a three-dimensional matrix for cell culture or as a tissue adhesive for wound healing. The in vivo study showed that the hydrogel is capable of effectively triggering skin wound healing with a significantly lower immune response in comparison to commercial tissue adhesives currently used in clinics. Therefore, our study provides new and critical insights into the design strategy to achieve adhesion and rehealability by taking advantages of the entanglement effect from double-network hydrogels and opens up a new avenue for the application of entanglement-driven hydrogels in regenerative medicine.

Osteoporosis is a wide-range disease with a negative impact on bone defect healing. Strontium ranelate (SR) has promising osteogenic potential for its dual function on stimulating osteoblasts and inhibiting osteoclast activity. However, it has limitations for its dose-dependent effect and side effects on systemic applications. Here, a sequentially cross-linking strategy including enzyme-cross-linking through tyrosinase from mushroom and physical folding is acquired to create SR loaded gelatin nanoparticle/silk fibroin aerogel (abbreviated as S/G-Sr-MT) with drug release controlling capacity. The results showed successful enzyme-cross-linking, excellent spatial structure, and enhanced mechanical properties of S/G-Sr-MT. Even Sr2+ loading and stable release with markedly inhibited initial burst release were detected. The biomineralization investigation showed rapid deposition of hydroxyapatite on the surface of S/G-Sr-MT. In vitro, spreading morphology and higher osteogenic gene expression of MC3T3-E1 seeded on S/G-Sr-MT were observed compared to other groups after 7 day culturing. In vivo, S/G-Sr-MT showed an obvious osteogenic capacity in calvaria defects of ovariectomized rats in which high Runx2 expression and inhibited TRAP activity were observed. Such results suggested the S/G-Sr-MT scaffold could stimulate osteogenic differentiation of osteoblasts while inhibiting osteoclast behaviors in vivo. These findings highlight the potential osteogenic ability and clinical application of SR incorporated enzyme-cross-linked scaffold in ovariectomized (OVX) bone healing.