The application of enzymatic crosslinking and Diels–Alder (DA) click chemistry for hydrogel formation has recently bloomed, because of the efficient chemical bonding and the mild biological reaction conditions. In this study, an injectable hyaluronic acid/PEG (HA/PEG) hydrogel was successfully fabricated for the first time through integrating two cross-linking processes, including firstly enzymatic crosslinking and subsequent DA click chemistry. The enzymatic crosslinking resulted in a fast gelation of HA/PEG in 5 min, leading to the formation of an injectable material. In addition, the DA click reaction crosslinking made a hydrogel that has outstanding shape memory and anti-fatigue properties. The storage modulus and breakage strength of the hydrogels were close to 27 kPa and 109.4 kPa, respectively. The compressive strain could reach up to 81.9%. After 10 cycles of a loading and unloading test, the hydrogel still could be loaded by 80 kPa for 1 min and the corresponding deformation could be completely recovered in 1 min after unloading. The ATDC-5 cells were capsulated into the hydrogel bulk in situ and showed high metabolic viability and proliferation. All of these results suggest that the HA/PEG injectable hydrogel formed by integrating the two cross-linking processes has a great potential in cartilage tissue engineering.

Treatment of diabetic wounds with a rapid healing performance remains a critical clinical challenge. An extracellular matrix (ECM)-biomimetic structure has shown promise in promoting tissue regeneration through a mediating cellular microenvironment. Herein, we report bone ECM-biomimetic cell-free nanofibrous scaffolds for enhancing healing in diabetic full-thickness wounds. This bioactive nanofibrous matrix was composed of ECM-componential collagen (Col, mimicking protein), polycaprolactone (PCL), and bioactive glass nanoparticles (BGNs, mimicking biological apatite) (CPB). The influence and mechanism of CPB on endothelial cell behaviors, angiogenic and healing abilities were investigated in a diabetic wound rat model. CPB significantly improved attachment and proliferation of endothelial cells, and upregulated the expression of the angiogenesis marker (CD31). In vivo, CPB also significantly enhanced the angiogenesis, through greatly upregulating the mRNA and protein expressions of Hif-1α, VEGF, Col1 and α-SMA. Furthermore, due to rapid angiogenesis, granulation tissue formation, collagen matrix remodeling and epidermis differentiation were accelerated in the CPB group, and as a result efficient diabetic wound healing was observed. Our results demonstrated that the cell-free bone-ECM-biomimetic BGN-based nanofibrous matrix could efficiently enhance blood tissue regeneration and diabetic wound healing without additional growth factors. Our biomimetic materials system may also be suitable for other blood vessel-related tissue repair and regeneration processes.