Tunable Hydrogels Derived from Genetically Engineered Extracellular Matrix Accelerate Diabetic Wound Healing

Hydrogels composed of solubilized decellularized extracellular matrix (ECM) are attractive materials because they combine the complexity of native ECM with injectability and ease of use. Nevertheless, these materials are typically only tunable by altering the concentration, which alters the ligand landscape, or by incorporating synthetic components, which can result in an unfavorable host response. Herein, we demonstrate the fabrication of genetically tunable ECM-derived materials, by utilizing wild type (WT) and (thrombospondin-2 knockout) TSP-2 KO decellularized skins to prepare hydrogels. The resulting materials exhibited distinct mechanical properties characterized by rheology and different concentrations of collagens when characterized by quantitative proteomics. Mixtures of the gels achieved intermediate effects between the WT and the KO, permitting tunability of the gel properties. In vivo, the hydrogels exhibited tunable cell invasion with a correlation between the content of TSP-2 KO hydrogel and the extent of cell invasion. Additionally, TSP-2 KO hydrogels significantly improved diabetic wound healing at 10 and 21 days. Furthermore, hydrogels derived from genetically engineered in vitro cell-derived matrix mimicked the trends observed for tissue-derived matrix, providing a platform for faster screening of novel manipulations and easier clinical translation. Overall, we demonstrate that genetic engineering approaches impart tunability to ECM-based hydrogels and can result in materials capable of enhanced regeneration.