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.