Initial Steps towards Spatiotemporal Signaling through Biomaterials Using Click-to-Release Chemistry

The process of wound healing is a tightly controlled cascade of events, where severe skin wounds are resolved via scar tissue. This fibrotic response may be diminished by applying anti-fibrotic factors to the wound, thereby stimulating regeneration over scarring. The development of tunable biomaterials that enable spatiotemporal control over the release of anti-fibrotics would greatly benefit wound healing. Herein, harnessing the power of click-to-release chemistry for regenerative medicine, we demonstrate the feasibility of such an approach. For this purpose, one side of a bis-N-hydroxysuccinimide-trans-cyclooctene (TCO) linker was functionalized with human epidermal growth factor (hEGF), an important regulator during wound healing, whereas on the other side a carrier protein was conjugated—either type I collagen scaffolds or bovine serum albumin (BSA). Mass spectrometry demonstrated the coupling of hEGF–TCO and indicated a release following exposure to dimethyl-tetrazine. Type I collagen scaffolds could be functionalized with the hEGF–TCO complex as demonstrated by immunofluorescence staining and Western blotting. The hEGF–TCO complex was also successfully ligated to BSA and the partial release of hEGF upon dimethyl-tetrazine exposure was observed through Western blotting. This work establishes the potential of click-to-release chemistry for the development of pro-regenerative biomaterials.