Bioorthogonal “Click-and-Release” Hydrogels for On-Demand Therapeutic Delivery in Regenerative Medicine

Inspired by the advances in click-to-release chemistry (Carlson et al., 2018; Adhikari et al., 2024), this idea proposes engineering hydrogels cross-linked via strain-promoted cycloaddition (SPAAC/TCO-tetrazine). Embed therapeutics (proteins, peptides, small molecules) within the network and engineer secondary “release handles”—such as acid-sensitive tetrazines or iminosydnones (Riomet et al., 2018)—that cleave in response to a mild, bioorthogonal trigger (e.g., pH, light, or a bioorthogonal small molecule). This dual-layer approach breaks ground by giving surgeons or clinicians precise, noninvasive temporal control over therapeutic release in tissue engineering or wound healing, which is not possible with current click-hydrogel systems (see Liu et al., 2023). It merges the concepts of click-based encapsulation and click-triggered release for next-generation biomaterials.

References:

1. Unraveling Tetrazine-Triggered Bioorthogonal Elimination Enables Chemical Tools for Ultrafast Release and Universal Cleavage. Jonathan C. T. Carlson, H. Mikula, R. Weissleder (2018). Journal of the American Chemical Society.
2. Design and Synthesis of Iminosydnones for Fast Click and Release Reactions with Cycloalkynes.. Margaux Riomet, E. Decuypère, K. Porte, Sabrina Bernard, L. Plougastel, S. Kolodych, D. Audisio, F. Taran (2018). Chemistry.
3. Trans-cyclooctene—a Swiss army knife for bioorthogonal chemistry: exploring the synthesis, reactivity, and applications in biomedical breakthroughs. Karuna Adhikari, Maarten Vanermen, Gustavo Da Silva, T. Van den Wyngaert, K. Augustyns, F. Elvas (2024). EJNMMI Radiopharmacy and Chemistry.
4. Bioorthogonal "Click Chemistry" Bone Cement with Bioinspired Natural Mimicking Microstructures for Bone Repair.. Xifeng Liu, Bipin Gaihre, Linli Li, A. Rezaei, M. Tilton, B. Elder, Lichun Lu (2023). ACS Biomaterials Science & Engineering.