Development of Bioorthogonally Degradable Tough Hydrogels Using Enamine <i>N</i>‐Oxide Based Crosslinkers

Inducibly degradable polymers present new opportunities to integrate tough hydrogels into a wide range of biomaterials. Rapid and inducible degradation enables fast transition in material properties without sacrificing material integrity prior to removal. In pursuit of bioorthogonal chemical modalities that will enable inducible polymer degradation in biologically relevant environments, enamine N-oxide crosslinkers are developed for double network acrylamide-based polymer/alginate hydrogels. Bioorthogonal dissociation initiated by the application of aqueous diboron solution through several delivery mechanisms effectively lead to polymer degradation. Their degradation by aqueous B₂(OH)₄ solution results in a fracture energy half-life of <10 min. The biocompatibility of the degradable hydrogels and B₂(OH)₄ reagent is assessed, and the removability of strongly adhered tough hydrogels on mice skin is evaluated. Thermoresponsive PNiPAAm/Alg hydrogels are fabricated and application of the hydrogels as a chemically inducible degradable intraoral wound dressing is demonstrated. It is demonstrated through in vivo maximum tolerated dose studies that diboron solution administered to mice by oral gavage is well tolerated. Successful integration of enamine N-oxides within the tough double network hydrogels as chemically degradable motifs demonstrates the applicability of enamine N-oxides in the realm of polymer chemistry and highlights the importance of chemically induced bioorthogonal dissociation reactions for materials science.