Cytocompatible hydrogels with good mechanical properties and predictable degradation are highly desired for many biomedical applications including stem cell and therapeutics delivery for guided tissue repair. However, existing methods for fabricating tough hydrogels usually involve non-physiological conditions, such as toxic starting materials, catalysts, or crosslinking chemistry. Moreover, precisely controlling hydrogel degradation over a broad range in a predictable manner has been extremely challenging while empirical tuning of most degradable materials’ degradation profiles often resulting in undesired changes in other properties. To solve these problems, we recently developed a versatile hydrogel formulation that allows us to fabricate cytocompatible tough hydrogels under physiological conditions with predicable and widely tunable degradations. This platform was based on a well-defined hydrogel network formed by two pairs of four-armed poly(ethylene glycol) macromers terminated with bioorthogonal azide and dibenzocyclooctyl endgroups, respectively, via labile or stable linkages. The high-fidelity, catalyst-free bioorthogonal crosslinking reaction between these pairs of macromers enabled robust crosslinking in water, phosphate buffered saline and cell culture media to afford tough hydrogels capable of withstanding >90% compressive strain. The strategic placement of labile ester linkages near the crosslinking site within this superhydrophilic network, accomplished by facile adjustments of the ratio of the macromers used, enabled broad tuning of the hydrogel disintegration rates from 2 days to >250 days that precisely matched with the theoretical prediction based on a first-order linkage cleavage kinetics. This platform holds great potential for many biomedical applications that demands cytocompatability, adequate mechanical integrity and precisely controlled temporal disintegration of the synthetic matrix.

Hydrogels with predictable degradation are highly desired for biomedical applications where timely disintegration of the hydrogel (e.g., drug delivery, guided tissue regeneration) is required. However, precisely controlling hydrogel degradation over a broad range in a predictable manner is challenging due to limited intrinsic variability in the degradation rate of liable bonds and difficulties in modeling degradation kinetics for complex polymer networks. More often than not, empirical tuning of the degradation profile results in undesired changes in other properties. Here we report a simple but versatile hydrogel platform that allows us to formulate hydrogels with predictable disintegration time from 2 to >250 days yet comparable macroscopic physical properties. This platform is based on a well-defined network formed by two pairs of four-armed polyethylene glycol macromers terminated with azide and dibenzocyclooctyl groups, respectively, via labile or stable linkages. The high-fidelity bioorthogonal reaction between the symmetric hydrophilic macromers enables robust cross-linking in water, phosphate-buffered saline, and cell culture medium to afford tough hydrogels capable of withstanding >90% compressive strain. Strategic placement of labile ester linkages near the cross-linking site within this superhydrophilic network, accomplished by adjustments of the ratio of the macromers used, enables broad tuning of the disintegration rates precisely matching with the theoretical predictions based on first-order linkage cleavage kinetics. This platform can be exploited for applications where a precise degradation rate is targeted.