A Combinatorial Approach to the Design of Boronate Ester Hydrogels Reveals the Remarkable Binding Properties of a Bicyclic Diol

Viscoelastic hydrogels are increasingly being used in the biomedical field, with applications ranging from 3D cell culture to drug delivery. Boronate ester (BE) formation is one of the dynamic covalent reactions that can be used for viscoelastic hydrogel design. BE formation stands out for the stability and relative bioorthogonality of its precursors, i.e., phenylboronic acids and diols. However, BE hydrogels usually lack stability, are soft, and behave like fast-relaxing viscoelastic liquids at physiological pH due to low BE binding strength. To address these limitations, we performed a combinatorial screening of BE crosslinking pairs based on PBAs and cyclic cis-diols, using hyaluronic acid as a base polymer. Our study revealed the unique ability of norbodiol, a bridged bicyclic cis-diol, to form BE hydrogels with all the PBAs tested. We demonstrated that this is due to norbodiol’s exceptional association constants (Ka) with PBAs, which can reach values of up to 6600 M–1. Compared to a list of other diols, we further showed that the remarkable properties of norbodiol could be explained by its rigid bicyclic structure and the specific three-dimensional orientation of its two hydroxyl groups. These findings provide initial insights toward a deeper understanding of the optimal diol structure for BE formation and stability. Norbodiol-based BE crosslinking produced hydrogels whose relaxation properties were 20- to 200-fold greater than those of previous systems. We further optimized two hydrogel formulations with single or dual BE crosslinking for use in various biomedical applications, highlighting the potential of our discovery.