Dynamic-covalent polymer networks with glucose-sensing bonding

The preparation of soft materials using dynamic-covalent motifs offers certain features and properties of both physical and covalent polymer networks. When dynamic-covalent interactions are used for network crosslinking, the resulting materials are dynamic arising from their equilibrium-governed mode of crosslinking, enabling properties like shear-thinning and self-healing and offering a useful approach to the design of injectable hydrogels for therapeutic delivery. One particular dynamic-covalent chemistry is the boronate ester that arises from bonding between phenylboronic acids (PBA) and cis-1,2 diols. We have leveraged this motif for its specific utility in the design of glucose-responsive materials; glucose, itself a cis-1,2 diol, can compete with immobilized diols on polymeric materials to reduce the extent of network crosslinking and accelerate the release of encapsulated payloads such as insulin. By designing PBA–diol crosslinking, hydrogel networks can be prepared with glucose-responsive mechanical properties and glucose-directed insulin release. These dynamic materials are furthermore amenable to molding protocols to prepare transdermal microneedles for minimally invasive therapeutic delivery. Addressing a limitation of this PBA–diol crosslinking chemistry, we also prepared a diboronate (DiPBA) variation that enabled bidentate glucose binding with enhanced affinity and specificity over other physiologically relevant analytes. The performance of dynamic-covalent networks was improved when the DiPBA motif was used in place of a traditional PBA motif for network crosslinking. Accordingly, we have developed several polymeric materials that sense glucose and adjust their crosslinking to direct the release and bioavailability of insulin and furthermore have tested these materials in an assortment of diabetes animal models. We envision that these approaches, centered on polymer-based formulation and delivery of unmodified or minimally modified protein drugs, will yield therapeutic solutions that are responsive, safe, and more efficacious in managing diabetes.