No abstract

A subclass of hydrogels which are prepared from supramolecular interactions can realized enhanced functionality, especially in the context of biomedical applications, upon the inclusion of temperature-responsive properties.

Nature achieves remarkable function from the formation of transient, nonequilibrium materials realized through continuous energy input. The role of enzymes in catalyzing chemical transformations to drive such processes, often as part of stimulidirected signaling, governs both material formation and lifetime. Inspired by the intricate nonequilibrium nanostructures of the living world, this work seeks to create transient materials in the presence of a consumable glucose stimulus under enzymatic control of glucose oxidase. Compared to traditional glucose-responsive materials, which typically engineer degradation to release insulin under highglucose conditions, the transient nanofibrillar hydrogel materials here are stabilized in the presence of glucose but destabilized under conditions of limited glucose to release encapsulated glucagon. In the context of blood glucose control, glucagon offers a key antagonist to insulin in responding to hypoglycemia by signaling the release of glucose stored in tissues so as to restore normal blood glucose levels. Accordingly, these materials are evaluated in a prophylactic capacity in diabetic mice to release glucagon in response to a sudden drop in blood glucose brought on by an insulin overdose. Delivery of glucagon using glucose-fueled nanofibrillar hydrogels succeeds in limiting the onset and severity of hypoglycemia in mice. This general strategy points to a new paradigm in glucose-responsive materials, leveraging glucose as a stabilizing cue for responsive glucagon delivery in combating hypoglycemia. Moreover, compared to most fundamental reports achieving nonequilibrium and/or fueled classes of materials, the present work offers a rare functional example using a disease-relevant fuel to drive deployment of a therapeutic.

The ongoing rise in diabetes incidence necessitates improved therapeutic strategies to enable precise blood glucose control with convenient device form factors. Microneedle patches are one such device platform capable of achieving therapeutic delivery through the skin. In recent years, polymeric microneedle arrays have been reported using methods of in situ polymerization and covalent crosslinking in microneedle molds. In spite of promising results, in situ polymerization carries a risk of exposure to toxic unreacted precursors remaining in the device. Here, a polymeric microneedle patch is demonstrated that uses dynamic-covalent phenylboronic acid (PBA)−diol bonds in a dual role affording both network crosslinking and glucose sensing. By this approach, a pre-synthesized and purified polymer bearing pendant PBA motifs is combined with a multivalent diol crosslinker to prepare dynamic-covalent hydrogel networks. The ability of these dynamic hydrogels to shear-thin and self-heal enables their loading to a microneedle mold by centrifugation. Subsequent drying then yields a patch of uniformly shaped microneedles with the requisite mechanical properties to penetrate skin. Insulin release from these materials is accelerated in the presence of glucose. Moreover, short-term blood glucose control in a diabetic rat model following application of the device to the skin confirms insulin activity and bioavailability. Accordingly, dynamic-covalent crosslinking facilitates a route for fabricating microneedle arrays circumventing the toxicity concerns of in situ polymerization, offering a convenient device form factor for therapeutic insulin delivery.

Stimuli-responsive hydrogels are an area of active discovery for approaches to deliver therapeutics in response to disease-specific indicators. Glucose-responsive delivery of insulin is of particular interest in better managing diabetes. Accordingly, hydrogels have been explored as platforms that enable both a rate and dose of insulin release aligning with the real-time physiological disease state; materials often include glucose sensing by dynamic-covalent cross-linking between phenylboronic acids (PBAs) and diols, with competition from ambient glucose reducing cross-link density of the material and accelerating release of encapsulated insulin. Yet, these materials historically have challenges with insulin leakage, offer limited glucose-responsive release of the insulin payload, and require unreasonably high injection pressures for syringe administration. Here, a thermogel platform prepared from temperature-induced micelles formed into a network by PBA–Diol cross-linking is optimized using a formulation-centered approach to maximize glucose-responsive insulin delivery. Importantly, the dual-responsive nature of this platform enables a low-viscosity sol at ambient temperature for facile injection, solidifying into a stable viscoelastic hydrogel network once in the body. The final optimized formulation affords acceleration in insulin release in response to glucose and enables single dose blood glucose control in diabetic rodents when subjected to multiple glucose challenges.