Polymeric Microneedle Arrays with Glucose-Sensing Dynamic-Covalent Bonding for Insulin Delivery

Abstract

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.

Glucose-Responsive Injectable Thermogels via Dynamic-Covalent Cross-Linking of Pluronic Micelles

“…Recent decades have seen a dramatic rise in the incidence of diabetes, and with it an increased focus on new routes for insulin delivery to improve treatment. − Glucose-responsive technologies and delivery approaches, including those based on hydrogels, constitute one ongoing effort to better recreate and replace the natural temporal signaling of insulin with more biomimetic therapeutics. − In this regard, dynamic-covalent bonding between phenyboronic acids (PBAs) and cis- 1,2 or cis- 1,3-diols offers one of the most commonly explored approaches to achieve glucose-responsive function. , PBAs are Lewis acids that form dynamic-covalent complexes with diols at pH values near or above a specific p K a governing the equilibrium between their neutral trigonal form and their anionic, diol-binding tetrahedral form; the PBA–Diol bond is furthermore susceptible to competition from ambient glucose, itself a cis- 1,2 diol . PBA–Diol bonds have thus been used to prepare hydrogels formed by dynamic-covalent cross-linking in order to afford glucose-responsive features such as network swelling, gel erosion, and the release of encapsulated insulin or other payloads. − …”

Catalytic Materials Enabled by a Programmable Assembly of Synthetic Polymers and Engineered Bacterial Spores

“…We synthesized five different fluorescent PBA probes from 4-carboxyphenylboronic acid and its derivatives bearing various substituents at the meta position (Figures 2b and S2.1−S2. 19). Ortho-substitutions to the boronic acid were avoided to minimize additional variables, such as steric strain, which could limit the desired π-conjugation.…”

“…In our previous study, boronic acids have been shown to react with teichoic acid diols in bacterial cell walls and were harnessed as a reliable chemical handle for material synthesis . Prior works in boronic acid-bearing polymers yielded self-healing hydrogels, glucose-responsive materials, and recyclable polymers through their reactivity toward diol and polyol species. − Application of this dynamic covalent chemistry at the interface between macromolecules and engineered bacterial spores should therefore offer a powerful method to access functional spore-based materials with all the tunability and sustainability merits of abiotic dynamic covalent networks, such as self-healing, adaptiveness, and on-demand recycling.…”

Biomimetic strain-stiffening in fully synthetic dynamic-covalent hydrogel networks

“…The dynamic-covalent bond between a phenylboronic acid (PBA) and a cis-1,2 or cis-1,3 diol has been widely explored in preparing glucose-responsive materials due to its susceptibility to competition from free glucose. [26][27][28][29][30][31][32] The PBA-diol interaction is also sensitive to environmental parameters such as pH or temperature, with bonds formed more readily in pH conditions at or above the pK a of the specic PBA motif and bond dynamics being accelerated with increased temperature. This has led to the preparation of biomimetic PBA-diol crosslinked hydrogels responsive to a variety of stimuli.…”