(Invited) Artificial on-Skin Pancreas Fabricated with Smart Hybrid Hydrogel for Self-Regulated Insulin Delivery

Abstract

Diabetes mellitus is the sixth leading cause of death. Traditional insulin injection not only involves pain, inconvenience, infection and nerve damage, but also is difficult to achieve persistent glycemic control. Current “closed-loop” delivery systems are either electronics-derived or protein-based, leading to the concerns of electrical failure or immunetoxicity. Phenylboronic acid (PBA), which can reversibly bind with glucose, is an attractive candidate for glucose sensing and self-regulated insulin delivery as it does not have the denaturing and immunetoxicity concerns. A totally synthetic smart PBA gel exhibiting supreme glucose-sensitivity at physiological pH and temperature was developed. [1] The release of insulin can be self-regulated by the skin layer formed on the gel surface and the insulin release rate was well corresponding to the external glucose concentration. [2] Recently, a catheter-combined device incorporating this smart gel has been successfully validated for mouse diabetes. [3] In order to deliver insulin in a glucose-responsive, painless, convenient and safe way, we developed an electronics-free, enzyme-free smart artificial on-skin pancreas, which is a microneedles (MNs) patch fabricated with smart hybrid hydrogel and silk fibroin. [4] The semi-interpenetrating network hydrogel was fabricated using PBA derivative for glucose sensing, N-isopropylacrylamide and silk fibroin for mechanical robustness. After skin insertion, the hybrid hydrogel in the tip region of MNs patch will continuously monitor the glucose level. At normoglycemic condition, the skin layer formed on the MNs surface will effectively block the release of insulin. However, with the increase of glucose concentration, the binding of PBA with glucose leads to the hydration of the hybrid MNs, and thus allows the release of insulin at hyperglycemia condition (Fig.1A). The hybrid hydrogel formulation was optimized by systematically investigating key parameters that may affect the gel properties, e.g. monomer concentration, silk fibroin proportion, crosslinking percentage, etc. The optimized hybrid hydrogel formed micro-porous and inter-connected structure, which enabled smooth and sustained release of loaded insulin (Fig. 1B). The physicochemical properties including swelling, stability, and glucose-responsive insulin release were explored. Furthermore, two-layer MNs were fabricated using micro-molding technology with hybrid hydrogel in the tip region and silk fibroin as the base layer. An insulin reservoir was attached to enhance the amount of loaded insulin. The morphology, gel & insulin distribution, mechanical strength of the MNs patch were characterized. The MNs patch penetrated the skin effectively, and could release insulin corresponding to the external glucose concentration (Fig. 1C). This novel on-skin pancreas is patient-friendly, possible to achieve persistent glycemic control, durable and disposable, which is promising to be the next-generation therapy for diabetes. R e ferences: [1]. A. Matsumoto et al., Chem. Commun., 2010, 46, 2203-2205. [2]. A. Matsumoto et al., Angew. Chem. Int. Ed., 2012, 51(9), 2124-2128 [3]. A. Matsumoto et al., Sci. Adv., 2017, 3(11), eaaq0723. [4]. A. Matsumoto and S. Chen, Japanese patent, No. 2018-053817, patent pending. Figure 1