DOI: 10.7274/28735253.v1
title: Engineering of Glucose-Responsive Dynamic-Covalent Platforms for Prolonged Insulin Release in Type-1 Diabetes Management

description: Diabetes management relies on exogenous insulin administration, yet current delivery strategies lack the ability to autonomously regulate insulin release in response to fluctuating blood glucose levels. This dissertation presents a series of glucose-responsive insulin delivery platforms designed to enhance injection convenience, improve glucose sensitivity, minimize insulin leakage, and extend therapeutic duration.
In this thesis, first, an injectable thermogel system was developed to facilitate easy administration while achieving glucose-responsive insulin release. By leveraging Pluronic micelle-based dynamic-covalent crosslinking, this hydrogel maintains a low-viscosity sol state for injection and rapidly transitions into a stable hydrogel upon reaching physiological temperature. The incorporation of glucose-sensitive phenylboronic acid (PBA) linkages enables controlled insulin release in response to hyperglycemia, offering improved usability and therapeutic precision in diabetic rodent models.
Building on this approach, a diboronate (DiPBA)-crosslinked hydrogel was designed to address the limitations of traditional PBA–diol interactions. This system significantly enhances glucose binding specificity and responsivity, overcoming competition from non-glucose analytes such as fructose and lactate. The superior glucose-triggered release profile demonstrated in vitro and in vivo suggests improved reliability and selectivity for glucose-responsive insulin delivery.
To further reduce unintended insulin leakage inherent to hydrogel-based systems, a hyaluronic acid (HA)-DiPBA conjugate was developed as a prodrug-like carrier. In this system, insulin is chemically modified with a glucose-sensitive diol motif, allowing dynamic-covalent binding to HA-DiPBA. Upon glucose elevation, competitive binding displaces insulin from the carrier, thereby achieving a controlled release mechanism while minimizing premature diffusion. This approach represents a shift away from traditional hydrogel entrapment, addressing key challenges in achieving stable and tunable insulin bioavailability.
For extended glucose-responsive insulin delivery, a dendrimer–insulin nanocomplex system was developed, integrating electrostatic interactions and DiPBA-mediated glucose-responsive dynamic-covalent bonding. This formulation demonstrated week-long insulin bioavailability in swine models, with insulin release precisely tuned to glucose fluctuations. The nanocomplex depot offers a promising solution for long-acting, glucose-responsive insulin therapy, reducing injection frequency while maintaining glycemic control.
Finally, a new strategy for optimizing PBA–diol glucose-responsivity was explored by modifying diol chemistry to reduce crosslinking affinity. This design enhances glucose competition at physiological concentrations, thereby improving glucose sensitivity of PBA-based hydrogel networks. This insight offers a new molecular engineering perspective for fine-tuning glucose-responsive drug delivery materials.
Together, these findings contribute to the advancement of autonomous insulin delivery systems, demonstrating innovative biomaterial-based approaches to achieve precise, sustained, and glucose-regulated insulin release. The integration of injectable thermogels, advanced crosslinking chemistries, prodrug carriers, nanocomplex formulations, and rationally designed diol derivatives offers a versatile platform for next-generation insulin therapies with the potential for clinical translation.