Synthetic “smart gel” provides glucose-responsive insulin delivery in diabetic mice

Abstract

A synthetic polymer gel–based insulin delivery device provides an artificial pancreas–like function in healthy and diabetic mice.

Biologically Inspired and Chemically Derived Methods for Glucose‐Responsive Insulin Therapy

“…This is essentially a tube with bored holes that are reversibly stoppered with the hydrogel material, capable of controlled release of insulin when appropriately stimulated by glucose in the surrounding milieu. C,D) Adapted with permission . Copyright 2017 AAAS.…”

“…Therefore, with increasing diol concentration, the equilibrium between neutral PBA, charged PBA, and diol–boronate ester shifts toward the charged/ester forms, which favors enlarged network dimensions and enables diol concentration‐driven swelling . In certain cases, a dehydrated “skin” layer on the outer surface of the hydrogel material forms under hypo‐/normoglycemic conditions, acting as a barrier to diffusive “leakage” of encapsulated insulin and addressing a challenge faced by many technologies in this field (Figure C,D) . The reversible skin layer affords a sharper release profile that more closely approximates an “on–off switch” for insulin release, a long‐term goal in the field to ensure benefit from material‐based approaches relative to other methodologies (e.g., pumps or glucose‐responsive insulin variants).…”

“…Compared to protein‐based platforms, including GOx and Con A, chemically derived sensing materials avoid complications related to protein immunogenicity or denaturation. These materials are generally amenable to heat and solvent exposure, and could undergo autoclave treatment or other sterilization methods that are incompatible with proteins . These furthermore avoid recombinant production pathways and can ordinarily be synthesized using relatively straightforward and scalable techniques from inexpensive precursors.…”

“…A subtle relationship also exists between PBA–glucose binding behavior and the apparent p K a and associated molecular structure of the PBA variant . However, this has proven difficult to optimize, as these features can simultaneously depend on hydration state, environmental parameters, polymer rigidity, and other factors …”

Glucose transporter inhibitor-conjugated insulin mitigates hypoglycemia

“…Therefore, tremendous efforts have been devoted to the development of smart insulin delivery systems that mimic the glucose-dependent dynamic insulin secretion of β-cells, thereby reducing hyperglycemic condition and mitigating the risk of insulin-induced hypoglycemia associated with a miscalculated exogenous insulin dose (6,7). To this end, chemically driven synthetic closed-loop insulin delivery systems integrating phenylboronic acid (7)(8)(9)(10)(11)(12)(13)(14)(15)(16), glucose-binding protein (17)(18)(19)(20), and glucose oxidase (21)(22)(23)(24)(25)(26) have been extensively studied. However, synthetic strategies to tightly regulate blood glucose levels with a low risk of hypoglycemia remain elusive in clinical practice (27).…”