In the era of the diabetes pandemic, Injectable hydrogels (HGs) capable of releasing the desired amount of insulin under hyperglycemic conditions will significantly advance smart insulin development. Several smart boronic...
Phenylboronic acid (PBA)-containing hydrogels (HGs),
capable of
glucose-responsive insulin release, have shown promise in diabetes
management in preclinical studies. However, sustainable material usage
and attaining an optimum insulin release profile pose a significant
challenge in such HG design. Herein, we present the development of
a straightforward fabrication strategy for glucose-responsive protein-polymer
hybrid HGs (PPHGs). We prepare PPHGs by crosslinking polyvinyl alcohol
(PVA) with various nature-abundant proteins, such as bovine serum
albumin (BSA), egg albumin, casein, whey protein, and so forth, using
formylphenylboronic acid (FPBA)-based crosslinkers. We showcase PPHGs
with diverse bulk rheological properties that are appropriately modulated
by the positions of aldehyde, boronic acid, and fluorine substitutions
in the FPBA-crosslinker. The orthogonal imine and boronate ester bonds
formed by FPBAs are susceptible to the acidic pH environment and glucose
concentrations, leading to the glucose-responsive dissolution of the
PPHGs. We further demonstrate that by an appropriate selection of
FPBAs, glucose-responsive insulin release profiles of the PPHGs can
be precisely engineered at the molecular level. Importantly, PPHGs
are injectable, incur no cytotoxicity, and, therefore, hold great
potential as smart insulin for in vivo applications in the near future.
Stimuli-responsive hydrogels (HGs) with a controlled drug release profile are the current challenge for advanced therapeutic applications. Specifically, antidiabetic drug-loaded glucose-responsive HGs are being investigated for closed-loop insulin delivery in insulindependent diabetes patients. In this direction, new design principles must be exploited to create inexpensive, naturally occurring, biocompatible glucose-responsive HG materials for the future. In this work, we developed chitosan nanoparticle/poly(vinyl alcohol) (PVA) hybrid HGs (CPHGs) for controlled insulin delivery for diabetes management. In this design, PVA and chitosan nanoparticles (CNPs) are cross-linked with a glucose-responsive formylphenylboronic acid (FPBA)-based cross-linker in situ. Leveraging the structural diversity of FPBA and its pinacol ester-based cross-linkers, we fabricate six CPHGs (CPHG1−6) with more than 80% water content. Using dynamic rheological measurements, we demonstrate elastic solid-like properties of CPHG1−6, which are dramatically reduced under low-pH and high-glucose environments. An in vitro drug release assay reveals size-dependent glucose-responsive drug release from the CPHGs under physiological conditions. It is important to note that the CPHGs show appreciable self-healing and noncytotoxic properties. Promisingly, we observe a significantly slower insulin release profile from the CPHG matrix in the type-1 diabetes (T1D) rat model. We are actively pursuing scaling up of CPHGs and the in vivo safety studies for clinical trial in the near future.
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