Nanotechnology‐Enabled Closed Loop Insulin Delivery Device: In Vitro and In Vivo Evaluation of Glucose‐Regulated Insulin Release for Diabetes Control

Abstract

Recently, a new multifunctional, bio‐inorganic nanocomposite membrane with the ability to self‐regulate the release of insulin in response to blood glucose (BG) levels was reported. Herein, the application of this material as part of a small, implantable, closed‐loop insulin delivery device designed to continuously monitor BG concentrations and regulate insulin release is proposed. The insulin delivery device consists of a nanocomposite glucose‐responsive plug covalently bound to an insulin reservoir made of surface‐modified silicone. The plug is prepared with crosslinked bovine serum albumin (BSA) and enzymes (glucose oxidase (GOx) and catalase (CAT)), pH‐responsive hydrogel nanoparticles, and multifunctional MnO2 nanoparticles. The plug functions both as a glucose sensor and controlled delivery unit to release higher rates of insulin from the reservoir in response to hyperglycemic BG levels and basal insulin rates at normal BG concentration. The surfaces of the device are modified by silanization followed by PEGylation to ensure its safety and biocompatibility and the stability of encased insulin. Our results show that insulin release can be modulated in vitro in response to glucose concentrations. In vivo experiments show that the glycemia of diabetic rats can be controlled with implantation of the prototype device. The glucose‐responsiveness of the device is also demonstrated by rapid drop in BG level after challenging diabetic rats with bolus injection of glucose solution. In addition, it is demonstrated that surface PEGylation of the device is necessary for reducing the immune response of the host to the implanted foreign object and maintaining insulin stability and bioactivity. With this molecular architecture and the bio‐inorganic nanocomposite plug, the device has the ability to maintain normal BG levels in diabetic rats.

Microneedle-array patches loaded with hypoxia-sensitive vesicles provide fast glucose-responsive insulin delivery

“…A chemical approach using an insulin-loaded matrix with glucose-sensing elements and a relevant actuator could avoid those limitations and may prove more effective for closed-loop insulin release. The matrix can undergo structural transformations (i.e., shrink, swell, dissociate) regulated by glucose concentration changes, leading to glucose-stimulated insulin release (11)(12)(13)(14). The typical glucose-sensing moieties include phenylboronic acid (PBA), glucose-binding protein (GBP), and glucose oxidase (GO x ) (12)(13)(14)(15)(16)(17)(18)(19)(20).…”

Microfabricated microporous membranes reduce the host immune response and prolong the functional lifetime of a closed-loop insulin delivery implant in a type 1 diabetic rat model

“…Closed-loop insulin delivery systems offer diabetic patients improved glycemic control, compliance and quality of life over conventional insulin therapy [12,37,38]. To date a number of such systems have demonstrated short-term success (~1 week) in maintaining normal blood-glucose levels in diabetic rats [17,18], Fig. 1.…”

“…We demonstrate this approach on a chemically-driven closedloop insulin delivery system that features a glucose-responsive hydrogel plug that is responsible for the self-regulated release of insulin from the implant reservoir in the presence of glucose [16,17,36]. Closed-loop insulin delivery systems offer diabetic patients improved glycemic control, compliance and quality of life over conventional insulin therapy [12,37,38].…”

Biomedical applications of nanobiosensors: the state-of-the-art

“…With reference to integrated architecture, cell phones may play an important role in bringing lives of people into the therapeutic application of medical nanorobotics. [94][95][96] …”