In vitro and in vivo testing of glucose-responsive insulin-delivery microdevices in diabetic rats

Abstract

We have developed glucose-responsive implantable microdevices for closed-loop delivery of insulin and conducted in vivo testing of these devices in diabetic rats. The microdevices consist of an albumin-based bioinorganic membrane that utilizes glucose oxidase (GOx), catalase (CAT) and manganese dioxide (MnO(2)) nanoparticles to convert a change in the environmental glucose level to a pH stimulus, which regulates the volume of pH-sensitive hydrogel nanoparticles and thereby the permeability of the membrane. The membrane is integrated with microfabricated PDMS (polydimethylsiloxane) structures to form compact, stand-alone microdevices, which do not require tethering wires or tubes. During in vitro testing, the microdevices showed glucose-responsive insulin release over multiple cycles at clinically relevant glucose concentrations. In vivo, the microdevices were able to counter hyperglycemia in diabetic rats over a one-week period. The in vitro and in vivo testing results demonstrated the efficacy of closed-loop biosensing and rapid response of the 'smart' insulin delivery devices.

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

“…The loss in device efficacy after 21 days may be due to increased insulin requirements due to increased animal weight over time and/or decreased insulin bioactivity in the reservoir over the duration of the experiment as plasma insulin levels remained elevated for at least 30 days. These in vivo results compare favorably with other closed-loop insulin-delivery implants reported in literature [17,18] and further demonstrate prolonged device lifetime associated with improved biocompatibility of microporous membrane-protected gap implants.…”

“…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.…”

“…Examples of such materials include metallic/semiconducting sensing electrodes [9e13], stimuli-responsive polymers [14e18], enzymes [16,18,19], and allogenic or transgenic cells or tissues [20]. As these components cannot simply be masked using biologically inert materials, these devices often fail shortly following implantation due to biocompatibility issues, namely fibrous encapsulation and cell-mediated degradation [21].…”

Microfluidic enzymatic biosensing systems: A review

“…Hydrogel nanoparticles made from poly(N-isopropylacrylamide) (PNIPAM) and poly(methacrylic acid) (PMAA) were immobilized with glucose oxidase in an albumin matrix to form a glucose responsive membrane sealing an insulin reservoir (Chu et al, 2012). When the membrane came into contact with glucose solution, the gluconic acid produced in the glucose oxidase reaction lowered the pH in the membrane, causing the PNIPAM-co-PMAA nanoparticles to shrink and thereby open pores in the membrane.…”

Synthesis of Y‐Shaped Copolymers Containing Phenylborate Ester and Biodegradable Poly(lactic acid) Blocks and Their Glucose‐Sensitive Behavior for Controlled Insulin Release

“…The worldwide prevalence of diabetes is recently made in the fi eld of pharmacy, biology, biochemistry, and biomaterials, [5][6][7][8][9][10][11] to realize the desired glycemic control effect by delivering an accurate dose of insulin in response to glucose level changes. Among them, one expedient strategy is to develop glucose-sensitive materials to be utilized in a self-regulated insulin delivery system, [ 12,13 ] which has a promising future within the application of diabetes treatment.…”