Glucose‐Responsive Composite Microneedle Patch for Hypoglycemia‐Triggered Delivery of Native Glucagon

Abstract

Insulin‐dependent patients with diabetes mellitus require multiple daily injections of exogenous insulin to combat hyperglycemia. However, administration of excess insulin can lead to hypoglycemia, a life‐threatening condition characterized by abnormally low blood glucose levels (BGLs). To prevent hypoglycemia associated with intensive insulin therapy, a “smart” composite microneedle (cMN) patch is developed, which releases native glucagon at low glucose levels. The cMN patch is composed of a photo‐crosslinked methacrylated hyaluronic acid (MeHA) microneedle array with embedded multifunctional microgels. The microgels incorporate zwitterionic moieties that stabilize loaded glucagon and phenylboronic acid moieties that provide glucose‐dependent volume change to facilitate glucagon release. Hypoglycemia‐triggered release of structurally unchanged glucagon from the cMN patch is demonstrated in vitro and in a rat model of type 1 diabetes (T1D). Transdermal application of the patch prevented insulin‐induced hypoglycemia in the diabetic rats. This work is the first demonstration of a glucose‐responsive glucagon‐delivery MN patch for the prevention of hypoglycemia, which has a tremendous potential to reduce the dangers of intensive insulin therapy and improve the quality of life of patients with diabetes and their caregivers.

A Double‐Layered Microneedle Platform Fabricated through Frozen Spray‐Coating

“…Gradual drop in blood glucose concentration is a positive phenomenon to prevent hypoglycemia which is a life threatening problem that the diabetic patients are facing. [ 24 ] The glucose concentrations detected in skin ISF correlated well with that in blood in all three groups, showing that there is continuous matrix and fluid exchange between the MNs and the skin ISF. However, the collected ISF needs further processing and analysis which remains to be addressed for the in situ and timely monitoring.…”

“…1.4 wt% agarose hydrogel (Sigma‐Aldrich) was used as model skin tissue for the insulin delivery study. [ 24 ] Insulin@MeHA MNs was inserted into agarose hydrogel with polymer membrane (parafilm, Merch) place on the hydrogel surface for 30 min, 1 h, and 2 h. The MNs was pressed into the hydrogel and a small glass bottle was placed on top of the MNs to provide downward pressure to maintain adherence. The delivered insulin was collected by cutting and dissolving the agarose in 1% w/v acetic acid (Sigma‐Aldrich).…”

Advances in the Formulations of Microneedles for Manifold Biomedical Applications

“…The H 2 O 2 would induce the disintegration of the polymeric vesicles and the subsequent release of insulin. Ghavaminejad et al recently designed a composite MN patch with crosslinked HA matrix and multifunctional microgels that could release glucagon in the event of hypoglycemia status ( Figure A) . Lower glucose level (hypoglycemia) triggered the shrinking of microgels, which caused the release of glucagon to restore the blood glucose level.…”

“…C) Hypoglycemia prevention (efficacy) studies of T1D rats. Reproduced with permission . Copyright 2019, Wiley‐VCH.…”

New uses and formulations of glucagon for hypoglycaemia

“…There are two possible approaches in the search for stable glucagon: native glucagon in different formulations to make it stable, or new stable glucagon analogues (Table 1). Furthermore, the development of microneedle transdermal patch delivery of native glucagon has been recently reported 69…”