Glucose-Responsive Microneedle Patches for Diabetes Treatment

Abstract

Antidiabetic therapeutics, including insulin as well as glucagon-like peptide 1 (GLP-1) and its analogs, are essential for people with diabetes to regulate their blood glucose levels. Nevertheless, conventional treatments based on hypodermic administration is commonly associated with poor blood glucose control, a lack of patient compliance, and a high risk of hypoglycemia. Closed-loop drug delivery strategies, also known as self-regulated administration, which can intelligently govern the drug release kinetics in response to the fluctuation in blood glucose levels, show tremendous promise in diabetes therapy. In the meantime, the advances in the development and use of microneedle (MN)-array patches for transdermal drug delivery offer an alternative method to conventional hypodermic administration. Hence, glucose-responsive MN-array patches for the treatment of diabetes have attracted increasing attentions in recent years. This review summarizes recent advances in glucose-responsive MN-array patch systems. Their opportunities and challenges for clinical translation are also discussed.

Keywords: closed-loop; glucose-responsive; insulin delivery; microneedle patch.

Figure 1.

(A) Schematic of the formation and release mechanism of GRVs and GRV-loaded MNs for in vivo insulin delivery. (B) Pulsatile release profile of GRVs presents the rate of insulin release as a function of glucose concentration (100 mg/dL and 400 mg/dL). (C) The indicated mouse skin was applied with an MN-array patch. The MN-array patch penetrated the dorsum skin of the mouse effectively, as evidenced by the trypan blue staining (top right) and H&E staining (bottom). Scale bar: top right 500 μm; bottom 100 μm. (D) BGLs of the diabetic mice treated with blank MNs made from HA, MNs loaded with insulin, MNs loaded with GRVs containing insulin and enzyme (GRV(E + I)), MNs loaded with GRVs containing insulin and half dose of enzyme (GRV(1/2E + I)), and MNs loaded with GRVs containing only insulin (GRV(I)). Reproduced with permission from Yu et al.

Figure 2.

Schematic of the glucose responsive system (GRS) based on a microneedle-array patch integrated with pancreatic β-cells and glucose signal amplifiers (GSA). (A) Without GSA, there is insignificant insulin release from the MN patch, neither in normoglycemia nor hyperglycemia state. The MN patch is composed of cross-linked hyaluronic acid (gray). (B) With GSA, there is significant promoted insulin release triggered by a hyperglycemia state. The MN patch is composed of cross-linked hyaluronic acid embedding assembled layers of α-amylose and GSA (from top to bottom). Reproduced with permission from Ye et al.

Figure 3.

(A) Schematic representation of the glucose-responsive core-shell MN-array patch for insulin delivery using an H₂O₂-responsive PVA-TSPBA matrix. (B) Representative images of core-shell MNs inserted into skins: the shell embedding rhodamine B labeled CAT (red), the core labeled by insulin-FITC (green), and their overlap. Scale bar: 100 μm. (C) BGLs of type 1 diabetic mice treated with different kinds of MN-array patches: (1) CAT-NG shelled MN array patch of GOx-NG and insulin-NBC-loaded gels (MN-CAT); (2) subcutaneous injection of human recombinant insulin; (3) MN-array patch of GOx-NG and insulin-NBC-loaded gels (MN-Gel(G+I)) without a shell; (4) MN-array patch only loaded with blank gel (MN-Gel); (5) MN-array patch of insulin-NBC-loaded gels (MN-Gel(I)); and (6) MN-array patch of GOx-NG, insulin-NBC, and CAT-NG-loaded gels (MN-Gel(G+C+I)). (D) Representative images of skins at the treated site of mice and their corresponding H&E staining results. Reproduced with permission from Wang et al.