Bioresponsive Microneedles with a Sheath Structure for H₂O₂ and pH Cascade‐Triggered Insulin Delivery

Abstract

Self-regulating glucose-responsive insulin delivery systems have great potential to improve clinical outcomes and quality of life among patients with diabetes. Herein, an H2O2-labile and positively charged amphiphilic diblock copolymer is synthesized, which is subsequently used to form nano-sized complex micelles (NCs) with insulin and glucose oxidase of pH-tunable negative charges. Both NCs are loaded into the crosslinked core of a microneedle array patch for transcutaneous delivery. The microneedle core is additionally coated with a thin sheath structure embedding H2O2-scavenging enzyme to mitigate the injury of H2O2 toward normal tissues. The resulting microneedle patch can release insulin with rapid responsiveness under hyperglycemic conditions owing to an oxidative and acidic environment because of glucose oxidation, and can therefore effectively regulate blood glucose levels within a normal range on a chemically induced type 1 diabetic mouse model with enhanced biocompatibility.

A Hydrogel Microneedle Patch for Point‐of‐Care Testing Based on Skin Interstitial Fluid

“…The major novelty of this work presents a new design of hydrogel microneedle patches to extract skin ISF with minimal tissue damage and recover target biomarkers by simple heating method without need of any bulky instrument. The selection of PVA to fabricate microneedle patches is based on its excellent biocompatibility, high swelling ability and porosity, and excellent mechanical properties . In addition, PVA can sensitively capture the iodine produced in the glucose enzyme reaction, showing a good resolution of red color, which can improve the sensitivity of glucose color reaction.…”

Insulin Delivery from Glucose‐Responsive, Self‐Assembled, Polyamine Nanoparticles: Smart “Sense‐and‐Treat” Nanocarriers Made Easy

“…In this sense, it is essential that the glucose responsiveness under hyperglycemia conditions generates a fast change of local pH that overcomes the physiological regulation and activates the selective release of Ins. Although direct comparison with other GOx‐based platforms is difficult due to the different experimental conditions used in each case, under in vitro conditions other pH‐controlled Ins release systems exhibit responses on timescales similar to that observed for our system . Interestingly, some of these systems were explored in vivo by subcutaneous administration in 3D‐gel‐based configurations and showed great ability to regulate blood glucose concentrations .…”

“…The use of tailorable polymeric (nano)particles offers attractive features for drug‐delivery systems, including suitable colloidal stability, large surface to volume ratios, high loading capacity, long circulation time in plasma, and ability to cross biological membranes . In this way, several self‐regulated Ins‐delivery systems based on vesicles, micelles, and nanogels have been presented . Typically, these nanocarriers are formed by self‐assembly or cross‐linking of sensitive block copolymers.…”

Biologically Inspired and Chemically Derived Methods for Glucose‐Responsive Insulin Therapy

“…One strategy in recent years has been to encapsulate GOx and insulin in vesicles encased within a polymeric transcutaneous microneedle patch. The enzyme and cargo can be distinctly compartmentalized, either through physical entrapment or through covalent linkage, enabling insulin to be released while GOx remains in place (Figure C) . The chemical mechanism of cargo release is varied in these studies.…”

“…The chemical mechanism of cargo release is varied in these studies. In addition to the use of relatively slow acid‐labile chemistries, a variety of hypoxia‐ and peroxide‐sensitive chemistries have been used, which are faster and also integrate with outputs from GOx activity (Figure B) . A closely related strategy was shown using ultrasound‐triggered release of insulin from chitosan microgels, which can be coupled to CGM sensors so as to enable an ultrasound stimulus to be provided when needed …”