Glucose-responsive Microneedle Patch For Closed-loop Dual-hormone Delivery

As a major public health problem,diabetes is currently affecting more than 537 million people worldwide.The traditional standard of care for patients with type 1 and advanced type 2 diabetes requires several daily subcutaneous injections of insulin,insulin analogs,or combination insulins.However,both painful methods of monitoring blood glucose levels and simple insulin administration based on practical experience may lead to inaccurate insulin dosing and failure to achieve tight glycemic control,leading to many chronic complications of diabetes.Although various glucose-responsive insulin delivery systems have been developed to address the issues in the last few decades,they mainly focused on glucose-triggered insulin delivery.The smart delivery of another essential hormone,glucagon that can prevent hypoglycemia,is lacking in these systems.Developing a delivery platform to substitute the impaired glucagon-secreting α-cells and insulin-secreting β-cells is highly demanding to mitigate the underlying hypoglycemia risk during diabetes treatment.To this end,we present a strategy to easily create a transdermal smart closed-loop dual hormone microneedle patch that achieves clinically relevant doses and rapid glucose-dependent insulin/glucagon release.Insulin and glucagon-loaded microneedles can mimic the “β-cells” and “α-cells” of the pancreatic islet.The synergistic counter-regulation of the two modules could enhance the capability of the closed-loop dual hormone patch to maintain normoglycemia during plasma glucose fluctuation.Under hyperglycemic conditions,the phenylboronic acid units within the polymeric matrix show an enhanced ability to bind glucose.The increased negative charge due to the formation of the glucose-boronic acid complex reduces the electrostatic interaction of negative-charged insulin with the polymeric matrix to facilitate its rapid release into the subcutaneous tissue.Meanwhile,the electrostatic attraction of the polymeric matrix to the positive-charged glucagon analog is enhanced to inhibit the undesired release of glucagon analog.By contrast,in the case of hypoglycemia,the net charge of the microneedle switches from negative to positive due to the disassociation of the glucose-borate complex,which promotes the release of glucagon analog and restrains the diffusion of insulin to restore normal blood glucose.Demonstrated with type 1diabetic mouse models,the closed-loop dual hormone patch effectively controls hyperglycemia while minimizing the occurrence of hypoglycemia in the setting of insulin therapy and simulated delayed meals or insulin overdose.