Engineering Biomimetic Glucose-Responsive Vesicles for Self-Regulated Insulin Delivery

点击翻译按钮获取中文摘要

Non-technical: Diabetes is a disorder in glucose regulation, and is characterized by increase in blood glucose. Globally, an estimated 422 million people had diabetes. In the United States, about 8.3% of the population currently has diabetes and that number is projected to grow to 1 in 3 adults by 2050. The current treatment for high blood sugar is frequent self-administration of insulin injections and monitoring of blood sugar levels throughout the day is necessary to sustain life for patients with type 1 or advanced type 2 diabetes. Lack of tight control of blood sugar levels accounts for many chronic complications of diabetes, such as limb amputation, blindness and kidney failure; while low blood sugar levels result in life disruption and the risk of seizures, unconsciousness, brain damage, or possible death. Current insulin infusion approaches, however, cannot mimic normal physiological conditions in which the pancreatic cells quickly releases insulin in response to increase in blood sugar levels, and insulin levels are shut down once the blood sugar is normal. This proposal is to develop the next-generation blood glucose-responsive insulin delivery systems that are based on synthetic vesicles in a biomimetic manner, inspired by the vesicles (or granules) of pancreatic celIs. The planned insulin delivery system will be able to automatically regulate insulin release continuously and repeatedly according to blood sugar levels. Towards this goal, the PI proposes to develop transformative glucose-responsive insulin nanoparticles (GRINs) for intelligently regulating blood sugar levels with fast and repeatable responsiveness. The activation of GRINs and subsequent release of insulin are expected to be triggered at a high blood sugar level, and the release is inhibited with a normal blood sugar range, thereby mimicking pancreatic cells to "secrete" insulin in response to fluctuating blood sugar levels. The GRINs prepared will be further loaded into a painless microneedle array-based patch on the skin to achieve easy administration and enhanced biocompatibility. This project will develop novel materials, formulations and devices that may be of broad use for development of other bio-responsive smart drug delivery systems. In addition, the proposed research will create dynamic and sustainable education activities, including a K-12 based outreach module 'Engineering Our Way to Stop Diabetes', an interdisciplinary curriculum targeting undergraduates and graduates, together with hands-on lab research. Such activities are expected to inspire students to pursue careers in science, technology, engineering and mathematics (STEM) disciplines.Technical: Diabetes is a major public health problem currently affecting about 422 million people across the world, and this number is expected to reach over 450 million by 2030. Current treatment for Type 1 and advanced Type 2 diabetic patients requires continuous monitoring of blood glucose (BG) levels and periodical insulin injections to maintain normal blood glucose levels. An artificial pancreas-like closed-loop insulin delivery system that continuously and intelligently releases insulin in response to changing blood glucose levels holds great promise for enhancing heath and improving quality of life for patients with type 1 and advanced type 2 diabetes. To date, mimicking the function of pancreatic cells, chemically-controlled closed-loop delivery strategy utilizing synthetic materials and/or modified insulin have been widely explored. This typically consisted of polymeric formulations that swell, shrink or dissociate to adjust the insulin release rate according to ambient glucose levels. However, challenges remain to demonstrate a system which would combine; i) fast response; ii) repeatable activation; iii) ease of administration; and iv) excellent biocompatibility. The proposed project aims to develop the next-generation glucose-responsive insulin delivery systems, inspired by the "natural" granules of pancreatic cells. The PI will explore 'artificial' glucose-responsive insulin nano-granules (GRINs) and their relevant devices. The activation of GRINs and subsequent release of insulin are expected to be rapidly triggered at high blood sugar state, and inhibited within a normal blood sugar levels in a repeatable manner. The GRINs developed will be further integrated into a painless microneedle array-based device for application on skin, and thus achieving easy administration and enhanced biocompatibility. This project will also guide the development of novel materials, formulations and devices for engineering other delivery systems which can be intelligently activated by the variation of physiological signals. Moreover, the proposed research program will be closely integrated with dynamic and sustainable educational activities, through development of a K-12 outreach module- 'Engineering Our Way to Stop Diabetes', a new interdisciplinary curriculum targeting undergraduates and graduates, as well as hands-on lab research. Students will be exposed to biomaterials, devices and micro-nanotechnology, inspiring them to pursue careers in science, technology, engineering and mathematics (STEM) disciplines.