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

非技术性：糖尿病是一种葡萄糖调节紊乱，以血糖升高为特征。全球估计有4.22亿人患有糖尿病。在美国，目前约有8.3%的人口患有糖尿病，预计到2050年，这一数字将增长到1 / 3。目前治疗高血糖的方法是经常自我注射胰岛素，全天监测血糖水平是维持1型或晚期2型糖尿病患者生命所必需的。缺乏对血糖水平的严格控制是糖尿病的许多慢性并发症的原因，如截肢、失明和肾衰竭；而低血糖会导致生活中断，并有癫痫发作、失去意识、脑损伤甚至可能死亡的风险。然而，目前的胰岛素输注方法无法模拟正常的生理条件，即胰腺细胞在血糖水平升高时迅速释放胰岛素，一旦血糖正常，胰岛素水平就会停止。这一建议是开发下一代血糖反应胰岛素递送系统，该系统以仿生方式基于合成囊泡，灵感来自胰腺细胞的囊泡（或颗粒）。计划中的胰岛素输送系统将能够根据血糖水平自动连续、反复地调节胰岛素释放。为了实现这一目标，PI建议开发变革性葡萄糖反应胰岛素纳米颗粒（GRINs），用于智能调节血糖水平，具有快速和可重复的反应性。预计GRINs的激活和随后的胰岛素释放在高血糖水平时被触发，在正常血糖范围内释放被抑制，从而模仿胰腺细胞“分泌”胰岛素以应对血糖水平的波动。制备的GRINs将进一步加载到皮肤上的无痛微针阵列贴片中，以实现易于给药和增强的生物相容性。该项目将开发新的材料、配方和设备，这些材料、配方和设备可能广泛用于开发其他生物反应智能药物输送系统。此外，拟议的研究将创建动态和可持续的教育活动，包括基于K-12的外展模块“工程我们的方式来阻止糖尿病”，一个针对本科生和研究生的跨学科课程，以及动手实验室研究。这些活动有望激励学生追求科学、技术、工程和数学（STEM）学科的职业生涯。技术：糖尿病是一个主要的公共卫生问题，目前影响全球约4.22亿人，预计到2030年这一数字将超过4.5亿。目前治疗1型和晚期2型糖尿病患者需要持续监测血糖（BG）水平，并定期注射胰岛素以维持正常血糖水平。一种人工胰腺样闭环胰岛素输送系统，可以根据血糖水平的变化不断智能地释放胰岛素，这对改善1型和晚期2型糖尿病患者的健康和生活质量有很大的希望。迄今为止，模拟胰腺细胞的功能，利用合成材料和/或修饰胰岛素的化学控制闭环递送策略已被广泛探索。这通常由聚合物配方组成，膨胀，收缩或解离，以根据环境葡萄糖水平调节胰岛素释放率。然而，要证明一种能够结合；1)快速响应；Ii)可重复激活；Iii)便于管理；iv)优良的生物相容性。该项目旨在开发下一代葡萄糖反应胰岛素输送系统，灵感来自于胰腺细胞的“天然”颗粒。PI将探索“人工”葡萄糖反应胰岛素纳米颗粒（GRINs）及其相关设备。预计在高血糖状态下，GRINs的激活和随后的胰岛素释放会被迅速触发，并在正常血糖水平下以可重复的方式被抑制。开发的GRINs将进一步集成到基于无痛微针阵列的设备中，用于皮肤应用，从而实现易于给药和增强生物相容性。该项目还将指导开发新的材料、配方和设备，用于工程设计其他可以通过生理信号的变化智能激活的输送系统。此外，拟议的研究计划将与动态和可持续的教育活动紧密结合，通过开发K-12外展模块-“工程我们的方式来阻止糖尿病”，这是一个针对本科生和研究生的新的跨学科课程，以及动手实验室研究。学生将接触到生物材料、器件和微纳米技术，激发他们在科学、技术、工程和数学（STEM）学科的职业生涯。

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.