A Wireless, Implantable Microdevice for Closed-Loop Drug Delivery to Prevent the Morbidity of Diabetes Therapy-Induced Hypoglycemia

项目总结 美国有近3000万患者患有1型或2型糖尿病。低血糖症 是糖尿病治疗的一种常见且可能危及生命的副作用。其临床意义 低血糖包括认知障碍、癫痫、心血管事件、脑损伤甚至 死亡，以及加速痴呆症的长期风险。降糖意识的逐渐丧失， 低血糖意识不清，损害对低血糖早期迹象的识别，增加高血压的严重性 急性并发症和住院的需要。严重低血糖的现行治疗方法 包括静脉注射葡萄糖或肌肉注射胰高血糖素。但是，这些方法需要 患者身边总是有紧急用药来源，并有必要依赖 可能没有接受过良好培训来实施这些治疗的照顾者。 一种精确释放降血糖药物的闭环式植入式给药系统(IDDS) 对低血糖水平的反应，并且足够小，可以植入最小的侵入性，可以 大幅改善低血糖管理。该项目的目标是开发新技术，以 使这样的IDDS成为现实。建议的IDDS是首个超声驱动的精密种植平台 微创并实现完全可编程、个性化和闭环式药物输送 分娩治疗严重低血糖。IDDS利用电响应性聚吡咯纳米颗粒(PPy NPs) 来储存所需的药物。当受到电刺激时，PPy NPs会改变形状和大小，从而释放 他们的毒品货物。IDDS是使用超声波无线供电的，这使得植入物能够微型化 为了最小的侵入性，以及在体内的安全操作。将实施闭环控制，以便 只有当商业血糖监测仪检测到血糖水平较低或迅速下降时，才会释放药物。 这一目标将通过追求以下三个具体目标来实现：(1)在目标I下，规模和 纳米颗粒的组成将进行优化，以有效释放抗降血糖药物。我们目前的情况 当药物附着在纳米颗粒上时，增强药物稳定性的模型也将得到验证和 在体外和体内对小鼠模型进行了优化。(2)AIM II将需要开发包装毫米尺寸的 IDDS植入物，将商业血糖监测仪集成到系统中，以及闭环系统的体外验证 功能性。(3)在AIM III下，将对诱导低血糖的小鼠进行体内试验，以优化 治疗逆转低血糖，并随后与集成植入平台进行可行性测试 使用该设备治疗糖尿病低血糖。这个项目意义重大，因为它的成功完成可能会 不仅导致未来低血糖治疗方式的范式转变，而且还改善了对 其他需要程序化、精准化和本地化给药的慢性疾病。

PROJECT SUMMARY Nearly 30 million patients in the United States suffer from either type 1 or type 2 diabetes. Hypoglycemia is a common and potentially life-threatening side effect of diabetes treatment. Clinical implications of hypoglycemia include acute risk of cognitive impairment, seizure, cardiovascular events, brain damage or even death, as well as long term risks of accelerated dementia. The progressive loss of hypoglycemic awareness, hypoglycemic unawareness, impairs recognition of the early signs of low blood sugar, increasing the severity of acute complications and the need for hospitalization. Current methods for management of severe hypoglycemia include intravenous dextrose infusion or intramuscular injection of glucagon. However, these methods require that an emergency source of medication is always available near the patient, and necessitate reliance on caregivers who may not be well trained to administer these treatments. A closed-loop implantable drug delivery system (IDDS) that releases anti-hypoglycemic drugs precisely in response to low blood glucose levels, and is small enough to be implanted with minimal invasiveness, could substantially improve hypoglycemia management. The goal of this project is to develop novel technologies to make such an IDDS a reality. The proposed IDDS is the first ultrasonically powered implant platform for precision drug delivery that is minimally invasive and enables fully programmable, personalized, and closed-loop drug delivery to treat severe hypoglycemia. The IDDS utilizes electroresponsive polypyrrole nanoparticles (PPy NPs) to store the required drugs. When electrically stimulated, the PPy NPs change shape and size, thereby releasing their drug cargo. The IDDS is wirelessly powered using ultrasound which enables miniaturization of the implants for minimal invasiveness, and safe operation in the body. Closed-loop control will be implemented in order to release the drugs only when a low or rapidly falling glucose level is detected by a commercial glucose monitor. The objective will be reached by pursuing the following three specific aims: (1) Under Aim I, the size and composition of the nanoparticles will be optimized for efficient release of anti-hypoglycemic drugs. Our current models for enhancement of the stability of the drugs when attached to the nanoparticles will also be verified and optimized in vitro and in vivo in mouse models. (2) Aim II will entail development of the packaged mm-sized IDDS implant, integration of a commercial glucose monitor into the system, and in vitro validation of closed-loop functionality. (3) Under Aim III, in vivo tests in mice with induced hypoglycemia will be performed to optimize therapeutic reversal of hypoglycemia and subsequently with the integrated implant platform to test the feasibility of using the device to treat diabetic hypoglycemia. This project is significant as its successful completion could not only lead to a paradigm shift in how hypoglycemia is treated in the future, but also improve the treatment of other chronic diseases that require programmed, precise and localized drug delivery.