权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

一种用于闭环药物输送的无线植入式微型装置，可预防糖尿病治疗引起的低血糖的发生

基本信息

批准号：
10090594
负责人：
Amin Arbabian
金额：
$ 51.37万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2022-07-31
项目状态：
已结题

项目摘要

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.

项目摘要在美国有近3000万患者患有1型或2型糖尿病。低血糖是糖尿病治疗的常见且可能危及生命的副作用。的临床意义低血糖症包括认知损害、癫痫发作、心血管事件、脑损伤或甚至死亡，以及加速痴呆症的长期风险。低血糖意识的逐渐丧失，低血糖无意识，损害对低血糖早期体征的识别，增加低血糖的严重性。急性并发症和需要住院治疗。严重低血糖症的当前管理方法包括静脉内葡萄糖输注或肌内注射胰高血糖素。然而，这些方法需要紧急药物源总是在患者附近可用，并且需要依赖护理人员可能没有受过良好的培训来管理这些治疗。一种闭环植入式药物输送系统（IDDS），可精确释放抗低血糖药物响应于低血糖水平，并且足够小以最小侵入性植入，可以显著改善低血糖管理。该项目的目标是开发新技术，让这样的梦想成为现实。拟议的IDDS是第一个超声波驱动的植入平台，药物输送是微创的，并且能够实现完全可编程的、个性化的和闭环的药物输送。用于治疗严重低血糖。IDDS利用电响应聚吡咯纳米颗粒（PPy NPs）储存所需药物。当电刺激时，PPy NP改变形状和大小，从而释放出他们的毒品IDDS使用超声波无线供电，使植入物小型化最小的侵入性和在体内的安全操作。将实施闭环控制，以便只有当商业葡萄糖监测仪检测到低或快速下降的葡萄糖水平时才释放药物。为达致这个目标，当局会致力达致以下三个具体目标：（1）在目标I下，纳米颗粒的组成将被优化以有效释放抗低血糖药物。我们目前还将验证用于增强药物在附着于纳米颗粒时的稳定性的模型，在小鼠模型中进行体外和体内优化。(2)第二个目标将需要开发包装的毫米大小的 IDDS植入，将商业葡萄糖监测仪集成到系统中，以及闭环的体外验证功能. (3)在目标III下，将在诱导低血糖的小鼠中进行体内试验，以优化低血糖的治疗逆转，随后使用集成植入物平台测试可行性使用该设备治疗糖尿病性低血糖症。该项目意义重大，因为它的成功完成可以不仅导致未来如何治疗低血糖症的范式转变，而且还改善了低血糖症的治疗。其他需要程序化、精确和局部给药的慢性疾病。