Accelerated absorption of insulin via a subcutaneously implanted, vascularized micro-chamber

通过皮下植入的血管化微室加速胰岛素的吸收

基本信息

批准号：
10721366
负责人：
Robert C Johnson
金额：
$ 30万
依托单位：
PROCYON TECHNOLOGIES, LLC
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-03 至 2024-08-02
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10721366
关键词：
Acceleration Animal Model Animals Area Arizona Blood Blood Glucose Blood Vessels Bolus Infusion Cannulas Catheters Cells Child Clinic Custom Data Dermis Device Designs Devices Diffusion Dose Drug Kinetics Engineering FDA approved Fatty acid glycerol esters Formulation Future Glucose Growth Histologic Hour Human Hypoglycemia Implant Infusion procedures Injections Insulin Insulin Infusion Systems Insulin-Dependent Diabetes Mellitus Intercellular Fluid Kinetics Laboratories Life Measures Medical Device Membrane Needles NovoLog Outcome Pancreas Patients Penetration Permeability Polyesters Polyethylenes Polytetrafluoroethylene Process Measure Pump Raccoons Reproducibility Rodent Safety Side Skin Subcutaneous Injections Subcutaneous Tissue Surface Syringes Technology Testing Therapeutic Effect Thinness Time Tissues Universities Vascularization absorption blood glucose regulation clinical translation design diabetes control diabetic patient diabetic rat experience implantation improved in vivo evaluation insulin secretion life history manufacture medical implant phase 1 study phase 2 study preservation prevent prototype seal subcutaneous type I diabetic uptake

项目摘要

Project Summary In Type I diabetic (T1D) patients, insulin is injected into the subcutaneous (SC) tissue, by needle or a pump and SC cannula. A bolus of insulin SC reaches its peak in about one hour or more. This slow absorption is in dramatic contrast to the secretion of insulin into the blood by the normal human pancreas, a process measured in seconds. Consequently, patients with T1D often struggle to control their glucose, experiencing swings into hyper- and hypoglycemia. Faster insulin absorption will greatly improve glucose control in T1D patients, reducing complications in the near and long term. In rodent studies performed in the laboratory of Dr. Papas at the University of Arizona, administering insulin via a subcutaneously implanted vascularized chamber resulted in a Tmax of 7.5 minutes versus 22.4 min after SC injection. If translatable to the clinic, accelerated insulin absorption would greatly improve glucose control. Procyon Technologies LLC proposes to capitalize on these preliminary findings and evaluate the absorption kinetics of insulin delivery through custom-designed, SC-implanted, durable, low-volume microchambers compatible with insulin dosing (which especially in children, is measured in the low µL range, volumes difficult to measure and accurately deliver by syringe and needle). Small doses can be accurately delivered by existing precision insulin pumps, but they do so into the relatively avascular SC space. The Procyon microchambers are specifically engineered to develop a vascular network at the implant-tissue interface to accelerate insulin absorption and can connect with pumps. The chambers will be manufactured with membranes and materials long approved by the FDA for implantable medical devices (e.g., PTFE, polyester, and polyethylene). We propose the following three Specific Aims (SA), to be investigated in a diabetic rat model. SA1: To manufacture and bench test fixed volume (5L) Procyon microchambers with three different vascularized surface area to volume ratios (A/V) for in vivo testing in SA 2. We hypothesize that a critical design parameter for subcutaneously implanted, vascularized microchambers is the A/V ratio. This Aim will quantify the impact of this parameter for future device designs. SA2: To compare pharmacokinetics of the three microchamber configurations fabricated in SA1 versus subcutaneous injection of insulin. Reproducible, detailed pharmacokinetic data, obtained after a single dose of regular human insulin (NovoLog), injected SC or into a vascularized microchamber, will be compared over a period of 3 months. SA3: To evaluate histologically the “life history” of the three Procyon microchamber configurations tested in vivo in SA2 over a period of 3 months. These studies focusing on evaluating the maturing vascularization at the implant- tissue interface will provide information about durability, safety and, especially, the continued functionality of delivering insulin via a microchamber over months. Successful completion of these aims will frame device configurations for future studies in large animals and ultimately humans.

项目概要在 I 型糖尿病 (T1D) 患者中，通过针头或泵将胰岛素注射到皮下 (SC) 组织中， SC 插管注射的胰岛素在大约一小时或更长时间内达到峰值，这种缓慢的吸收是非常显着的。与正常人类胰腺将胰岛素分泌到血液中不同的是，这个过程只需几秒钟。 1 型糖尿病 (T1D) 患者经常难以控制血糖，出现高血糖和高血糖的情况。更快的胰岛素吸收将大大改善 T1D 患者的血糖控制，从而减少低血糖。近期和长期的并发症。在亚利桑那大学帕帕斯博士的实验室进行的啮齿动物研究中，通过注射胰岛素皮下植入血管室的 Tmax 为 7.5 分钟，而 SC 后为 22.4 分钟如果应用于临床，加速胰岛素吸收将大大改善血糖控制。 Procyon Technologies LLC 提议利用这些初步发现并评估吸收情况通过定制设计、SC 植入、耐用、低容量微室输送胰岛素的动力学与胰岛素剂量兼容（特别是在儿童中，在低 µL 范围内测量，体积难以确定）小剂量可以通过现有的技术准确地输送精密胰岛素泵，但它们是在相对无血管的 SC 空间中进行的。经过专门设计，可在植入物-组织界面处形成血管网络，以加速胰岛素分泌吸收室可以用膜和材料制造。长期获得 FDA 批准用于植入式医疗器械（例如 PTFE、聚酯和聚乙烯）。我们提出以下三个具体目标（SA），在糖尿病大鼠模型中进行研究：制造和台架测试固定体积（5μL）Procyon 微室，具有三种不同的 SA 2 体内测试的血管化表面积与体积比 (A/V)。皮下植入的血管化微室的设计参数是 A/V 比。量化该参数对未来设备设计的影响 SA2：比较药代动力学。 SA1 中制造的三种微室配置与皮下注射胰岛素的比较。单剂量常规人胰岛素 (NovoLog) 后获得的可重复、详细的药代动力学数据，皮下注射或血管化微室中，将在 3 个月的时间内进行比较：评估 SA3。 SA2 体内测试的三种 Procyon 微室配置的组织学“生命史” 这些研究的重点是评估植入物的成熟血管化。组织界面将提供有关耐用性、安全性，特别是持续功能的信息成功完成这些目标将构成设备的框架。用于未来大型动物和最终人类研究的配置。