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

• 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
• 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

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。 SC 胰岛素推注在大约一小时或更长时间内达到峰值。这种缓慢的吸收是戏剧性的 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。 因此，1 型糖尿病患者常常难以控制血糖，从而出现高血糖和高血糖的情况。 低血糖。更快的胰岛素吸收将大大改善 T1D 患者的血糖控制，减少 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 注射。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） 通过注射器和针头测量并准确输送）。小剂量可通过现有技术准确输送 精密胰岛素泵，但它们是进入相对无血管的 SC 空间。 Procyon 微室是 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 吸收并可与泵连接。腔室将用膜和材料制造 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），以在糖尿病大鼠模型中进行研究。 SA1：至 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)。我们假设一个关键 皮下植入的血管化微室的设计参数是 A/V 比。这个目标将 量化该参数对未来设备设计的影响。 SA2：比较药物的药代动力学 SA1 中制作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， 皮下注射或注射到血管微室中，将在 3 个月的时间内进行比较。 SA3：评估 SA2 体内测试的三种 Procyon 微室配置的组织学“生命史” 超过3个月的时间。这些研究的重点是评估植入物处成熟的血管化 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 在数月内通过微室输送胰岛素。成功完成这些目标将框架装置 用于未来大型动物和最终人类研究的配置。