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.

项目摘要 在I型糖尿病（T1 D）患者中，通过针或泵将胰岛素注射到皮下（SC）组织中， SC套管。胰岛素SC的推注在约1小时或更长时间内达到其峰值。这种缓慢的吸收是在戏剧性的 与正常人胰腺分泌胰岛素进入血液的过程不同，这一过程以秒计。 因此，患有T1 D的患者通常难以控制他们的葡萄糖， 低血糖更快的胰岛素吸收将大大改善T1 D患者的血糖控制， 近期和长期的并发症。 在亚利桑那大学Papas博士的实验室进行的啮齿动物研究中， 皮下植入血管化腔室导致Tmax为7.5分钟，而SC后为22.4分钟 注射如果能应用于临床，加速胰岛素吸收将大大改善血糖控制。 Procyon Technologies LLC建议利用这些初步调查结果， 通过定制设计、SC植入、耐用、低容量微室的胰岛素输送动力学 与胰岛素剂量相容（尤其是在儿童中，测量范围为低µL，体积难以测量）， 通过注射器和针头测量和准确输送）。小剂量可以通过现有的 精确的胰岛素泵，但他们这样做到相对无血管的SC空间。南河三号的微室 专门设计用于在植入物-组织界面处形成血管网络， 吸收并可与泵连接。腔室将使用膜和材料制造 FDA长期批准用于可植入医疗装置（例如，PTFE、聚酯和聚乙烯）。 我们提出了以下三个具体目标（SA），在糖尿病大鼠模型中进行研究。SA 1：至 制造和台架测试固定体积（5 μ L）的Procyon微室， 血管化表面积与体积比（A/V），用于SA 2中的体内测试。我们假设一个关键的 皮下植入的血管化微室的设计参数是A/V比。这一目标将 量化该参数对未来器件设计的影响。SA 2：比较 在SA 1中制造的三种微室构造与皮下注射胰岛素的比较。 常规人胰岛素（NovoLog）单次给药后获得的可重现的详细药代动力学数据， 将在3个月的时间段内比较SC注射或注射到血管化微室中。SA 3：评价 在SA 2中体内测试的三种Procyon微室配置的组织学“生活史” 在3个月的时间里。这些研究侧重于评价植入物处的成熟血管化- 组织界面将提供有关耐用性、安全性，特别是持续功能性的信息， 通过微室输送胰岛素数月。这些目标的成功实现将为设备 为将来在大型动物和最终人类中的研究提供配置。