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型糖尿病患者（T1D）患者中，胰岛素被用针或泵注入皮下（SC）组织， SC套管。胰岛素SC的推注大约一小时或更长时间。这种缓慢的遗憾是戏剧性的 与正常的人胰腺分泌胰岛素对血液的分泌形成鲜明对比，正常的人类胰腺（以秒为单位测量的过程）。 因此，T1D患者经常难以控制其葡萄糖，经历了超级和 低血糖。更快的胰岛素滥用会大大改善T1D患者的葡萄糖控制，从而减少 近期和长期的并发症。 在亚利桑那大学帕帕斯博士实验室进行的啮齿动物研究中，通过 皮下植入的血管化腔室导致TMAX为7.5分钟，而SC后22.4分钟 注射。如果可以翻译成诊所，则加速的胰岛素滥用会大大改善葡萄糖的控制。 Procyon Technologies LLC提案，以利用这些初步发现并评估滥用 通过定制设计的，SC植入，耐用，低量微量室的胰岛素传递动力学 与胰岛素剂量兼容（尤其是在儿童中，在低µL范围内测量，容量难以 测量并通过注射器和针头准确输送）。现有的小剂量可以准确地交付 精确的胰岛素泵，但它们会进入相对的血管SC空间。 Procyon Microchambers是 专门设计用于在植入物 - 组织接口上开发血管网络以加速胰岛素 抽象，可以与泵连接。钱伯斯将用机制和材料制造 长期以FDA批准了可植入的医疗设备（例如PTFE，聚酯和聚乙烯）。 我们建议在糖尿病大鼠模型中研究以下三个特定目标（SA）。 SA1：到 制造和台式测试固定体积（5L）Procyon Microchambers具有三种不同 Sa 2中的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，血管化微室的设计参数是A/V比。这个目标 量化此参数对将来设备设计的影响。 SA2：比较药代动力学 SA1与皮下注射胰岛素的三种微室构型。 可重现的详细药代动力学数据，在单剂量的常规人胰岛素（Novolog）（Novolog）中获得 在3个月的时间内将比较注射的SC或进入血管化的微室。 SA3：评估 在组织学上，在SA2中在体内测试的三种procyon微型室配置的“生命史” 在3个月的时间内。这些研究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，尤其是持续功能的信息 几个月来，通过微培训传递胰岛素。这些目标的成功完成将构架设备 将来在大型动物和最终人类中进行研究的配置。