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

项目摘要 在I型糖尿病(T1D)患者中，胰岛素通过针或泵注入皮下(SC)组织，然后 SC插管。一剂SC胰岛素在大约一小时或更长时间内达到峰值。这种缓慢的吸收是戏剧性的 相比之下，正常人类胰腺将胰岛素分泌到血液中，这一过程以秒为单位。 因此，患有T1D的患者经常难以控制自己的血糖，经历波动进入高血糖和高血糖。 低血糖症。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 皮下植入血管化室的Tmax为7.5分钟，而SC后为22.4分钟 注射。如果可以移植到临床上，加速胰岛素吸收将极大地改善血糖控制。 Procyon Technologies LLC建议利用这些初步发现并评估吸收 通过定制设计、SC植入、耐用、低容量微腔给药的动力学 与胰岛素剂量兼容(特别是在儿童中，测量范围在低µL范围内，容量难以 通过注射器和针头测量并准确传递)。小剂量可通过现有的 精密胰岛素泵，但他们这样做是为了进入相对无血管的SC空间。冥王星微室是 专门设计用于在植入物-组织界面形成血管网络以加速胰岛素 吸收，并可与泵连接。这些腔体将用膜和材料制造 长期被FDA批准用于植入式医疗设备(例如，聚四氟乙烯、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的(SA)。SA1：TO 三种不同体积(5L)普鲁西酮微室的研制与台架试验 血管表面积与体积比(A/V)用于体内测试SA 2。我们假设一个关键的 皮下植入的血管化微腔的设计参数是A/V比。这一目标将 量化此参数对未来设备设计的影响。SA2：比较两种药物的药代动力学 在SA1中制造的三种微腔配置与皮下注射胰岛素的比较。 可重复的、详细的药代动力学数据，在单剂量常规人胰岛素(NovoLog)后获得， 在3个月的时间里，将SC或注入血管化微腔内进行比较。SA3：评估 在SA2体内测试的三种Procyon微室配置的组织学“生活史” 超过3个月的时间。这些研究集中在评估种植体处成熟的血管形成- 组织界面将提供有关耐用性、安全性的信息，特别是关于持续功能的信息 在几个月的时间里通过微腔输送胰岛素。这些目标的成功完成将构成一个装置 未来在大型动物和最终人类身上进行研究的配置。

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.