Development of a miniaturized, single-port automated insulin delivery system utilizing a glucose sensing catheter, ultra-concentrated insulin, and an optimized control algorithm

摘要 重要性：美国有超过500万人患有胰岛素治疗的糖尿病， 在2370亿美元的直接医疗费用中，糖尿病占了不成比例的大部分。使用 连续葡萄糖监测（CGM）已被证明可以降低HbA 1c水平，这是一种已被证明的健康预测指标 该人群的结局，当CGM与 持续皮下胰岛素输注（CSII）。CGM和胰岛素泵的最新融合 启用了第一代自动胰岛素输送（AID）系统，有望改善血糖 胰岛素治疗的糖尿病的控制。然而，当前的AID系统复杂、笨重且昂贵 因为他们需要在身体上佩戴多个设备：葡萄糖传感器，胰岛素 泵和胰岛素输送导管。我们开发了一种葡萄糖传感导管， 皮下组件的数量从两个减少到一个，显著减少了这些组件的尺寸和复杂性。 系统.通过将传感导管集成到贴片泵中，我们将进一步简化系统， 的足迹，并启用第一个完全集成的单组件AID系统。因此， 系统的规模、复杂性和成本将提高AID的采用率，有助于提高合规性，降低 HbA 1c水平，并改善1型糖尿病患者的健康状况。初步数据：我们有 已经证明的葡萄糖感测可以在胰岛素递送部位处进行。然而我们发现 在分配液体（胰岛素或生理盐水）后立即出现葡萄糖测量伪影 可能是周围组织液稀释所致。初步数据显示， 伪影的大小与团的体积有关。具体目标：本提案是第一个 将两用插管与微型贴片泵和AID算法集成的努力阶段， 利用新型浓缩胰岛素来减小CGM伪影大小。在具体目标1中，我们将减少 通过使用超浓缩胰岛素稀释伪影的影响。我们将描述 在猪研究中使用较小剂量的U 500胰岛素的伪影。在具体目标2中，我们将创建校准 基于卡尔曼滤波器和未来传感器值的预测模型的算法，以进一步减轻稀释 神器在具体目标3中，我们将U-500胰岛素的动力学整合到模型预测控制中 (MPC)AID算法，并对该算法进行优化， (1)结合Thermalin胰岛素的动力学模型和（2）消除任何剩余的稀释伪影 可能仍然存在的。我们将在数据上评估新校准算法的性能 在目标1中收集的数据以及我们使用葡萄糖传感导管收集的其他人体数据。的 将使用OHSU虚拟患者人群对MPC算法进行计算机模拟评价，以准备进行完整的 集成到本提案第2阶段的Thermalin StampPump中。总之，这种合作努力 PDT，OHSU和Thermalin之间的联系汇集了唯一已发表的电流葡萄糖传感 这是一种具有容错AID算法和唯一快速浓缩胰岛素的导管。总之，我们是唯一 团队目前能够为统一的自动胰岛素输送设备提供这种新颖的解决方案。

ABSTRACT Significance: There are over 5 million people with insulin-treated diabetes in the United States who represent a disproportionately large share of the $237B in direct medical costs attributable to diabetes. The use of continuous glucose monitoring (CGM) has been shown to reduce HbA1c levels, a proven predictor of health outcomes within this population, with the greatest improvement achieved when CGM is coupled with continuous subcutaneous insulin infusion (CSII). The recent convergence of CGM and insulin pumps has enabled the first generation of automated insulin delivery (AID) systems, promising even better glycemic control for insulin-treated diabetes. However, current AID systems are complex, cumbersome, and expensive for the patient because they require multiple devices to be worn on the body: a glucose sensor, an insulin pump, and an insulin delivery catheter. We have developed a glucose sensing catheter that reduces the number of subcutaneous components from two to one, significantly reducing the size and complexity of these systems. By integrating the sensing catheter into a patch pump, we will further simplify the system by reducing the footprint, and enabling the first fully-integrated single component AID system. Resulting reductions in system size, complexity, and cost will increase adoption rates for AID, helping improve compliance, lower HbA1c levels, and improve health outcomes among people with type 1 diabetes. Preliminary Data: We have demonstrated glucose sensing can be performed at the site of insulin delivery. However, we have discovered that there is a glucose measurement artifact that occurs immediately after dispensing liquid (insulin or saline) from the cannula, likely caused by dilution of the surrounding interstitial fluid. Preliminary data suggest the magnitude of the artifact is related to the volume of the bolus. Specific Aims: This proposal represents the first phase of an effort to integrate the dual-use cannula with a miniaturized patch pump and an AID algorithm, taking advantage of a novel concentrated insulin to reduce CGM artifact size. In Specific Aim 1, we will reduce the impact of the dilution artifact through the use of ultraconcentrated insulin. We will characterize the impact of the artifact using smaller boluses of U500 insulin in a swine study. In Specific Aim 2, we will create a calibration algorithm based on a Kalman filter and a predictive model of future sensor values to further mitigate the dilution artifact. In Specific Aim 3, we will integrate the kinetics of the U-500 insulin into a model predictive control (MPC) AID algorithm developed by Oregon Health & Science University (OHSU) and optimize the algorithm to (1) incorporate a model of the kinetics of the Thermalin insulin and (2) eliminate any remaining dilution artifact that may still be present. We will evaluate the performance of the new calibration algorithm on the data collected in Aim 1 as well is in other human data that we have collected with the glucose sensing catheter. The MPC algorithm will be evaluated in silico using the OHSU virtual patient population in preparation for full integration into the Thermalin StampPump in phase 2 of this proposal. In summary, this collaborative effort between PDT, OHSU, and Thermalin brings together the only published amperometric glucose sensing catheter with a fault-tolerant AID algorithm and the only rapid, concentrated insulin. In short, we are the only team currently capable of providing this novel solution for a unified automated insulin delivery device.