An Implanted Intraperitoneal (IP-IP) Artificial Pancreas; a quantum leap forward

描述（由申请人提供）：本项目的目标是为1型糖尿病患者开发一种腹膜内植入的闭环葡萄糖监测/胰岛素输送装置（又名人工胰腺）。人工胰腺可以改善患者的短期和长期健康和生活质量，并可以降低整体医疗费用。然而，目前大多数人工胰腺原型使用皮下胰岛素泵和皮下葡萄糖传感器，这与显著的滞后时间（分别约60分钟和约10分钟）相关。此外，胰岛素输注部位和传感器需要每隔几天更换一次，导致胰岛素吸收和葡萄糖测量的可变性。这些滞后和可变性对使用皮下胰岛素递送和葡萄糖感测的任何人工胰腺的性能施加了上限。幸运的是，这些挑战可以通过使用腹膜内胰岛素输送和腹膜内葡萄糖传感的植入式人工胰腺来克服-IP-IP AP。与皮下胰岛素相比，腹膜内胰岛素的起效和消退更快且更可预测;与皮下传感相比，腹膜内传感在跟踪血糖变化方面显得更准确和及时。在腹膜内环境中，日内变异性极小，每年仅需重新植入一次（每三个月对泵进行一次经皮再灌注）。展望现实世界的影响，本研究的最终目标是开发一种完全闭环的可商业化设备，其总成本与当前泵/CGM治疗相同（或更低）。IP-IP AP的开发将是一项多学科的工作。因此，该项目团队包括：一家开发基于荧光的植入式葡萄糖传感器的公司;一家开发腹腔内植入式微型胰岛素泵的公司;一家开发热稳定的高浓度胰岛素类似物的公司;一家拥有腹膜内葡萄糖传感专业知识的公司;一家拥有葡萄糖控制算法专业知识的学术机构;以及一家拥有糖尿病技术专业知识的临床研究机构。该项目有五个具体目标：1）将现有的基于荧光的葡萄糖传感器整合到腹膜内胰岛素导管中，并为动物和人类研究建造大约50个传感器导管; 2）开发和制造下一代可植入的基于MEMS的胰岛素泵，该胰岛素泵可以作为闭环系统的一部分无线操作; 3）确认热稳定的胰岛素类似物与在37 ℃下在腹膜内泵中使用长达一年的相容性，并表征类似物的腹膜内PK和PD; 4）优化用于腹膜内感测和腹膜内胰岛素递送的闭环控制算法，并利用计算机模拟来验证该算法; 5）在猪研究中验证植入的人工胰腺，并在人类中进行初步研究。

DESCRIPTION (provided by applicant): The goal of this project is to develop an intraperitoneally implanted, closed-loop glucose-monitoring / insulin- delivery device (aka artificial pancreas) for people with type 1 diabetes. An artificial pancreas could improve patients short- and long-term health and quality of life, and it could decrease overall healthcare costs. However, most current artificial-pancreas prototypes use subcutaneous insulin pumps and subcutaneous glucose sensors, which are associated with significant lag times (~60 minutes and ~10 minutes, respectively). Furthermore, insulin infusion sites and sensors require replacement every several days, contributing to variability in insulin absorption and glucose measurement. These lags and variabilities impose a ceiling on the performance of any artificial pancreas that uses subcutaneous insulin delivery and glucose sensing. Fortunately, these challenges could be overcome by an implantable artificial pancreas that uses both intraperitoneal insulin delivery and intraperitoneal glucose sensing - an IP-IP AP. Compared to subcutaneous insulin, intraperitoneal insulin is faster and more predictable in both onset and offset; compared to subcutaneous sensing, intraperitoneal sensing appears more accurate and timely for tracking blood glucose changes. Intraday variability is minimal in the intraperitoneal environment, and re-implantation would be required only once per year (with the pump re-filled transcutaneously once every three months). Looking toward real-world impact, the ultimate goal of this research is development of a fully closed-loop, commercializable device with total costs that are identical (or lower) compared to current pump/CGM therapy. Development of an IP-IP AP will be a multidisciplinary effort. Thus, the project team includes: a company developing fluorescence-based implantable glucose sensors; a company developing intraperitoneally implantable, miniaturized insulin pumps; a company developing a heat-stable, highly concentrated insulin analog; a company with expertise in intraperitoneal glucose sensing; an academic institution with expertise in glucose-control algorithms; and a clinical research institut with expertise in diabetes technology. The project has five specific aims: 1) To adapt an existing fluorescence-based glucose sensor for integration into an intraperitoneal insulin catheter, and to build roughly 50 sensor-catheters for animal and human studies; 2) To develop and manufacture a next-generation implantable, MEMS-based insulin pump that can be wirelessly operated as part of a closed-loop system; 3) To confirm that the heat-stable insulin analog is compatible with use in an intraperitoneal pump at 37¿ C for up to one year, and to characterize the analog's intraperitoneal PK and PD; 4) To optimize a closed-loop control algorithm for intraperitoneal sensing and intraperitoneal insulin delivery, and to validate this algorithm with i silico simulations; 5) To validate the implanted artificial pancreas in swine studies, and to perform a pilot study in humans.