Improving the Kinetics and Reliability of Continuous Glucose Monitoring

描述（由申请人提供）：当最终实现人工胰腺工程化的目标时，1型糖尿病（T1DM）患者的生活质量和预期寿命将显著改善。这种系统的一个关键组成部分是能够快速、准确和连续地测量血糖的变化。植入式连续葡萄糖监测仪是对几十年来一直是规范的手指针刺测量的改进，但其性能受到组织间质性葡萄糖代谢的基本限制的阻碍。目前植入的（皮下）空间：1）在血糖的变化和间质葡萄糖的变化之间存在显著的滞后时间，2）由于间质空间的灌注是可变的，因此滞后时间存在显著的可变性，3）由于间质氧张力的正常波动而存在稳态不准确性，以及4）由于组织封装，间隙传感器需要经常更换。 这些限制阻止了间质传感器用于在涉及血糖快速变化的常规活动（例如进食和运动）周围实现严格的血糖控制。实现严格的血糖控制是我们研究项目的长期目标，因为这对于预防T1DM患者的毁灭性长期后遗症至关重要。 本申请的目的是确定使用腹膜间隙进行葡萄糖感知（而不是组织间隙）将在多大程度上推动我们实现这一目标。我们的中心假设是，腹膜空间中的液体跟踪血糖变化，其滞后时间和滞后时间变异性小于间质空间，因为流向该中心受保护空间的血液充足且对温度和心输出量的变化稳健，并且因为已知腹膜空间的葡萄糖动力学快速。我们还假设，腹膜传感器将表现出更少的传感器间的变异性和氧分压相关的不准确性比相同的传感器放置在腹膜。我们的假设得到了生理学文献和我们使用血糖激发的初步研究的支持，这些研究显示腹膜腔的葡萄糖反应比间质传感器更快。 我们将通过比较植入腹膜与间质间隙的传感器的连续葡萄糖读数，同时将实验动物（猪）暴露于静脉内葡萄糖耐量试验，来检验这些假设。这些测试将在基线条件下进行，然后在体温和血压变化期间再次进行，以测试稳健性。我们将测量所有情况下的滞后时间和滞后时间变异性。 此外，我们将测试我们的专有技术，以防止组织包囊，这是长期植入传感器所面临的主要挑战之一。

DESCRIPTION (provided by applicant): Patients with type 1 diabetes mellitus (T1DM) will experience dramatic improvements in their quality of life and life expectancy when the goal of engineering an artificial pancreas is finally realized. A critical component of such a system is to be able to measure changes in blood glucose rapidly, accurately, and continuously. Implantable continuous glucose monitors are an improvement over the fingerstick measurements that have been the norm for decades, but their performance is hampered by fundamental limitations of the interstitial (subcutaneous) space where they are currently implanted: 1) there is substantial lag time between changes in blood glucose and changes in interstitial glucose, 2) there is substantial variability in the lag time because perfusion of the interstitial space is variable, 3) there are steady-state inaccuracies due normal fluctuations in interstitial oxygen tension, and 4) due to tissue encapsulation, interstitial sensors need to be replaced frequently. These limitations prevent interstitial sensors from being used to achieve tight glycemic control around routine activities that involve rapid changes in blood glucose, such as eating and exercise. Achieving tight glycemic control is the long-term goal of our research program, as it is critical to preventing the devastating long-term sequelae in patients with T1DM. The objective of this application is to determine the extent to which using the peritoneal space for glucose sensing (instead of the interstitial space) will move us toward this goal. Our central hypothesis is that the fluid in the peritoneal space tracks blood glucose changes with less lag time and less lag-time variability than the interstitial space, because the blood flow to this central, protected space is copious and robust to changes in temperature and cardiac output, and because the glucose kinetics of the peritoneal space are known to be fast. We additionally hypothesize that peritoneal sensors will exhibit less intersensor variability and oxygen- tension-related inaccuracies than the same sensors placed interstitially. Our hypothesis is supported by the physiology literature and by our pilot studies using a glycemic challenge, which show a faster glucose response for the peritoneal space vs. interstitial sensors. We will test these hypotheses by comparing continuous glucose readings from sensors implanted in the peritoneal vs. interstitial spaces while exposing experimental animals (pigs) to intravenous glucose tolerance tests. These tests will be done under baseline conditions, then again during changes in body temperature and blood pressure, to test robustness. We will measure lag times and lag-time variability in all cases. Additionally, we will test our proprietary technology for preventing tissue encapsulation, which is one of the principle challenges facing efforts to implant sensors chronically.