Improving the Kinetics and Reliability of Continuous Glucose Monitoring

描述(由申请人提供)：当设计人工胰腺的目标最终实现时，1型糖尿病(T1 DM)患者的生活质量和预期寿命将得到显著改善。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。植入式连续血糖监测仪是对几十年来一直是标准的手指测量的改进，但是它们的性能受到当前植入的组织(皮下)空间的基本限制的阻碍：1)血糖的变化和组织间血糖的变化之间存在很大的滞后时间，2)由于组织间隙的灌注是可变的，所以滞后时间有很大的变异性，3)由于组织间氧分压的正常波动，存在稳态的不准确性，以及4)由于组织包裹，间质传感器需要经常更换。这些限制阻碍了间质传感器在日常活动中实现严格的血糖控制，这些活动涉及血糖的快速变化，如饮食和运动。实现严格的血糖控制是我们研究计划的长期目标，因为这对预防T1 DM患者的破坏性长期后遗症至关重要。这项应用的目的是确定使用腹膜间隙(而不是间质间隙)进行血糖检测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，与间质间隙相比，腹膜间隙中的液体跟踪血糖变化的滞后时间更短，滞后时间变异性更小，因为流向这个中央受保护间隙的血液丰富，对温度和心输出量的变化很健壮，而且众所周知，腹膜间隙的葡萄糖动力学很快。我们还假设，腹膜传感器将比放置在组织间的相同传感器表现出更少的传感器间变异性和与氧分压相关的不准确性。我们的假设得到了生理学文献的支持，并得到了我们使用血糖挑战的初步研究的支持，这些研究表明，与间质传感器相比，腹膜间隙的葡萄糖反应更快。我们将通过比较植入腹膜和间质的传感器的连续血糖读数来验证这些假设，同时将实验动物(猪)暴露于静脉葡萄糖耐量测试中。这些测试将在基线条件下进行，然后在体温和血压变化时再次进行，以测试健壮性。我们将在所有情况下测量滞后时间和滞后时间变异性。此外，我们将测试我们的专利技术，以防止组织封装，这是努力长期植入传感器面临的主要挑战之一。 公共卫生相关性：血糖控制不佳会导致1型糖尿病患者的长期器官损害。通过设计人工胰腺来改善血糖控制的努力受到植入最先进的连续血糖传感器的位置的阻碍：间质空间，其葡萄糖动力学缓慢，对正常生理变化不稳定。本建议试图通过将传感器重新放置到腹膜腔来解决这些限制，以便利用更适合血糖监测的性能要求的腹膜特性：快速的葡萄糖动态、对血压和温度变化的稳健性、异物耐受性以及通过防止组织包裹来增强耐用性的能力。

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. PUBLIC HEALTH RELEVANCE: Poor control of blood glucose results in devastating long-term organ damage in patients with Type 1 diabetes mellitus. Efforts to improve glucose control by engineering an artificial pancreas are hampered by the location in which state-of-the-art continuous glucose sensors are implanted: the interstitial space, which has slow glucose kinetics that are labile to normal physiologic variations. The present proposal seeks to address these limitations by relocating the sensor to the intraperitoneal space in order to take advantage of peritoneal properties which are better suited to the performance demands of glucose monitoring: fast glucose dynamics, robustness to changes in blood pressure and temperature, foreign body tolerance, and ability to enhance durability by preventing tissue encapsulation.