Use of Stem Cells to Enhance and Extend Continuous Glucose Monitoring in Vivo

基于植入式血糖传感器的糖尿病患者血糖水平监测已可用于 40多年了。然而，尽管传感器功能得到了改进，传感器设备的重新校准通常是 这是为了补偿不可靠的传感器性能所必需的。高精度和高精度仪器的发展 长寿命的植入式传感器对“人工胰腺”的发展至关重要。因为看起来 传感器引起的组织反应(炎症和伤口愈合)限制了植入的准确性和寿命 在体内的传感器，关键是制定策略，以显著提高长期生物相容性 植入式葡萄糖传感器。我们假设，为了实现这些传感器的长期生物兼容性，我们 需要防止这些传感器的破坏性组织反应，并“重建”植入周围的组织 传感器变成了“传感器友好的组织”。为了实现这一目标，我们建议使用干细胞来源的 “微囊/外切体”，抑制炎症，控制目标组织的结构和功能。 Exosome是包含蛋白质、DNA和RNA(称为“货物”)的小包装， 它们是从激活的源细胞释放出来的。外切体与特定的靶细胞结合，并“控制” 目标单元的功能。外体对靶细胞的靶向和控制在隐喻上类似于病毒 绑定到特定单元格并控制该目标单元格。Exosome的重要性通过以下几个方面得到强调 授予2013年诺贝尔奖以表彰他们的发现。对于目前的应用程序，我们建议开发 用于传感器的Exosome基质涂层，可用于增强传感器的生物兼容性和 精确度。具体地说，我们将关注间充质干细胞(MSC)来源的外体，因为它们不是 不仅能消炎，还能促进组织再生。根据上面提供的信息，我们假设 我们可以在活体内显著提高传感器的长期准确性和寿命。我们计划写一部小说 通过将MSC外切体掺入我们现有的基底膜来获得生物活性传感器涂层，以便 提高传感器在体内的生物相容性。这些基于MSC exosome的传感器涂层被指定为Exo- MSC-Matrix。Exo-MSC-Matrix将被用来覆盖透皮和完全可植入的传感器。这些Exo- MSC-Matrix涂层传感器将首先在我们的小鼠CGM模型中进行评估。这种涂层的功效将是 通过传感器功能以及植入部位的组织病理学进行评估。如果成功地增强了 在体内的传感器功能，这些MSC外体将被分析的“货物”组成，例如DNA，RNA和 蛋白质。在未来，这些信息可以用来开发设计者外显体，方法是对 通过引入新的基因、基因缺失和/或基因表达调节而形成的外体来源细胞 (例如，miRNA基因沉默剂)，以产生更有效地抑制炎症的外体 并重新设计传感器植入地点。

Implantable glucose sensor-based monitoring of blood glucose levels in diabetic patients has been available for over 40 years. However, despite improvements to sensor functionality, recalibration of the sensor device is often a necessity in order to compensate for unreliable sensor performance. The development of highly accurate and long-lived implantable sensors is critical to the development of the “artificial pancreas”. Since it appears that sensor-induced tissue reactions (inflammation and wound healing) limits accuracy and lifespan of implanted sensors in vivo, it is critical to develop strategies to dramatically enhance the long-term biocompatibility of implantable glucose sensors. We hypothesize that to achieve long-term biocompatibility for these sensors, we need to prevent destructive tissue reactions from these sensors and “rebuild” the tissue surrounding implanted sensors into a “sensor friendly tissue”. To achieve this goal, we propose to utilize stem cell-derived “microvesicles/exosomes” to suppress inflammation and control the structure and function of targeted tissue. Exosomes are small packages that contain a combination of proteins, DNA and RNAs (referred to as “Cargo”), which are released from activated source cells. Exosomes bind to specific target cells and “take control” of the target cell’s functions. Exosomes targeting and control of target cells is metaphorically similar to the way viruses bind to specific cells and take control of that target cell. The importance of exosomes was underscored by the awarding of the 2013 Nobel Prize for their discovery. For the present application, we propose to develop exosome matrix-based coatings for sensors, which can be used to enhance sensor biocompatibility and accuracy. Specifically, we will focus on mesenchymal stem cell (MSC)-derived exosomes because they are not only anti-inflammatory, but also tissue regenerative. Based on the information provided above, we hypothesize that we can dramatically improve long-term sensor accuracy and lifespan in vivo. We plan to develop a novel bioactive sensor coating by incorporating MSC exosomes into our existing basement membrane in order to enhance sensor biocompatibility in vivo. These MSC exosome-based sensor coatings are designated as Exo- MSC-Matrix. Exo-MSC-Matrix will be used to coat both transdermal and totally implantable sensors. These Exo- MSC-Matrix coated sensors will first be evaluated in our mouse CGM model. Efficacy of this coating will be evaluated through sensor function, as well as histopathology of the implantation sites. If successful in enhancing sensor function in vivo, these MSC exosomes will be analyzed for “cargo” composition, e.g., DNA, RNA and proteins. In the future, this information can be used to develop designer exosomes by genetically modifying the exosome source cells by the introduction of new genes, gene deletions and/or regulators of gene expression (e.g. miRNA gene silencers), to create exosomes that will be even more effective in suppressing inflammation and re-engineering sensor implantation sites.