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

使用干细胞增强和扩展体内连续血糖监测

• 批准号: 9671761
• 负责人: DON KREUTZER
• 金额: $ 27万
• 依托单位: CELL/MOLECULAR TISSUE ENGINEERING LLC
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-18 至 2021-09-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9671761
• 关键词: Adipocytes; Anti-inflammatory; Architecture; Artificial Pancreas; Aspirin; Award; Basement membrane; Binding; Blood Glucose; Cell physiology; Cells; DNA; Dendritic Cells; Development; Devices; Diabetes Mellitus; Engineering; Evaluation; Fibroblasts; Fibrosis; Foundations; Future; Gene Deletion; Gene Expression; Genes; Goals; Histopathology; Immunosuppression; In Vitro; Inflammation; Inflammatory; Leukocytes; Liposomes; Longevity; Lymphatic Endothelial Cells; Lymphocyte; Mesenchymal; Mesenchymal Stem Cells; Metaphor; MicroRNAs; Modeling; Modernization; Monitor; Mus; Nobel Prize; Peptide Sequence Determination; Performance; Pharmaceutical Preparations; Phase; Polymers; Population; Proteins; RNA; Reaction; Reaction Time; Recombinant Proteins; Recombinants; Regulation; Regulator Genes; Regulatory T-Lymphocyte; Site; Source; Speed; Stem cells; Structure; System; Tablets; Technology; Time; Tissues; Triad Acrylic Resin; Vascular Endothelial Cell; Virus; Wound Healing; base; biomaterial compatibility; capsule; diabetic patient; exosome; extracellular vesicles; glucose monitor; glucose sensor; immunoregulation; implantation; implanted sensor; improved; in vivo; in vivo monitoring; macrophage; mast cell; microvesicles; mouse model; nanocapsule; novel; pill; prevent; regenerative; sensor; sensor technology; subcutaneous; success; tissue regeneration; transcriptome sequencing; vessel regression

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.

基于植入式葡萄糖传感器的糖尿病患者血糖水平监测已经可用于 超过40年。然而，尽管对传感器功能进行了改进，但是传感器设备的重新校准通常是不可能的。 这是为了补偿不可靠的传感器性能所必需的。开发高精度和 长寿命的可植入传感器对于“人工胰腺”的发展至关重要。因为看起来 传感器诱导的组织反应（炎症和伤口愈合）限制了植入的准确性和寿命 传感器在体内，关键是要制定战略，以显着提高长期的生物相容性， 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相容性，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， 将传感器变成“传感器友好组织”。为了实现这一目标，我们建议利用干细胞衍生的 因此，本发明提供了一种“微泡/外来体”以抑制炎症并控制靶组织的结构和功能。 外来体是含有蛋白质、DNA和RNA的组合的小包装（称为“货物”）， 它们是从激活的源细胞释放的。外泌体与特定的靶细胞结合，并“控制”细胞的增殖。 靶细胞的功能。外泌体靶向和控制靶细胞的方式与病毒类似 与特定细胞结合并控制目标细胞。外泌体的重要性被强调， 2013年诺贝尔奖授予他们的发现。对于本申请，我们提出开发 用于传感器的基于外泌体基质的涂层，其可用于增强传感器的生物相容性， 精度具体来说，我们将专注于间充质干细胞（MSC）衍生的外泌体，因为它们不是 不仅能消炎还能再生组织根据上述信息，我们假设 我们可以大大提高传感器在体内的长期精度和寿命。我们计划写一部小说 通过将MSC外泌体并入我们现有的基底膜， 增强传感器在体内的生物相容性。这些基于MSC外泌体的传感器涂层被指定为外泌体。 MSC矩阵。Exo-MSC-Matrix将用于涂覆透皮和完全植入式传感器。这些外- 首先将在我们的小鼠CGM模型中评价MSC-Matrix涂层传感器。该涂层的功效将是 通过探头功能以及植入部位的组织病理学进行评价。如果成功地提高了 在体内的传感器功能，这些MSC外来体将被分析“货物”组成，例如，DNA、RNA和 proteins.在未来，这些信息可用于通过基因修饰来开发设计者外泌体。 通过引入新的基因、基因缺失和/或基因表达的调节剂 (e.g. miRNA基因沉默剂），以产生在抑制炎症方面更有效的外泌体 重新设计传感器植入部位