Development and Validation of Novel Coatings that Extend Glucose Sensor Accuracy and Lifespan in vivo

开发和验证可延长体内血糖传感器精度和寿命的新型涂层

• 批准号: 9898181
• 负责人: DON KREUTZER
• 金额: $ 29.85万
• 依托单位: CELL/MOLECULAR TISSUE ENGINEERING LLC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-20 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898181
• 关键词: Anti-inflammatory; Antiinflammatory Effect; Architecture; Artificial Pancreas; Basement membrane; Biological; Blood Glucose; Blood Vessels; Cannulas; Cells; Chronic; Cicatrix; DNA; Dendritic Cells; Development; Devices; Diabetes Mellitus; Engineering; Evaluation; Failure; Family suidae; Fibrosis; Foreign-Body Reaction; Foundations; Future; Generations; Genetic Engineering; Goals; Grant; Hernia; Human; Implant; In Vitro; Inflammation; Inflammatory; Laboratories; Letters; Longevity; Lymphocyte; Macrophage Activation; MicroRNAs; Modeling; Modernization; Monitor; Mus; Nature; Performance; Pharmaceutical Preparations; Phase; Polymers; Population; Proteins; Publishing; RNA; Reaction; Reaction Time; Regulatory T-Lymphocyte; Research; Site; Skin Tissue; Skin wound; Small Business Innovation Research Grant; Stem cells; Stents; Surgical Mesh; System; Tissues; Translations; Triad Acrylic Resin; Universities; Validation; Wound Healing; base; biomaterial compatibility; diabetic patient; early onset; engineered exosomes; exosome; experience; extracellular vesicles; glucose monitor; glucose sensor; immunoregulation; implantable device; implantation; implanted sensor; improved; in vivo; inhibitor/antagonist; macrophage; mast cell; microvesicles; mouse model; nanoparticle; novel; prevent; repaired; sensor; sensor technology; subcutaneous; success; tissue regeneration; vessel regression

An overarching factor in the development of any successful “artificial pancreas” system is the advancement of a highly accurate and long-lived glucose sensor, without the need for numerous recalibrations. Frequently, implantable glucose sensors demonstrate insufficient reliability with respect to performance (accuracy and response time), which is thought to be the result of poor biocompatibility. Central to these complications is the failure of these sensors to successfully integrate into surrounding tissue. In fact, one of the major paradigms of modern glucose sensor technology is that “if the sensor is not biocompatible, it will not last”. Generally, poor sensor performance has been attributed to the triad of inflammation, fibrosis, and vessel regression (sensor induced tissue reactions (SITR)). This failure is the result of initial chronic inflammation, tissue destruction, and intense scarring induced by the sensor, i.e. sensor induced tissue reactions. This class of implant-induced tissue reactions is referred to as foreign body reactions (FBR). These FBRs are driven by activated pro-inflammatory-macrophages (M1MQ). Thus, suppressing M1 macrophage function is key to overcoming SITR/FBR and the associated complications. Preventing the early onset of FBR is central to promoting successful integration of sensor into tissue (i.e. ingrowth of fibro-vascular tissue) rather than intense scaring resulting in a wide range of complications. Previous efforts to overcome SITR have generally focused on the usage of synthetic polymer coatings (+/- drugs), but with limited success. In addition, a variety of sensor coatings, both synthetic and biologic in nature, have been used, but with limited success. In the present application, we propose to develop and validate a new generation of biologically active exosome-based sensor coatings that will suppress macrophage function and thereby prevent sensor-induced FBR (inflammation and fibrosis), in so doing, enhancing successful sensor integration into surrounding tissue. To achieve this goal, we propose to utilize microvesicles (i.e. exosomes) from anti-inflammatory cells (e.g. regulatory T cells (Treg)). These exosomes will be incorporated into basement membrane matrices, and utilized as bioactive sensor coatings, which will suppress sensor-induced inflammation, fibrosis, as well as promote tissue regeneration at sensor implantation sites. If these bioactive exosome-based coatings (i.e. Exo-Matrices) are successful in suppressing macrophage activation and enhancing sensor integration in vivo, in the future (Phase 2 SBIR), these exosomes will be analyzed for “cargo” composition, e.g., RNA, DNA and protein. Previous studies of exosome cargo have demonstrated that the microRNAs in microvesicles/exosomes are powerful “cell re-programmers”, and synthetic miRNAs are being developed into cutting edge therapies. Using this information, in the future, we will develop “designer exosomes” using genetically engineered exosomes from anti- inflammatory & pro-wound healing cells, ultimately leading to the development of “synthetic exosomes” for uses in Exo-Matrices. We anticipate the miRNAs will likely be the key exosome cargo component that will suppress macrophage function during SITR/FBR, and will be the foundation for future artificial/synthetic exosomes, which will be used in our Exo-Matrices coatings of sensors. !

任何成功的“人工胰腺”系统的发展的首要因素是一个先进的