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.
The goal of the present application is to develop a totally new paradigm for biocompatibility coatings for implantable glucose sensors that will utilize anti- inflammatory exosome-based coatings to prevent inflammation and fibrosis, as well as promote tissue re-engineering of the sensor implantation sites to allow re-utilization of this site for future CGM applications.
