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. !
The present application focuses on the development of a new generation of glucose sensor coatings that have the ability to control tissue bio-reactions induced by implantable glucose sensors. These matrices are comprised of exosomes isolated from anti-inflammatory cells (Regulatory T cells), which are added to our existing glucose sensor coatings (designated as Exo-Matrices) and used to suppress inflammatory reactions induced by the sensor in vivo. We hypothesize that the anti- inflammatory effect of these Exo-Matrices will improve sensor accuracy and lifespan in vivo.
