DUAL FOREIGN BODY RESPONSE MITIGATION STRATEGIES FOR IMPROVING THE ANALYTICAL PERFORMANCE OF IMPLANTABLE GLUCOSE BIOSENSORS

Continuous glucose monitors (CGMs) have been invaluable in the management of diabetes. However, their analytical lifetime is compromised by the innate foreign body response (FBR). Several FBR mitigation strategies have been explored to extend the lifetime of CGMs, including nitric oxide (NO) release from the sensor surface. While successful, improved sensor accuracy from NO requires sustained release. Electrospun fibers, a passive FBR mitigation strategy, promote tissue integration and angiogenesis for improved glucose delivery. A combination of NO and electrospun fibers on CGMs have the potential to extend sensor analytical lifetimes past the duration of NO release.Two sizes of electrospun fibers were developed by changing various electrospinning process parameters. Neither size of electrospun fiber affected NO release kinetics. When implanted in a diabetic porcine model, mock sensors electrospun with fibers of a smaller diameter demonstrated a more pro-wound healing response at 11, 28, and 42 d post-implantation compared to mock sensors electrospun with larger fibers. When combined with NO release, electrospun fibers with a smaller diameter appeared to continue promoting a pro-wound healing response once NO release had ceased.A combination of NO release and electrospun fibers with the smaller diameter were used on functional glucose sensors to evaluate sensor accuracy in a diabetic porcine model over six weeks. While fiber-coated sensors, with or without NO release, appeared to result in improved sensor performance, results were not significant. However, all types of sensors (i.e., non-fibrous NO- and non-NO-releasing and fibrous NO- and non-NO-releasing) maintained similar clinical and numerical accuracies over six weeks of implantation. Translational potential, in terms of sterilization and shelf-life, of NO-releasing glucose sensors was evaluated. The NO donor used herein, S-nitrosothiols, are light and heat sensitive. As such, traditional sterilization methods (i.e., ethylene oxide gas) resulted in premature NO release. Ultraviolet light was able to sterilize NO-releasing glucose sensors to at 10-6 sterility assurance level while maintaining short- and long-term NO release kinetics and glucose sensor performance. In addition, NO-releasing glucose sensors were stored for up to one year at -80°C or up to six months at -20°C without any loss of NO.