Local drug delivery targeting mast cells to improve the functional lifetime of continuous glucose sensors
Creators: name: Avula, Mahender nath
Publisher: name: University of Utah
Year: 2014
Subjects: Biomaterials
Biosensors
Continuous glucose sensors
Foreign body response
Local drug delivery
Mast cells

description: Diabetes mellitus affects 5% of the world's population and requires constant monitoring to avoid fatality. Tight control of blood glucose levels has shown to reduce the long-term effects of diabetes. Finger-stick blood glucose measurements are the gold standard for glucose monitoring that are painful and only provide intermittent glucose values. Continuous glucose monitoring (CGM) is an improvement in this technology but is severely limited in its performance abilities beyond the currently approved implantation time lasting up to a week. CGM is still performed as an adjunct to finger-stick measurements since they are unreliable even during the approved usage durations. Implantation of a biomaterial induces a wound (catheter, hernia meshes, etc.) or disturbance in local tissue (contact lens, etc.). Wound healing response in the host mediates the formation of scar tissue and healing of the injury site. Host foreign body response (FBR) deviates from its healing response in the presence of a foreign body i.e, an implant, and tries to isolate it from the host via fibrous encapsulation. FBR is considered as one of the primary reasons for CGM sensor failure. FBR encapsulates the sensor implant, creating a barrier between the sensing electrode and essential analytes (glucose, oxygen, etc.) required for measuring glucose levels. This phenomenon results in painful and expensive CGM sensor replacements. Work described in this dissertation focuses on improving the clinical performance of CGM sensors by extending their functional lifetimes. Combination device strategies involving the use of a drug (dexamethasone, etc.), or a biologic (VEGF, siRNA, etc.), or a combination of these have been studied to reduce implant-associated FBR. In this dissertation, we targeted mast cells that are believed to orchestrate the FBR by secreting several key granules containing inflammatory cytokines, vasodilators, chemokines, etc. that result in an increased influx of inflammatory cells to the wound site. A novel tyrosine kinase inhibitor- masitinib was used to target the c-KIT receptor on the cell surface of mast cells. Stem cell factor and its ligand c-KIT are considered critical for mast cell survival, proliferation, and degranulation and the hypothesis driving this research is that targeting mast cell degranulation via the c-KIT pathway results in a reduced foreign body response. To test our hypothesis, we developed a local drug delivery formulation comprised of PLGA microsphere drug carriers embedded in a PEG matrix around implants. The effect of the drug was initially evaluated in wild-type (mast cell competent) and sash (mast cell-deficient) mice for up to 28 days. The results from these studies confirmed previous claims that mast cells play an important role in mediating FBR-associated fibrosis around implanted biomaterials and that the use of a mast cell stabilizing tyrosine kinase inhibitor reduced fibrous capsule thickness around implants in wild-type mice but had no effect in sash mice. The drug-releasing coating was then tested in CGM sensors in a wild-type murine percutaneous model for 21 days. Results from the CGM study indicate that drug-releasing coated sensors exhibit relatively stable response compared to control implants, suggesting that reduced fibrosis resulting from stabilizing mast cells results in improving CGM performance. The translation of these results to human subjects would enable better control of diabetes and provide the ability to better diagnose long-term effects of diabetes through long-term continuous glucose monitoring.