Impact of the Vascular System and CGM

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The concept that increasing blood vessel (BV) density and proximity to glucose sensors increases real time interstitial glucose levels and sensor function in vivo is accepted, despite limited experimental data to support that concept. Currently there is no previous data or even conjecture in the literature on the role of lymphatic vessels (LV) or the combinations of BV & LV in enhancing sensor function in vivo. Likewise nothing is known about the mediators and mechanisms involved in the formation and function of these vascular networks at sensor implantation sites. Recent gene therapy studies in our laboratories have demonstrated that 1) VEGF-A based local gene therapy increases vascular networks (blood vessels and lymphatic vessels) at sites of glucose sensor implantation; and 2) this local increase of vascular networks enhances and extends glucose sensor function in vivo from 7 days to greater than 28 days post sensor implantation. This exciting data provides "proof of concept" that increasing vascular networks at sites of glucose sensor implantation enhances performance of continuous glucose monitoring (CGM). Among the key questions that this data leads to is: 1) what are the key cells, mediators and mechanism(s) that control vascular networks (blood vessels (BV) and lymphatic vessels (LV)) at sites of sensor implantation; 2) how do they control CGM; 3) are BV, LV or the combination of vascular networks critical to enhancing and extending CGM in vivo; 4) what is the role of inflammation and fibrosis in controlling vascular networks at sensor implantation sites, and 5) can bio- enhanced extracellular matricies (ECM) be developed to control vascular network formation and enhance and extend CGM for both transcutaneous and totally implantable glucose sensors? The 3 major research goals for this application are: 1) develop and validate ECM based sensor coatings with drug delivery capability to control inflammation, fibrosis and promote vascular network formation in normal and diabetic mice; 2) determine the impact of BV, LV and BV+LV on tissue reactions and CGM in normal and diabetic mice; 3) characterize the cells, mediators and pathways that control angiogenesis, lymphangiogenesis using traditional and laser capture microsurgery technology and tissue from sensor implantation sites and correlate with CGM diabetic status.