In Vivo Analytical Performance Assessment of Nitric Oxide-Releasing Glucose Biosensors Public Deposited

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  • March 21, 2019
Creator
  • Soto, Robert
    • Affiliation: College of Arts and Sciences, Department of Chemistry
Abstract
  • The utility of implantable glucose biosensors as continuous glucose monitoring technologies is limited by poor in vivo accuracy, resulting primarily from the foreign body response (FBR). Polymeric membranes capable of releasing nitric oxide (NO)—an endogenous gas and key mediator of inflammation and angiogenesis—have been shown to mitigate the FBR and thus hold promise for improving in vivo glucose sensor function. Herein, the effect of a reduced FBR on in vivo glucose sensor function was studied using NO-releasing membranes. To address the low NO storage of silica nanoparticles, a new particle system (mesoporous silica) was synthesized for use in glucose sensor membranes. Briefly, an interfacial ion exchange reaction was developed and used to chemically modify mesoporous silica nanoparticles with NO donors. The resulting materials were capable of large NO storage (0.8–2.4 µmol mg-1) and tunable NO-release kinetics (NO-release durations 2–40 h). The NO-releasing nanoparticles were employed as dopants within polyurethane materials and adapted as coatings for amperometric glucose biosensors. The in vivo analytical performance of the NO-releasing glucose biosensors was evaluated in a pre-clinical swine model. Two separate NO-releasing sensors were designed to release similar amounts of NO (~3.1 µmol cm-2) for 16.0 h (short) or 3.1 d (extended) durations. Relative to controls, both NO-releasing sensors exhibited improved accuracy during the acute (3 d) implantation period. Sensors capable of ~3 d NO release were also characterized by a shorter response time (<4.2 min) to changing blood glucose levels than burst NO-releasing and control sensors (>5.8 min) at 3, 7, and 10 d. The NO-releasing sensor membranes were also used to study the FBR in a streptozotocin-induced diabetic swine model. Histopathological evaluation of tissue surrounding control (i.e., non-NO-releasing) materials revealed a more severe inflammatory response, reduced collagen deposition, and inhibited angiogenesis associated with diabetes. Materials capable of ~7–14 d NO release were uniquely capable of mitigating inflammation and increasing blood vessel formation at the implant-tissue interface (relative to 2–3 d NO release). The ~7–14 d NO-releasing membranes also reduced collagen deposition in healthy pigs, but did not produce an effect in the diabetic animal model.
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  • In Copyright
Advisor
  • Jorgenson, James
  • Nichols, Timothy
  • Gu, Zhen
  • Wightman, R. Mark
  • Schoenfisch, Mark H.
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2016
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