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Design Considerations for Silica Particle-Doped Nitric OxideReleasing Polyurethane Glucose Biosensor Membranes Robert J. Soto, Jonathon B. Schofield, Shaylyn E. Walter, Maggie J. Malone-Povolny, and Mark H. Schoenfisch ACS Sens., Just Accepted Manuscript • DOI: 10.1021/acssensors.6b00623 • Publication Date (Web): 28 Nov 2016 Downloaded from http://pubs.acs.org on November 28, 2016
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ACS Sensors
Design Considerations for Silica Particle-Doped Nitric OxideReleasing Polyurethane Glucose Biosensor Membranes Robert J. Soto, Jonathon B. Schofield, Shaylyn E. Walter, Maggie J. Malone-Povolny, and Mark H. Schoenfisch* Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States KEYWORDS: Glucose biosensor, nitric oxide, silica nanoparticle, foreign body response, continuous glucose monitor, biocompatibility, in vivo sensor
ABSTRACT: Nitric oxide (NO)-releasing polymers have proven useful for improving the biocompatibility of in vivo glucose biosensors. Unfortunately, leaching of the NO donor from the polymer matrix remains a critical design flaw of NO-releasing membranes. Herein, a toolbox of NO-releasing silica nanoparticles (SNPs) was utilized to systematically evaluate SNP leaching from a diverse selection of biomedical-grade polyurethane sensor membranes. Glucose sensor analytical performance and NO-release kinetics from the sensor membranes were also evaluated as a function of particle and polyurethane chemistries. Particles modified with N-diazeniumdiolate NO donors were prone to leaching from PU membranes due to the zwitterionic nature of the NO donor modification. Leaching was minimized (0.99 was used for the linear correlation coefficient. Glucose sensitivities are reported as the slope of the linear trend line correlating the measured anodic current to glucose concentration over the linear response range. Amperometric selectivity coefficients for glucose over common electroactive interfering species were calculated according to published 36,44 methods.
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RESULTS AND DISCUSSION Polyurethane (PU) materials have been utilized as glucose sensor membranes because they generally elicit only a mild FBR and, depending on their composition, have appropriate glucose/oxygen permeabilities necessary 47-48 for fabricating glucose sensors. Unfortunately, the literature is not clear as to how glucose sensor analytical performance depends on PU composition and water uptake, important parameters that may also impact NO release and NO donor leaching. Initial experiments thus focused on identifying PUs that could be used to fabricate functional electrochemical glucose sensors prior to modification with the NO-releasing scaffolds. Glucose biosensors were systematically modified with glucose diffusion-limiting PU coatings via a 43,45 loopcasting method. The analytical performance of the sensors was evaluated as a function of PU water uptake and the concentration of the PU loop-casting solution using four commercially-available PUs: HP-93A100, AL-25-80A, SG-85A, and PC-3585A. Regardless of PU type, sensors that were prepared using low concentration PU solutions (20 and 35 mg mL-1) did not yield stable glucose response (data not shown), whereas 50 mg mL-1 PU solutions lead to more predictable sensor
Table 1. Analytical performance merits of glucose biosensors coated with different PUs.a,b
PU Type HP-93A-100 AL-25-80A SG-85A PC-3585A
PU Water uptake Linear Dynamic Sensitivity (nA -1 d e -1 -2 f (mg mg ) Range mM mm ) c
2.6±0.3 c 0.6±0.3 c 0.2±0.2 0.0±0.0
1–3 mM 1–6 mM 1–15 mM 1–15 mM
38.2±15.0 44.7±15.2 29.5±15.3 20.1±4.2
Sensitivity Retention (%)
g
3d
5d
7d
14 d
54.3±29.6 80.2±10.7 86.1±10.1 80.5±13.6
57.2±7.3 82.9±28.8 85.5±18.3 77.0±7.2
44.3±8.9 58.5±10.2 64.9±6.1 55.2±2.5
42.3±7.3 58.3±11.0 67.2±8.1 56.2±2.4
a Error bars represent standard deviation for n>3 separate experiments. bPU concentration in the loop-casting solution was 50 mg mL-1. cWater uptake measurements described in Koh et al., Biosensors and Bioelectronics 2011, 28, 17–24. dWater uptake expressed as mgwater per mgPU. eLinear dynamic range determined from glucose sensor calibration curves as the concentration range over which the associated linear trendline had an R2 value >0.99. fDetermined as the slope of the trendline fit to the sensor current-glucose response over the linear dynamic range on the first day of testing. gGlucose sensitivity after soaking sensors in PBS at 37 oC (relative to the sensitivity on the first day of testing).
Membrane and particle characterization Morphology of the nanoparticles was evaluated using a FEI Helios 600 Nanolab scanning electron microscope (SEM; Hillsboro, OR). Scanning electron micrographs of the N-diazeniumdiolate- and Snitrosothiol-modified particles are provided in the Supporting Information (Figures S2 and S3, respectively). Sensor membranes were imaged using a FEI Quanta 200 environmental scanning electron microscope (Hillsboro, OR). Nitrogen sorption isotherms were used to evaluate SNP porosity and were collected on a Micromeritics Tristar II 3020 surface area and porosity analyzer (Norcross, GA). Samples were dried at 110 oC under N2 gas for 18 h and degassed for 2 h prior to analysis. BrunauerEmmett-Teller (BET) analysis of the monolayer adsorption isotherm region (0.05
