Design Considerations for Silica-Particle-Doped Nitric-Oxide-Releasing Polyurethane Glucose Biosensor Membranes

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 (PU) 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 (<5% of the entrapped silica over 1 month) in low water uptake PUs. However, SNP modification with neutral S-nitrosothiol (RSNO) NO donors lead to biphasic leaching behavior. Particles with low alkanethiol content (<3.0 wt % sulfur) leached excessively from a hydrogel PU formulation (HP-93A-100 PU), while particles with greater degrees of thiol modification did not leach from any of the PUs tested. A functional glucose sensor was developed using an optimized HP-93A-100 PU membrane doped with RSNO-modified SNPs as the outer, glucose diffusion-limiting layer. The realized sensor design responded linearly to physiological concentrations of glucose (minimum 1-21 mM) over 2 weeks incubation in PBS and released NO at >0.8 pmol cm^-2 s^-1 for up to 6 days with no detectable (<0.6%) particle leaching.