Understanding and improving in vivo materials related to signal stability and preservation for active chemical sensor and biosensor transduction systems is critical in achieving implantable medical sensors for long-term in vivo applications. During human in vivo clinical testing of an implantable glucose sensor based on a glucose sensitive hydrogel, post-explant analysis showed that the boronate recognition element had been oxidized from the fluorescent indicator, causing a rapid loss of signal within hours after implant. Additional wet-bench analytical evidence and reproduction in vitro suggests reactive oxygen species, particularly hydrogen peroxide (H2O2), stemming from natural inflammatory response to the material, to be the cause of the observed oxidative de-boronation. A 3-nm thick deposition of metallic platinum (Pt) placed by plasma sputtering onto the porous surface of the hydrogel, showed immediate protection from sensor signal loss due to oxidation both in vitro and in vivo, greatly extending the useful lifetime of the implantable glucose sensor from 1 day to an expected ≥6 months. This finding may represent a new strategy to protect an implanted material and/or device from in vivo oxidative damage, leading to much improved overall stability and reliability for long-term applications. © 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2013.