Diabetes is a chronic metabolic disorder whereby the body loses its ability to maintain normal glucose levels. Despite of development of implantable glucose sensors in long periods, none of the biosensors are capable of continuously monitoring glucose levels during long-term implantation reliably. Progressive loss of sensor function occurs due in part to biofouling and to the consequences of a foreign body response such as inflammation, fibrosis, and loss of vasculature. In order to improve the function and lifetime of implantable glucose sensors, a new 3D porous and bio-stable collagen scaffold has been developed to improve the biocompatibility of implantable glucose sensors. The novel collagen scaffold was crosslinked using nordihydroguaiaretic acid (NDGA) to enhance biostability. NDGA-treated collagen scaffolds were stable without any physical deformation in the subcutaneous tissue of rats for 4 weeks. The scaffold application does not impair the function of our sensor. The effect of the scaffolds on sensor function and biocompatibility was examined during long-term in vitro and in vivo experiments and compared with control bare sensors. The sensitivity of the short sensors was greater than the sensitivity of long sensors presumably due to less micro-motions in the sub-cutis of the rats. The NDGA-crosslinked scaffolds induced much less inflammation and retained their physical structure in contrast to the glutaraldehyde (GA)-crosslinked scaffolds. We also have developed a new dexamethasone (Dex, anti-inflammatory drug)-loaded poly(lactic-co-glycolic acid) (PLGA) microspheres/porous collagen scaffold composite for implantable glucose sensors. The composite system showed a much slower and sustained drug release than the standard microspheres. The composite system was also shown to not significantly affect the function of the sensors. The sensitivity of the sensors with the composite system in vivo remained higher than for sensors without the composites (no scaffold, scaffold without microspheres). Histology showed that the inflammatory response to the Dex-loaded composite was much lower than for the control scaffold. The Dex-loaded composite system might be useful to reduce inflammation to glucose sensors and therefore extend their function and lifetime.