A double bead microsphere device that functions as a 3D scaffold and also delivers bioactive molecules to cells has been developed. The system we developed consists of large polymeric microspheres that were loaded with dexamethasone (DEXA) and coated with DHEA, which were physically immobilized using a layer-by-layer (LbL) system. The initial step in this strategy involves the creation of microparticles that contain DHEA, which were simply produced using a water-in-oil-in-water (W/O/W) emulsion method. In the second step, small sized microparticles containing DHEA were coated onto positively-charged poly(d,l-lactic-co-glycolic acid) (PLGA) microspheres that contained DEXA pretreated with poly(ethyleneimmine) (PEI). Microsphere constructs that contain DEXA and DHEA showed a significantly higher number of specific lacuna phenotypes at the end of a 4-week study in vitro and at the end of a 6-week study in vivo, irrespective of the presence of DEXA and DHEA. Therefore, the dual delivery of DEXA and DHEA can be used to engineer inflammation-free tissue in the vicinity of the implant. These double beaded PLGA microsphere constructs containing DEXA and DHEA show promise as coatings for implantable biomedical devices to improve biocompatibility and ensure in vivo performance.