Post-orthodontic relapse remains a challenging and undesirable consequence of orthodontic treatment. Relapse occurs in part due to the presence of relatively immature bone in the direction of tooth relapse that can be readily resorbed by osteoclasts. Because current approaches to retain tooth alignment have well-known caveats, recent studies, including several from our group, have explored the utility of biologic agents such as osteoprotegerin (OPG) in mitigating post-orthodontic relapse. In proof-of-concept studies the repeated submucosal injection of naked OPG resulted in a 3.5-fold increase in post-orthodontic tooth stability. In contrast, the administration of a single dose of OPG-loaded PLGA microbeads contributed only to modest increases in tooth stability. This was attributed to an initial bolus release of OPG from the delivery system. Therefore, the goal of the current study was to design and test in vitro other methods of drug delivery for slow sustained release of OPG at optimal concentrations to have clinical efficacy. We tested the hypothesis that optimally constituted OPG-loaded polythelyne glycol (PEG) nanoparticles would result in a slow, sustained, and optimal release of OPG in vitro. We also designed and tested a novel method of intraoral drug delivery using thin film devices. The microspheres were loaded with 330μg of OPG into PEG microspheres and were placed in PBS and the eluated assayed every day for 28 days. The findings showed gradually decreasing but sustained release of OPG over a 28 day period. Further enhancements in PEG microsphere fabrication and OPG concentrations will be instituted for ongoing studies to optimize the release kinetics. The thin films were constructed from polyethylene glycol, customized to fit onto the rat palate and loaded with 90μg of OPG. Following further enhancements to the PEG microspheres, thin film fabrication, and optimization of OPG release kinetics, these delivery systems will be tested for their efficacy in enhancing tooth stability in a rat model for orthodontic relapse.