The regeneration of bone with a biodegradable, biocompatible carrier and osteo-regenerative proteins may be possible if the carrier has the appropriate architecture to support osteoconduction and prevent soft-tissue prolapse into ablated bone segments. Using radiomorphometry and histomorphometry, our group assessed individually and combined the components of a multiphase system bone implant (MSI) in rabbit cranial defects (critical-size defects: CSDs): two disks of biodegradable polymer (PLG) and demineralized bone matrix (DBM), a recognized osteo-regenerative material. We used 48 rabbits evenly divided between four treatment groups and two time periods. Six weeks after treatment, both DBM and PLG had significant positive effects on bone regeneration (based on a three-factor analysis of variance, p < 0.05). These effects were synergistic when the components were combined (MSI). Defects treated with DBM or PLG alone continued to regenerate bone through 12 weeks. By this time, bone within the defects treated with MSI appeared to be maturing and consolidating. We conclude that the concept of placing osteo-regenerative factors between two biodegradable disks for regenerating segments of calvaria is viable.