Improving Soldier Recovery from Catastrophic Bone Injuries: Developing an Animal Model for Standardizing the Bone Reparative Potential of Emerging Progenitor Cell Therapies

摘要

During the final year of this award, we have completed the analysis of three different models of skeletal repair that can be used to assess different strategies of progenitor cells, scaffolds and host preparation used to heal a critical sized defect. GFP reporters harbored in the mice provide a cellular explanation for the outcome and image analytical techniques afford an objective quantitation of the results. The major finding include: (1) the importance of the right type of progenitor cells for type of skeletal defect to be repaired; (2) the importance of robust progenitor cells which are easily obtained from the mice but will be a challenge for human donor sources; (3) the subtle but highly structured cellular response to fracture repair and its relevance to successful healing of a segmental long bone defect. Multipotential progenitors, marked by a SMAA reporter recreate the bone, cartilage and periosteum and each structure plays a necessary role in a successful repair; discovery that a sublineage distinct from osteoblasts and marked by a DKK3 reporter leads to fibrocartilage and periosteal development; (4) the cryohistology that facilitates the rapid and informative analysis of a repair defect can be applied to non-transgenic models including larger animals; (5) a concept of centralized and uniform processing and imaging of repair defects accessible via database archiving is present that would be useful in identifying the most promising repair strategies and providing the most consistent preclinical data for approval for clinical trials.