There are 4 specific aims for this study.
Specific Aim #1 is to determine the effects of extracorporeal shock waves (ESWs) on the proliferation of osteogenic cells in the periosteum of the tibia and edentulous mandible of the same animals, by conducting a dose-response experiment. Three energy densities will be employed (0, 0.15, and 0.45 mJ/mm2;a one-time application of 3,000 shocks for each energy density), and the results compared after 2, 4, and 8 days. The outcome variables will be selected cell counts and periosteum thickness measurement from histomorphometry employing immunohistochemistry, and osteogenic cell culture assay. Our objective is to find the dose (0.15 vs 0.45 mJ/mm2) and time post-treatment that yields the greatest number of osteogenic cells prior to the formation of bone. The goal is to be able to elevate or harvest the proliferating cambium layer of cells;the presence of bony trabeculae would interfere with the harvest of the cells. Our initial goal, in this proposal, is to harvest the osteogenic cells;future studies may be directed toward harvesting the cancellous bone that forms in the ESW-stimulated periosteum.
Specific Aim #2 is to determine the effects of ESWs on the osteogenic cells in the marrow of the same tibial and mandibular samples employed in Specific Aim #1. We have already found in prior work that ESWs induce changes in the marrow. We have been informed by a pathologist that the changes are consistent with those that would be expected to be reversible, and of no adverse clinical consequence. We would like to determine if the ESW-stimulated marrow contains a greater percentage of mesenchymal stem cells (MSCs;i.e., marrow stromal cells, or osteoprogenitor cells). We will make this determination by assaying the osteogenic potential of the marrow in the cell culture assay. If we find that ESWs do, in fact, stimulate osteogenic cellular activity in the marrow, this will be investigated in future studies. The findings could be of value in developing a simple, non-invasive procedure for enhancing an alternative autologous cell source (i.e., marrow) for bone reconstruction procedures.
Specific Aim #3 is to determine the effects of ESW-stimulated periosteum on bone regeneration in porous calcium phosphate (CaP) blocks in defects in the mandible. The ESW dose that yields the greatest number of osteogenic cells in Specific Aim #1 will be applied to the periosteum of the edentulous premolar region of goats. After the prescribed period post-ESW, the periosteum will be elevated and a porous CaP block containing 2 threaded titanium implants placed into the surgically prepared site. The elevated periosteum will then be applied to the surface of the block. In another group of animals the ESW-stimulated periosteum of the tibia will be harvested as a free autologous graft to be applied to the CaP block.
In Specific Aim #4, recombinant human (rh) PDGF-BB will be incorporated into the CaP block before it is implanted into the defect and covered with the ESW-stimulated periosteum as in Specific Aim #3.

Public Health Relevance

Mandibular, maxillofacial, and craniofacial injuries to bone are devastating and have two features which make them especially challenging to treat: the absence of sufficient pools of osteoprogenitor cells in the vicinity of the defect;the necessity to provide contour to the bone and have that contour maintained for the long term. The system which we propose includes 3 devices: a shock wave apparatus;a porous bone mineral scaffold;and a bone growth factor. The devices are currently approved by the Food and Drug Administration (FDA) individually for other applications. The key feature of the bone reconstruction system is the use of extracorporeal (non-invasive) shock waves to stimulate the proliferation of osteoprogenitor cells a few days prior to the bone reconstruction procedure.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Translational Rehab (Basic) (RRD0)
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VA Boston Health Care System
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