Distraction Osteogenesis – Nature’s Own Endogenous Tissue Engineering
By understanding how the body naturally engineers new tissues, investigators can determine “blueprints” from which they can begin to develop strategies to augment wound healing or engineering complex replacement structures. We investigate the biology of murine mandibular distraction osteogenesis (DO), a well-established form of endogenous bone engineering commonly used by craniofacial surgeons. Although DO has been clinically successful, the exact mechanisms governing DO remain unclear.
Our laboratory began 5 years ago to systematically investigate the mechanisms of successful DO. We began by establishing a rat mandibular DO model, which consisted of a unique gradual distraction protocol (GD, successful DO) and an acute lengthening protocol (AL, unsuccessful DO).
Working closely with the Stanford Bioengineering Department, we have examined the mechanical environments during GD and AL utilizing a customized mechanical testing device. The data demonstrated distinct different mechanical environments between GD and AL. To further characterize the mechanical environment of successful DO, we performed finite element analysis (FEA) based on our mechanical testing data. By continually refining our FEA model, we will be able to reach an optimal DO protocol and achieve maximal bone induction.
Recently, we have applied microarray technology to analyze large-scale gene expression during the processes of GD and AL. The result, again, demonstrated dramatic differences between GD and AL at transcriptional level. For instance, there were many angiogenesis-related genes with higher and more sustained expression in the GD group compared to the AL group. These genes include VEGF, FGF-2, PDGF, and MMP-9. These data suggested that angiogenesis might be critical to bone formation during successful DO. To further explore the role of angiogenesis during DO, we utilized a novel nano-imaging system to visualize integrin avß3 expressions during GD and AL. The preliminary results demonstrated higher avß3 expressions in GD than AL. We also blocked angiogenesis during GD using TNP-470, a selective inhibitor of endothelial cell proliferation. Blocking angiogenesis resulted in complete inhibition of new bone formation and led to atrophic fibrous non-union.
Aiming to further dissect the mechanisms governing DO, we recently developed a mouse model of mandibular DO. The mouse model will allow us to access widely available molecular reagents; as well as transgenic and knockout animals. It will give us unique opportunity to define the relationships of mechanical environment, molecular biology, and angiogenesis during DO. The overall goals of our research efforts are to fully decipher the mechanical microenvironment and molecular processes leading to successful bone generation during distraction and apply these principles in the development of translational strategies that may expedite the distraction process, augment fracture healing, and allow for engineering of replacement mandibular bone for reconstruction.
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