A. Zheutlin1, S. Deshpande1, N. Nelson1, J. Rodriguez1, A. Donneys1, E. Carey1, S. R. Buchman1 1University Of Michigan,Craniofacial Research Laboratory, Plastic Surgery Section, Department Of Surgery,Ann Arbor, MI, USA
Introduction: Radiation-induced injury to endogenous tissue in head and neck cancer patients can impede the use of Distraction Osteogenesis (DO) as a viable option for reconstruction of the mandible. Therapeutic options which restore the viability of irradiated bone for reconstruction hold the promise to allow DO to become an effective alternative for reconstruction in patients who have undergone radiation therapy (XRT). Bone marrow stem cells possess the capability to differentiate into osteoblasts and stimulate endogenous growth factors. Additionally, intermittent parathyroid hormone is known to stimulate bone deposition. We posit that the effects of these therapeutic agents will act synergistically to improve cellularity and function, and curtail the destructive effects of XRT in a murine model of mandibular DO.
Methods: Lewis rats were divided into 5 groups: non-radiated distraction (DO), radiated distraction (xDO), radiated distraction with intermittent parathyroid hormone (PTH), radiated distraction with intraoperatively placed bone marrow stem cells (BMSC), and radiated distraction with both therapies (Combined). Groups receiving radiation were exposed to a human-equivalent dose of 35 Gy over a 5-day period. All groups underwent distraction to a distance of 5.1 mm. Coronal sections from the distraction site were stained using Hematoxylin & Eosin, Safranin O, and Gomori’s Trichrome. Statistical analysis was performed with ANOVA and subsequent Tukey or Games-Howell post-hoc tests.
Results: Rats in the combined therapy group demonstrated improved metrics of histology and histomorphometry when compared to the xDO group. Osteocyte count was significantly improved by combination therapy over xDO (p=0.00). Additionally, empty lacunae were decreased in the combined therapy group as compared to the xDO group (p=0.00) and both singular therapies. Combination therapy also improved the histomorphometric quality of the regenerate bone demonstrating less immature osteoid volume (p=0.01) and much more mature woven bone (p=0.00). Furthermore, the composition of relative mature bone volume in the combined group (0.56±0.09) approached that of the bone regenerated by non-irradiated DO (0.52±0.11), indicating that the combination therapy was able to overcome the XRT-induced devastation to the endogenous tissue.
Conclusion: In a murine model of DO, BMSCs in combination with intermittent PTH reverses XRT-induced cellular depletion, resulting in significant improvement in osteocyte presence with decreased empty lacunae. Regenerated bone treated with the combined therapy resembled bone that underwent DO without XRT, and resulted in better complete histomorphometric outcomes than bone treated with either therapy alone. Our combined therapy demonstrates the capability to assuage the damage incurred ensuing XRT and offers promise in the treatment of patients requiring mandibular reconstruction following XRT.