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Improved Biomechanical Metrics in the Treatment of Radiotherapy-Induced Non-Unions with a Novel Combination Therapy
Noah S. Nelson, BS, Alexis Donneys, MD, MS, Jordan T. Blough, BS candidate, Sagar S. Deshpande, BS, Peter A. Felice, MD, Erin E. Page, BS candidate, Joseph E. Perosky, MS, Kenneth M. Kozloff, PhD, Steven R. Buchman, MD.
University of Michigan, Ann Arbor, MI, USA.
Radiation-induced non-unions are complex morbidities with limited management solutions. In prior studies we have utilized a rat model of mandibular fracture healing after a Human Equivalent Dose of Radiotherapy (HEDR), and have established a reproducible non-union rate of approximately 75-80%. In this study, we sought to combine adipose-derived stem cells (ADSCs) with deferoxamine in order to treat established non-unions in our model. We posit that ADSCs will act as a cellular replacement, while DFO will function to enhance angiogenesis at the non-union site, resulting in improvements in biomechanical metrics after treatment.
Thirty-six Lewis rats were administered a HEDR two weeks prior to osteotomy of the mandible and external fixation. Following a 40-day healing period, the rats were assessed radiographically for bony union. Those exhibiting non-unions (30/36) were further utilized and divided into two groups: surgical debridement (non-treatment; n=15) and surgical debridement with combination therapy (treatment; n=15). The second surgery consisted of debridement of necrotic tissue for both groups. The mandibular defects in treatment animals were implanted with scaffolds loaded with previously harvested ADSCs and were administered multiple DFO injections after surgery, as described in the literature. After a second 40-day healing period, mandibles were harvested for biomechanical testing (BMT). In the non-treatment group, two animals died, and two mandibles exhibited complete non-unions (no fibrous bridging) making BMT impossible. Groups were compared with an independent t-test and p<0.05 was considered statistically significant.
Upon harvesting our specimens, BMT analysis demonstrated a statistically significant increase in the combination therapy group in comparison to the surgical debridement group. Specifically, significant differences were found in the biomechanical metrics of Yield (65.39±28.55 vs 35.06±14.91; p=.015) and Energy (16.96±11.78 vs 6.67±4.45; p=.026). Additionally, results trending toward significance were observed for Ultimate Load (75.82±32.03 vs 50.17±22.93; p=.066), Failure Load (73.99±33.82 vs 50.17±22.93; p=.095), and Elastic Energy (10.70±10.92 vs 2.96±3.38; p=.057).
Consistent with our hypothesis, our results demonstrate that combined ADSC and DFO therapy is superior to surgical debridement alone in the treatment of radiation induced non-unions. The combination therapy of cellular replacement and angiogenic stimulation functions to significantly improve the biomechanical properties of the mandibles. Further experimentation with this novel treatment option will hopefully enable us to take this or a similar therapy to the clinic in order to mitigate the deleterious effects of radiation-induced non-unions and their related pathologies.
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