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Deferoxamine in Combination with Adipose-Derived Stromal Cells Rescues Mineralization and Improves Union Rate in the Treatment of Established Radiotherapy Induced Non-Unions
Jordan T. Blough, Bachelor Candidate, Alexis Donneys, MD, MS, Noah S. Nelson, BS, Sagar S. Deshpande, BS, Peter A. Felice, MD, Erin E. Page, Bachelor Candidate, Joseph E. Perosky, MS, Kenneth M. Kozloff, Ph.D, Steven R. Buchman, MD.
University of Michigan, Ann Arbor, MI, USA.
Radiotherapy induced non-unions occurring in the head and neck cancer patient population are a devastating morbidity that can cause significant functional deficits, persistent pain and often have a dreadful impact on quality of life. Twenty-three percent of patients with advanced osteoradionecrosis proceed to develop pathologic fractures and associated non-unions. Unfortunately, clinicians have few efficacious treatment options for this catastrophic problem. Previously, we have demonstrated a reproducible non-union rate of approximately 75-80% in a non-treated, rat model of pathologic fracture healing after radiotherapy. Here, we report the utilization of a therapeutic strategy, combining adipose-derived stromal cells (ADSCs) with deferoxamine (DFO) to treat established non-unions in this validated model. Our hypothesis is that ADSCs will act to replenish cellular volume, while DFO will function to augment angiogenesis at the site of the non-union, thereby improving mineralization metrics and union formation after treatment.
Thirty-six Lewis rats were administered a bioequivalent dose of radiotherapy two weeks prior to mandibular osteotomy and external fixation. Rats were assessed radiographically for bony union formation following a 40-day healing period. Only rats exhibiting non-unions (83%) were further utilized and divided into two groups: radiated fracture with surgical debridement (surgical debridement; n=15) and radiated fracture with both surgical debridement and combination therapy (combination therapy; n=15). The second surgery consisted of non-union confirmation and debridement of necrotic tissue for both groups. The mandibular defects in treatment animals were implanted with scaffolds loaded with ADSCs, and multiple DFO injections were delivered after surgery as previously described in the literature. ADSCs were harvested from the flanks of isogenic Lewis rats and allowed to reach confluence prior to implantation. After a second 40-day healing period, mandibles were dissected, assessed for bony union and imaged with micro-CT for mineralization outcomes. Groups were compared with an independent t-test and p<0.05 was considered statistically significant.
Enhanced mineralization metrics were found for the combination therapy group in comparison to the surgical debridement group. Improvements were found for bone volume fraction (0.78±0.069 versus 0.85±0.073; p=0.034), bone mineral density (665.64±56.23 versus 722.08±65.20; p=0.038) and tissue mineral content (16.18±4.14 versus 20.42±3.29; p=0.013). Perhaps even more clinically significant, the combination therapy group demonstrated a 65% improvement in the remediation of non-unions compared to the surgical debridement group. Specifically, the combination therapy group displayed a 7% incidence of non-union, while the surgical debridement group exhibited a 20% incidence of non-union.
Our results support the contention that combined ADSC and DFO therapy is superior to surgical debridement alone in the treatment of radiotherapy induced non-unions. The combination therapy of cellular replacement and angiogenic stimulation functions to significantly improve mineralization, as well as demonstrate a substantial increase in bony union rate. Our goal is to further explore this novel treatment option in an effort to take this treatment paradigm from the bench to the bedside, providing an attractive alternative to the current inadequate treatment strategies for non-unions caused by adjuvant radiotherapy.
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