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Parathyroid Hormone Improves Stem Cell Therapy Mitigation of Radiation Induced Non Union in the Murine Mandible
Sagar S. Deshpande, BS, Alexis Donneys, MD; MS, Kelly Gallagher, MD, Catherine Tchanque-Fossuo, MD, Deniz Sarhaddi, BA, Hong-Li Sun, PhD, Paul Krebsbach, DDS, Steven Buchman, MD.
University of Michigan, Ann Arbor, MI, USA.
Purpose: Radiation therapy is known to be detrimental to bone and soft tissue repair, resulting in an unacceptably high incidence of devastating wound healing complications as well as the associated morbidity of late pathologic fractures and non-unions. Our global hypothesis is that the pathologic effects of radiation on bone formation and healing are mediated through a mechanism of direct cellular depletion as well as diminished function of the cells responsible for the generation and maintenance of osteogenesis. Furthermore, resident vascularity is diminished following radiation. We posit that transplanted bone marrow stromal cells (BMSCs), a type of mesenchymal stem cell, will provide sufficient cellular replacement and increased cell signaling (of osteogenic and angiogenic factors) to enhance the generation and quality of new bone during distraction osteogenesis (DO) and that intermittent doses of parathyroid hormone (PTH) will assist in differentiation and recruitment of these cells.
Methods: 26 male isogenic Lewis rats were randomly split into four groups. XRT/DO (n=6), BMSC (n=7), and BMSC+PTH (n=6) underwent 5 day fractionated XRT of the left mandible at 7 Gy per day. DO (n=7), received no radiation. All animals were allowed to recover for two weeks, then underwent mandibular distractor placement. The BMSC and BMSC+PTH groups received a Surgifoam scaffold loaded with 2 million BMSCs intra-operatively placed within the distraction gap. All groups were then distracted at 0.3mm every 12 hrs to a total distance of 5.1mm (a critical-sized defect for an irradiated, distracted mandible). The BMSC+PTH group received 60 mg/kg of PTH starting concomitant with distraction and for the subsequent 3 weeks. The regenerate was allowed to consolidate for 40 days after surgery was completed, after which tissue was harvested and underwent radiomorphometric and biomechanical response analysis.
Results: We have previously reported that BMSC treatment restores union quality and radiomorphometric parameters (bone mineral density, BMD, and bone volume fraction, BVF) and partially mediates as biomechanical response. Both BMSC and BMSC+PTH radiomorphometric parameters had no difference from DO and were significantly improved over XRT/DO. Ultimate load (XRT/DO=1.81N, BMSC=32.21N*, BMSC+PTH=68.65N**,\0, failure load (XRT/DO=0.56N, BMSC=30.78N*, BMSC+PTH=51.98N**) and yield (XRT/DO=1.49 N, BMSC=30.02N*, BMSC+PTH=52.11N**) were also significantly improved by addition of parathyroid hormone. The BMSC+PTH values are much improved over BMSC in comparison to DO (Ultimate load=93.14N**, failure load=92.89N**, yield=70.99N**). *=p<0.05; **=p<0.001 in comparison to XRT/DO. \60p<0.05 in comparison to BMSC.
Conclusion: Our previous results indicate that the union quality and radiomorphometric parameters are completely rescued by BMSC therapy, and that biomechanical parameters were partially remediated where union was otherwise not routinely seen. These results indicate that addition of PTH to this protocol creates a regenerate of superior biomechanical strength (73.1% of control) when compared to BMSC treatment alone (34.4% of control). Our results show that joint treatment with BMSCs and PTH rescue the ability for irradiated bone to undergo distraction osteogenesis, thereby producing a solid, bony union with improved parameters of bone quality in an otherwise nonfunctional mandible. As such, this therapy has great promise for the reconstruction of head and neck cancers.
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