Head and neck cancers (HNC) impose a significant biomedical burden by accounting for over 8000 deaths and 50,000 new cases each year. HNC patients often require multimodality treatment with surgery, radiation (XRT), and chemotherapy. Although XRT has increased survival it also results in damage to adjacent normal tissues leading to significant morbidity. The corrosive impact of these XRT-induced side effects can be unrelenting and their complex management is rarely remedial. Severely problematic wound healing issues impact the reconstructive efforts to replace the bone and soft tissue removed by tumor extirpation and the options to treat XRT-induced pathologic fractures and osteoradionecrosis. Standard of care currently dictates complex mandibular reconstruction utilizing free tissue transfer from other parts of the body requiring extended hospitalizations. Attendant complications often lead to delays in initiation of therapy jeopardizing prognosis as well as quality of life. Advances in biotechnology have afforded a unique opportunity to innovate new remedies for XRT-induced side effects by bringing novel and more effective therapeutic strategies into the actual operating theater. Distraction Osteogenesis (DO), the creation of new bone by the gradual separation of two osteogenic fronts, generates an anatomical and functional replacement of deficient tissue from local substrate and could have immense potential for reconstruction after oncologic resection. XRT drastically impairs fracture healing, however, precluding the utilization of DO as a durable reconstructive method for HNC. The central hypothesis to be tested in this proposal is that the deleterious effects of XRT on bone formation can be mitigated to allow successful regeneration of the mandible and restore the capacity for normal bone healing. We further posit that new treatment strategies can be designed to combine tissue engineering techniques and pharmacological optimization in order to develop applications that can be utilized synchronously with operative reconstruction, to fundamentally transform current surgical paradigms. Our laboratory recently demonstrated specific metrics of diminished bone quality at the healing interface of irradiated mandibles. We then employed a series of pharmacologic and tissue engineering strategies to assuage the adverse impact of XRT induced injury. Each of our therapies demonstrated remediation of the XRT-induced degradation of bone healing. The consequential finding of these experiments was the ability to generate new bone formation and a bony union in scenarios where this was not previously possible. Although, the key metrics of bone healing were successfully enhanced, they were not completely restored and candidate cell lines and cell-based remedies that could benefit from therapeutic synergies and potentially be isolated and manipulated directly in the operating room still require innovative solutions in order to be fully optimized for translation to the clinical aena. The current proposal entails developing those synergies and innovative solutions in order to translate our findings from the bench to the operative suite to improve the treatment for this severely compromised patient population.

Public Health Relevance

Every year in the United States approximately 50,000 new cases of head and neck cancer (HNC) are diagnosed having grave consequences for the patients and imposing a significant biomedical burden on society. Radiation therapy is a destructive but necessary treatment regimen for HNC, however it commonly elicits severe side effects such as damage to the surrounding healthy tissues and devastating healing complications. The purpose of this research is to combine state-of-the-art medical therapies with tissue engineering strategies and surgical techniques that will ultimately lead to enhancements in reconstructive solutions that will improve the structure, function, and quality of care to this special population of patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA125187-07
Application #
8591378
Study Section
Musculoskeletal Tissue Engineering Study Section (MTE)
Program Officer
Prasanna, Pat G
Project Start
2007-09-28
Project End
2017-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
7
Fiscal Year
2014
Total Cost
$220,267
Indirect Cost
$78,616
Name
University of Michigan Ann Arbor
Department
Surgery
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Tchanque-Fossuo, Catherine N; Donneys, Alexis; Deshpande, Sagar S et al. (2018) Radioprotection With Amifostine Enhances Bone Strength and Regeneration and Bony Union in a Rat Model of Mandibular Distraction Osteogenesis. Ann Plast Surg 80:176-180
Urlaub, Kevin M; Ettinger, Russell E; Nelson, Noah S et al. (2018) Nonvascularized Bone Graft Reconstruction of the Irradiated Murine Mandible: An Analogue of Clinical Head and Neck Cancer Treatment. J Craniofac Surg :
Snider, Alicia E; Lynn, Jeremy V; Urlaub, Kevin M et al. (2018) Topical Deferoxamine Alleviates Skin Injury and Normalizes Atomic Force Microscopy Patterns Following Radiation in a Murine Breast Reconstruction Model. Ann Plast Surg 81:604-608
Carey, Edward G; Deshpande, Sagar S; Urlaub, Kevin M et al. (2017) Significant Differences in the Bone of an Isogenic Inbred Versus Nonisogenic Outbred Murine Mandible: A Study in Rigor and Reproducibility. J Craniofac Surg 28:915-919
Kang, Stephen Y; Deshpande, Sagar S; Zheutlin, Alexander R et al. (2017) Role of parathyroid hormone in regeneration of irradiated bone in a murine model of mandibular distraction osteogenesis. Head Neck 39:464-470
Donneys, Alexis; Nelson, Noah S; Perosky, Joseph E et al. (2016) Prevention of radiation-induced bone pathology through combined pharmacologic cytoprotection and angiogenic stimulation. Bone 84:245-252
Rodriguez, Jose J; Kung, Theodore; Wang, Yao et al. (2016) Changes in Skin Vascularity in a Murine Model for Postmastectomy Radiation. Ann Plast Surg 76:494-8
Donneys, Alexis; Blough, Jordan T; Nelson, Noah S et al. (2016) Translational treatment paradigm for managing non-unions secondary to radiation injury utilizing adipose derived stem cells and angiogenic therapy. Head Neck 38 Suppl 1:E837-43
Momeni, Arash; Rapp, Scott; Donneys, Alexis et al. (2016) Clinical Use of Deferoxamine in Distraction Osteogenesis of Irradiated Bone. J Craniofac Surg 27:880-2
Deshpande, Sagar S; Gallagher, Kathleen K; Donneys, Alexis et al. (2015) Stem cells rejuvenate radiation-impaired vasculogenesis in murine distraction osteogenesis. Plast Reconstr Surg 135:799-806

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