UNCORRECTED PROOF 1 Vascular analysis as a proxy for mechanostransduction response in an 2 isogenic, irradiated murine model of mandibular 3 distraction osteogenesis ☆ 4 Q1 Sagar S. Deshpande a , Alexis Donneys a , Steven Y. Kang a,b , Erin E. Page c , Peter A. Felice d , Lauren Kiryakoza c , 5 Noah S. Nelson a , Jose L. Rodriguez a , Samir S. Deshpande a,e , Steven R. Buchman a,f, ⁎ 6 a Craniofacial Research Laboratory, University of Michigan Health System, Ann Arbor, MI, United States 7 b Department of Otalaryngolagy, University of Michigan Health System, Ann Arbor, MI, United States 8 c College of Literature, Science, and Arts, University of Michigan, Ann Arbor, MI, United States 9 d Department of General Surgery, Medical University of South Carolina, Charleston, SC, United States 10 e Kalamazoo College, Kalamazoo, MI, United States 11 f Section of Plastic Surgery, Department of Surgery, University of Michigan Health System, Ann Arbor, MI, United States abstract 12 article info 13 Article history: 14 Accepted 20 August 2014 15 Available online xxxx 16 Keywords: 17 Head and neck cancer 18 Distraction osteogenesis 19 Tissue engineering 20 Vasculogenesis 21 Angiogenesis 22 Radiation therapy 23 Mechanotransduction 24 Isogenic 25 Introduction: Head and neck cancer is a debilitating and disfiguring disease. Although numerous treatment 26 options exist, an array of debilitating side effects accompany them, causing physiological and social problems. 27 Distraction osteogenesis (DO) can avoid many of the pathologies of current reconstructive strategies; however, 28 due to the deleterious effects of radiation on bone vascularity, DO is generally ineffective. This makes investigat- 29 ing the effects of radiation on neovasculature during DO and creating quantifiable metrics to gauge the success of 30 future therapies vital. The purpose of this study was to develop a novel isogenic rat model of impaired 31 vasculogenesis of the regenerate mandible in order to determine quantifiable metrics of vascular injury and 32 associated damage. 33 Methods: Male Lewis rats were divided into two groups: DO only (n = 5) AND Radiation Therapy (XRT) + DO 34 (n = 7). Afterwards, a distraction device was surgically implanted into the mandible. Finally, they were distracted 35 a total of 5.1 mm. Animals were perfused with a radiopaque casting agent concomitant with euthanasia, and sub- 36 sequently demineralization, microcomputed tomography, and vascular analysis were performed. 37 Results: Vessel volume fraction, vessel thickness, vessel number, and degree of anisotropy were diminished by 38 radiation. Vessel separation was increased by radiation. 39 Conclusion: The DO group experienced vigorous vessel formation during distraction and neovasculariza- 40 tion with a clear, directional progression, while the XRT/DO group saw weak vessel formation during 41 distraction and neovascularization. Further studies are warranted to more deeply examine the impair- 42 ments in osteogenic mechanotransductive pathways following radiation in the murine mandible. This 43 isogenic model provides quanti fiable metrics for future studies requiring a controlled approach to 44 immunogenicity. 45 © 2014 Published by Elsevier Inc. 46 47 48 49 50 Introduction 51 In 2013, an estimated 53,640 Americans will be affected by head and 52 neck cancer. Comprising 3%–5% of all cancers in the United States, an es- 53 timated 11,520 will be fatal (American Cancer Society, 2013). Treatment 54 options for most head and neck cancers vary depending on the stage of 55 the cancer and location of the primary tumor, but can include a combi- 56 nation of chemotherapy, surgery and adjuvant radiation therapy. Radi- 57 ation is used to treat more than half of all cancer patients (American 58 Cancer Society, 2013). While clearly in wide use, the side effects of 59 this treatment can cause an extensive array of debilitating sequelae for 60 patients, particularly those later in need of reconstructive surgery. 61 In head and neck cancer treatment specifically, patients who re- 62 ceive radiotherapy may experience decreased mobility of the jaw, 63 swelling, pain, or bony exposure of the mandible or maxilla 64 (www.oralcancerfoundation.org. (n.d.)). Moreover, many patients 65 have bone defects as a result of oncological resection and segmen- 66 tal mandibulectomy (Meazzini et al., 2012; Zhang et al., 2009). 67 Perhaps the most devastating of all possible side effects of Microvascular Research xxx (2014) xxx–xxx ☆ Funding: Funding was provided by National Institutes of Health grant RO1 CA 12587-01 to Steven R Buchman, M.D. and NIH-T32 GM 008616 to C. L Marcelo. ⁎ Corresponding author at: 1540 E. Hospital Drive, 4-730 Mott Children's Hospital, Ann Arbor, MI 48104. E-mail address: sbuchman@umich.edu (S.R. Buchman). YMVRE-03468; No. of pages: 6; 4C: http://dx.doi.org/10.1016/j.mvr.2014.08.005 0026-2862/© 2014 Published by Elsevier Inc. Contents lists available at ScienceDirect Microvascular Research journal homepage: www.elsevier.com/locate/ymvre Please cite this article as: Deshpande, S.S., et al., Vascular analysis as a proxy for mechanostransduction response in an isogenic, irradiated murine model of mandibular distraction osteogenesis, Microvasc. Res. (2014), http://dx.doi.org/10.1016/j.mvr.2014.08.005