A Histomorphometric Analysis of Radiation Damage in an Isogenic Murine Model of Distraction Osteogenesis

Abstract

Purpose The devastation radiation therapy (XRT) causes to endogenous tissue in head and neck cancer (HNC) patients can be a prohibitive obstacle in reconstruction of the mandible, demanding a better understanding of XRT-induced damage and options for reconstruction. Our study investigates the cellular damage caused by radiation in an isogenic murine model of mandibular distraction osteogenesis (DO). We posit that radiation will result in reduced osteocytes, with elevated empty lacunae and immature osteoid. Methods Twenty Lewis rats were randomly assigned to two groups: DO (n=10) and XRT/DO (n=10). Both groups underwent an osteotomy and mandibular DO across a 5.1 mm gap. XRT was administered to the XRT/DO group at a fractionated, human equivalent dose of 35 Gy prior to surgery. Animals were sacrificed on postoperative day 40 and mandibles were harvested and sectioned for histological analysis. Results Bone that underwent radiation revealed a significantly decreased osteocyte count and complementary increase in empty lacunae when compared to non-XRT bone (p=0.019, p=0.000). Additionally, XRT bone demonstrated increased immature osteoid and decreased mature woven bone when compared to non-radiated bone (p=0.001 and p=0.003, respectively). Furthermore, analysis of the ratio of immature osteoid to woven bone volume exhibited a significant increase in the XRT bone, further revealing the devastating damage brought by XRT (p=0.001). Conclusion These results clearly demonstrate the cellular diminution that occurs as a result of radiation. This foundational study provides the groundwork upon which to investigate cellular therapies in an immunoprivileged model of mandibular DO.

Evaluation of Effects of Systemic Zoledronic Acid Application on Bone Maturation in the Consolidation Period in Distraction Osteogenesis

“…Distraction osteogenesis has been researched in many different animal models, including sheep, dogs, pigs, rats, and rabbits 11,14,20–26 . The rat DO method is a well-established experimental model, and has been used widely in DO studies, thanks especially to its ease of use and proper bone size 27–32 . In the light of the studies, we carried out our work on rats.…”

“…11,14,[20][21][22][23][24][25][26] The rat DO method is a well-established experimental model, and has been used widely in DO studies, thanks especially to its ease of use and proper bone size. [27][28][29][30][31][32] In the light of the studies, we carried out our work on rats. In the study conducted by Leblein et al and Li et al, the number of subjects was evaluated as 8.…”

Efeitos da radiação ionizante no osso imaturo: influência na rede de osteócitos, padrão de colágeno e microarquitetura

“…Os efeitos da radiação no reparo incluem diminuição da atividade osteoblástica (Zhang et al, 2017) e morte de osteócitos (Dudziak et al, 2000). A presença de lacunas vazias e diminuição de osteócitos afetam negativamente a mecanotransdução, a mecanosensibilização , retardam o reparo e aumentam a formação de osso imaturo (Inyang et al, 2010;Zheutlin et al, 2015). Os danos aos osteoblastos causam diminuição da produção de matriz óssea e reabsorção sem oposição pelos osteoclastos (Williams & Davies, 2006;Donneys et al, 2014).…”

“…Porém, a longo prazo, há uma depleção dessas células que prejudica o turnover ósseo homeostático e permite a continuação da deposição de matriz de baixa qualidade (Oest et al, 2016). Há um aumento de matriz imatura, não mineralizada que indica retardo do reparo, devido à função prejudicada dos osteoblastos (Inyang et al, 2010;Zheutlin et al, 2015).…”

“…A radiação provoca alterações na microarquitetura óssea (Rabelo et al, 2010) que incluem perda de osso trabecular (Oh & Huh, 2014), espessamento do osso cortical, aumento da densidade mineral (Oest et al, 2016). Na nanoestrutura, a radiação provoca alterações físico-químicas na matriz que contribuem para a fragilidade óssea e prejudicam a formação de osso maduro, pois afetam a maturação do colágeno e os cristais de hidroxiapatita (Zheutlin et al, 2015;Oest et al, 2016). A radiação ionizante rompe a estrutura molecular do colágeno, induz alterações na composição química e no alinhamento molecular das fibrilas e minerais (Oest & Damron, 2014;Oest et al, 2016).…”