DataSheet1_An in silico micro-multiphysics agent-based approach for simulating bone regeneration in a mouse femur defect model.docx

Bone defects represent a challenging clinical problem as they can lead to non-union. In silico models are well suited to study bone regeneration under varying conditions by linking both cellular and systems scales. This paper presents an in silico micro-multiphysics agent-based (micro-MPA) model for bone regeneration following an osteotomy. The model includes vasculature, bone, and immune cells, as well as their interaction with the local environment. The model was calibrated by time-lapsed micro-computed tomography data of femoral osteotomies in C57Bl/6J mice, and the differences between predicted bone volume fractions and the longitudinal in vivo measurements were quantitatively evaluated using root mean square error (RMSE). The model performed well in simulating bone regeneration across the osteotomy gap, with no difference (5.5% RMSE, p = 0.68) between the in silico and in vivo groups for the 5-week healing period – from the inflammatory phase to the remodelling phase – in the volume spanning the osteotomy gap. Overall, the proposed micro-MPA model was able to simulate the influence of the local mechanical environment on bone regeneration, and both this environment and cytokine concentrations were found to be key factors in promoting bone regeneration. Further, the validated model matched clinical observations that larger gap sizes correlate with worse healing outcomes and ultimately simulated non-union. This model could help design and guide future experimental studies in bone repair, by identifying which are the most critical in vivo experiments to perform.

骨缺损是一类极具挑战性的临床难题，可引发骨不连（non-union）。计算机模拟（in silico）模型可通过衔接细胞尺度与系统尺度，在多样条件下开展骨再生相关研究。本研究提出一种用于截骨术（osteotomy）后骨再生研究的计算机模拟微观多物理场智能体（micro-MPA）模型。该模型涵盖脉管系统、骨组织与免疫细胞，及其与局部微环境的相互作用。研究通过C57Bl/6J小鼠股骨截骨模型的延时微型计算机断层扫描（micro-computed tomography）数据对该模型进行校准，并采用均方根误差（root mean square error, RMSE）定量评估预测骨体积分数与纵向体内（in vivo）测量值之间的差异。在截骨间隙范围内的5周愈合周期（从炎症阶段到重塑阶段）内，该模型在模拟截骨间隙骨再生方面表现优异，计算机模拟组与体内组的骨体积分数无显著差异（RMSE为5.5%，p=0.68）。综上，本研究提出的micro-MPA模型能够模拟局部机械微环境对骨再生的影响，且该微环境与细胞因子（cytokine）浓度均为促进骨再生的关键调控因素。此外，经过验证的模型与临床观测结果一致：更大的截骨间隙尺寸与更差的愈合效果相关，并最终可模拟骨不连的发生。该模型可通过明确最具研究价值的体内实验方案，为骨修复领域未来的实验研究提供设计指导与参考依据。