School of Mechanical Engineering, Purdue University, West Lafayette, Indiana, United States of America.
Institute for Mechanical Systems (IMES), Department of Mechanical and Process Engineering, ETH Zurich, Zurich, Switzerland.
PLoS Comput Biol. 2023 Mar 9;19(3):e1010902. doi: 10.1371/journal.pcbi.1010902. eCollection 2023 Mar.
Injuries to the skin heal through coordinated action of fibroblast-mediated extracellular matrix (ECM) deposition, ECM remodeling, and wound contraction. Defects involving the dermis result in fibrotic scars featuring increased stiffness and altered collagen content and organization. Although computational models are crucial to unravel the underlying biochemical and biophysical mechanisms, simulations of the evolving wound biomechanics are seldom benchmarked against measurements. Here, we leverage recent quantifications of local tissue stiffness in murine wounds to refine a previously-proposed systems-mechanobiological finite-element model. Fibroblasts are considered as the main cell type involved in ECM remodeling and wound contraction. Tissue rebuilding is coordinated by the release and diffusion of a cytokine wave, e.g. TGF-β, itself developed in response to an earlier inflammatory signal triggered by platelet aggregation. We calibrate a model of the evolving wound biomechanics through a custom-developed hierarchical Bayesian inverse analysis procedure. Further calibration is based on published biochemical and morphological murine wound healing data over a 21-day healing period. The calibrated model recapitulates the temporal evolution of: inflammatory signal, fibroblast infiltration, collagen buildup, and wound contraction. Moreover, it enables in silico hypothesis testing, which we explore by: (i) quantifying the alteration of wound contraction profiles corresponding to the measured variability in local wound stiffness; (ii) proposing alternative constitutive links connecting the dynamics of the biochemical fields to the evolving mechanical properties; (iii) discussing the plausibility of a stretch- vs. stiffness-mediated mechanobiological coupling. Ultimately, our model challenges the current understanding of wound biomechanics and mechanobiology, beside offering a versatile tool to explore and eventually control scar fibrosis after injury.
皮肤损伤通过成纤维细胞介导的细胞外基质（ECM）沉积、ECM 重塑和伤口收缩的协同作用来愈合。涉及真皮的缺陷会导致纤维化瘢痕，其特征是硬度增加以及胶原含量和组织改变。尽管计算模型对于揭示潜在的生化和生物物理机制至关重要，但对不断发展的伤口生物力学的模拟很少与测量值进行基准测试。在这里，我们利用最近对小鼠伤口局部组织硬度的定量分析来改进先前提出的系统-机械生物有限元模型。成纤维细胞被认为是参与 ECM 重塑和伤口收缩的主要细胞类型。组织重建是通过细胞因子波（例如 TGF-β）的释放和扩散来协调的，细胞因子波本身是对由血小板聚集引发的早期炎症信号的反应而产生的。我们通过自定义开发的分层贝叶斯逆分析过程来校准不断发展的伤口生物力学模型。进一步的校准是基于在 21 天的愈合期间发表的生化和形态学小鼠伤口愈合数据。校准后的模型再现了以下方面的时间演变：炎症信号、成纤维细胞浸润、胶原蛋白积累和伤口收缩。此外，它还支持在计算机上进行假设检验，我们通过以下方法进行了探索：（i）量化与局部伤口硬度测量值的变化相对应的伤口收缩曲线的变化；（ii）提出替代的本构关系，将生化场的动力学与不断变化的机械性能联系起来；（iii）讨论基于拉伸或基于硬度的机械生物耦合的合理性。最终，我们的模型挑战了当前对伤口生物力学和机械生物学的理解，同时提供了一种探索和最终控制受伤后疤痕纤维化的多功能工具。
