Controlling the Mechanobiology of Cutaneous Wounds to Reduce Hypertrophic Scar

描述（由申请人提供）：肥厚性瘢痕是一种主要的临床问题，其特征是过度纤维化。在几种治疗策略中，纤维化和瘢痕形成的减少似乎与伤口部位的力的减少有关。然而，相关机制仍不清楚。多尺度机械相互作用（MMI）可能是重要的，并最终确定的纤维化，控制瘢痕表型在愈合的手术伤口。MMI是由凝块的几何形状、结构和组织、内部细胞牵引和伤口的外部约束之间的相互作用发展而来的。PI最近的研究表明，体外环境中的重塑受到MMI的强烈影响，MMI联合收割机产生纤维蛋白和ECM对齐的模式。形成的初始模式控制宏观力如何通过微观结构分布到细胞以及替代ECM将如何组织。MMI在创面愈合中也起重要作用。在涉及改变伤口部位的机械环境的策略中（例如应力屏蔽片、形状记忆缝线、具有弹性梯度的缝线和粘合剂），许多重要变量未得到最佳定义。例如，尚不清楚是否存在用于应力屏蔽伤口部位的最佳时间窗口，应施加多大或何种力，力的量是否应随时间变化，或者这些参数应如何随解剖部位、伤口大小和形状变化。要回答这些问题，涉及MMI的多尺度的角度来看是必要的。这里详细介绍的实验和建模将有助于提供这一新的重要视角。目的1测试的假设，MMI控制纤维化过程中的重塑过程中，在体外设置。在这里，我们将观察和定量成纤维细胞- ECM相互作用和重塑纤维蛋白凝胶作为功能的初始纤维蛋白 本发明提供了一种基于细胞排列、细胞空间分布、机械负荷和几何形状的细胞模型，然后评估在稍后的时间点改变负荷环境如何能够积极地改变ECM重塑以减少瘢痕。这一目标的完成将为指导MMI减少瘢痕形成和开发可用于优化愈合的新干预措施提供新的知识。目的2开发了一种伤口部位的计算多尺度力学模型，该模型与从纤维蛋白凝胶收集的体外微观结构和力学数据密切相关。这一目标的完成将提供一个详细的视图的负载传输，纤维重组，和纤维蛋白凝胶中的机械微环境。长期目标是将这项工作作为开发伤口愈合预测模型的基础，使临床医生能够制定针对患者的策略 以减少疤痕的形成。然后，这些模型可用于推荐位置和时间依赖性压缩和张力的优化方案，该方案由患者特定器械/敷料基于伤口参数（如位置、几何形状和年龄）递送。因此，拟议的项目可以显著影响瘢痕形成的临床管理。

DESCRIPTION (provided by applicant): Hypertrophic scarring is a major clinical problem characterized by excessive fibrosis. In several treatment strategies reduced fibrosis and scarring appears connected to a reduction in force at the wound site. However, the underlying mechanisms responsible remain unclear. Multiscale mechanical interactions (MMI) could be important and ultimately deterministic of the fibrogenesis that controls scar phenotype in a healed surgical wound. MMI develop from the interplay between the geometry, structure, and organization of the clot, internal cell tractions, and external constraints of the wound. Recent work by the PI suggests that remodeling in an in vitro setting is strongly influenced by MMI that combine to produce a pattern of fibrin and ECM alignment. The initial pattern that forms controls both how macroscopic forces are distributed through the microstructure to the cells and how replacement ECM will be organized. MMI could also play an important role in wound healing. In strategies that involve changing the mechanical environment of the wound site (e.g. stress shielding sheets, shape memory sutures, sutures with elastic gradients, and adhesives), many important variables are not optimally defined. For example, it is not clear if there is an optimal window in time for stress shielding the wound site, how much or what kind of force should be applied, whether the amount of force should change over time, or how these parameters should change with anatomical site, wound size, and shape. To answer these questions, a multiscale perspective involving MMI is required. The experiments and modeling detailed here will help provide this new and important perspective. Aim 1 tests the hypothesis that MMI control fibrogenesis during the remodeling process in an in vitro setting. Here we will observe and quantify fibroblast- ECM interactions and remodeling in fibrin gels as a function of initial fibrin alignment, cell spatial distribution, mechanical load, and geometry, and then assesses how changing the loading environment at later time points can positively alter ECM remodeling to reduce scar. Completion of this aim will provide new knowledge on directing MMI to reduce scar formation and on developing new interventions that could be used to optimize healing. Aim 2 develops a computational multiscale mechanical model of the wound site that is strongly linked to in vitro microstructural and mechanical data collected from fibrin gels. Completion of this aim will provide a detailed view of load transmission, fiber reorganization, and the mechanical microenvironment in fibrin gels. The long-term goal is to use this work as a basis for developing predictive models of wound healing that will allow clinicians to devise patient-specific strategies to minimize scar formation. These models could then be used to recommend an optimized regimen of location and time dependent compression and tension that is delivered by patient-specific devices/dressings based on wound parameters such as location, geometry, and age. The proposed project therefore can significantly impact clinical management of scar formation.