Controlling the Mechanobiology of Cutaneous Wounds to Reduce Hypertrophic Scar

描述(申请人提供)：增生性瘢痕是一种以过度纤维化为特征的主要临床问题。在几种治疗策略中，纤维化和疤痕的减少似乎与伤口处力量的减少有关。然而，对此负责的潜在机制仍不清楚。多尺度机械相互作用(MMI)可能是控制愈合的手术伤口的瘢痕表型的纤维形成的重要和最终决定性因素。MMI的形成源于血栓的几何、结构和组织、内部细胞牵引力和伤口的外部约束之间的相互作用。PI最近的工作表明，体外环境下的重塑受到MMI的强烈影响，MMI结合起来产生纤维蛋白和ECM排列的模式。形成的初始模式既控制宏观力量如何通过微观结构分配到细胞，也控制替代ECM将如何组织。MMI也可能在伤口愈合中发挥重要作用。在涉及改变伤口部位机械环境的策略中(例如，应力屏蔽板、形状记忆缝合线、弹性梯度缝合线和粘合剂)，许多重要变量没有得到最佳定义。例如，目前还不清楚是否有一个最佳的时间窗口来保护伤口部位，应该施加多少或什么样的力，力量是否应该随着时间的推移而变化，或者这些参数应该如何随着解剖位置、伤口大小和形状的变化而变化。要回答这些问题，需要一个涉及人机界面的多尺度视角。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在体外实验中验证MMI在重塑过程中控制纤维形成的假说。在这里，我们将观察和量化成纤维细胞-细胞外基质的相互作用和纤维蛋白凝胶中作为初始纤维蛋白功能的重塑 然后评估在以后的时间点改变加载环境如何积极地改变ECM重塑以减少瘢痕。这一目标的完成将为指导MMI减少疤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中收集的体外微结构和力学数据密切相关。这一目标的完成将提供关于负荷传递、纤维重组和纤维蛋白凝胶中的机械微环境的详细信息。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，使临床医生能够设计出针对患者的策略。 最大限度地减少疤痕的形成。然后，这些模型可用于根据位置、几何形状和年龄等伤口参数，推荐由患者特定的设备/敷料提供的位置和时间依赖的压迫和张力的优化方案。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.