Controlling the Mechanobiology of Cutaneous Wounds to Reduce Hypertrophic Scar

描述（由申请人提供）：增生性瘢痕形成是一种以过度纤维化为特征的主要临床问题。在一些治疗策略中，减少纤维化和瘢痕形成似乎与伤口部位的力量减少有关。然而，其背后的机制尚不清楚。多尺度机械相互作用（MMI）可能是重要的，并最终决定了在愈合的外科伤口中控制疤痕表型的纤维发生。MMI是由血块的几何形状、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发展而来的。PI最近的工作表明，体外环境中的重塑受到MMI的强烈影响，MMI结合产生纤维蛋白和ECM对齐的模式。形成的初始模式既控制着宏观力如何通过微观结构分布到细胞中，也控制着替代ECM将如何组织。MMI也可能在伤口愈合中发挥重要作用。在涉及改变创面机械环境的策略中（例如，应力屏蔽片、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，目前尚不清楚是否存在应力屏蔽创面的最佳时间窗口，应施加多少或何种力，力的大小是否应随时间变化，或这些参数应如何随解剖部位，创面大小和形状而变化。为了回答这些问题，需要一个涉及MMI的多尺度视角。这里详细的实验和建模将有助于提供这个新的和重要的视角。目的1在体外环境中验证MMI在重塑过程中控制纤维形成的假设。在这里，我们将观察和量化成纤维细胞- ECM的相互作用和纤维蛋白凝胶中的重塑作为初始纤维蛋白的功能

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.