Controlling the Mechanobiology of Cutaneous Wounds to Reduce Hypertrophic Scar

控制皮肤伤口的力学生物学以减少增生性疤痕

• 批准号: 8692478
• 负责人: EDWARD A SANDER
• 金额: $ 7.55万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8692478
• 关键词: Adhesives; Age; Biochemical Genetics; Biological Models; Bioreactors; Cells; Cellular Structures; Cicatrix; Clinical; Clinical Management; Coagulation Process; Collagen; Complex; Computer Simulation; Cutaneous; Data; Devices; Distress; Environment; Experimental Models; Extracellular Matrix; Fiber; Fibrin; Fibroblasts; Fibrosis; Forms Controls; Foundations; Gel; Geometry; Goals; Healed; Health; Hypertrophic Cicatrix; Image; In Vitro; Intervention; Knowledge; Link; Location; Mechanics; Memory; Microscope; Modeling; Pain; Patients; Pattern; Phenotype; Play; Process; Regimen; Role; Shapes; Site; Skin; Spatial Distribution; Sterile coverings; Stress; Structure; Surgical sutures; Surgical wound; Testing; Time; Tissues; Traction; Work; Wound Healing; base; cost; fibrogenesis; healing; innovation; loss of function; macrophage; multi-scale modeling; predictive modeling; public health relevance; repaired; research study; response; tissue repair; transmission process; treatment strategy; wound

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.

描述（由申请人提供）：肥厚性疤痕是一个主要的临床问题，其特征是过度纤维化。在几种治疗策略中，降低纤维化和疤痕似乎与伤口部位的力量减少有关。但是，负责的基本机制尚不清楚。多尺度机械相互作用（MMI）可能是重要的，最终是确定性的，该纤维发生控制了治愈的手术伤口中疤痕表型。 MMI是根据凝块的几何形状，结构和组织之间的相互作用，内部细胞障碍以及伤口外部约束的相互作用。 PI的最新工作表明，在体外环境中进行的重塑受到MMI的强烈影响，MMI结合起来产生纤维蛋白和ECM比对模式。形成的初始模式既控制着如何通过微观结构分布到细胞的宏观力量，又如何组织替代ECM。 MMI也可以在伤口愈合中发挥重要作用。在涉及改变伤口部位的机械环境的策略中（例如，应力屏蔽板，形状的记忆缝合线，带有弹性梯度的缝合线和粘合剂），许多重要的变量并未最佳定义。例如，目前尚不清楚是否有一个最佳的时间来掩盖伤口部位的应力，应施加多少力量或哪种力，是否应随着时间的推移而变化，或者这些参数应如何随着解剖部位，伤口大小和形状而变化。要回答这些问题，需要一个涉及MMI的多尺度观点。此处详细介绍的实验和建模将有助于提供这一新的重要视角。 AIM 1检验了以下假设：MMI在体外环境中控制重塑过程中的纤维发生。在这里，我们将观察并量化成纤维细胞 - ECM相互作用并在纤维蛋白凝胶中重塑作为初始纤维蛋白的函数 对齐，细胞空间分布，机械载荷和几何形状，然后评估如何在以后的时间点更改加载环境，可以积极改变ECM重塑以减少疤痕。该目标的完成将提供有关指示MMI减少疤痕形成和开发可用于优化治疗的新干预措施的新知识。 AIM 2开发了伤口部位的计算多尺度机械模型，该模型与从纤维蛋白凝胶收集的体外微结构和机械数据密切相关。该目标的完成将提供纤维蛋白凝胶中的负载传输，纤维重组和机械微环境的详细视图。长期的目标是利用这项工作作为开发伤口愈合的预测模型的基础，这将使临床医生能够制定特定于患者的策略 最大程度地减少疤痕形成。然后，这些模型可用于推荐一种优化的位置和时间依赖性压缩和张力的方案，该方案是由患者特异性设备/调味料基于伤口参数（例如位置，几何图形和年龄）提供的。因此，拟议的项目可以显着影响疤痕形成的临床管理。

项目成果

A Combined In Vitro Imaging and Multi-Scale Modeling System for Studying the Role of Cell Matrix Interactions in Cutaneous Wound Healing.

• DOI: 10.1371/journal.pone.0148254
• 发表时间: 2016
• 期刊: PloS one
• 影响因子: 3.7
• 作者: De Jesus AM;Aghvami M;Sander EA
• 通讯作者: Sander EA

Substrate Stiffness Affects Human Keratinocyte Colony Formation.

• DOI: 10.1007/s12195-015-0377-8
• 发表时间: 2015-03-01
• 期刊: CELLULAR AND MOLECULAR BIOENGINEERING
• 影响因子: 2.8
• 作者: Zarkoob, Hoda;Bodduluri, Sandeep;Ponnaluri, Sailahari V.;Selby, John C.;Sander, Edward A.
• 通讯作者: Sander, Edward A.