Predicting cell deformation from body level mechanical loads

描述（由申请人提供）：项目概述已知肌肉骨骼系统的细胞对变形有生物反应。当变形的幅度、持续时间和/或频率异常时，可导致细胞损伤并可能破坏细胞外基质的稳态。这些机制可以以孤立的方式进行研究，但将机械细胞反应与器官水平力学和人体运动联系起来需要多尺度方法。在器官层面，医生进行外科手术，调查人员试图了解损伤的风险，临床医生开出预防和治疗干预措施。许多此类手术旨在管理和预防细胞损伤，并将关节水平的故障机械标记与细胞水平的故障机制联系起来。通过人体运动，探索神经肌肉控制机制和身体活动对肌肉骨骼组织特性的影响。在较低的层次上，细胞变形的机械感觉调节着运动控制。物理康复和锻炼方案是为了促进组织愈合和/或通过细胞再生加强。机械途径是机体水平负荷在器官之间、组织内部以及细胞外基质和细胞之间分布的途径，了解机械途径对各种干预措施的成功至关重要。然而，这一信息是不确定的。本研究计划的目标是描述作用在人体上的载荷对细胞变形的预测，因此，如果使用多尺度模拟方法，就有可能清楚地描述机械途径。膝关节的多分辨率模型，代表关节，组织和细胞结构和力学，将为此目的而发展。膝关节软组织结构的创伤性损伤发生率很高，主要受骨关节炎的影响，慢性骨关节炎是由机械负荷异常或转移到软骨的方式引起的。通过这些模型的多尺度力学耦合，将获得软骨、韧带和半月板在各种胫股关节载荷下的细胞变形图。将在关节、组织和细胞水平上进行全面的力学测试，以进行参数估计和验证，包括膝关节的体外加载，代表逼真的加载场景。此外，成像模式将捕获关节和组织解剖结构，以及来自细胞和细胞外基质的空间和变形相关信息。先进的计算方法将用于获得模型属性和促进多尺度模拟。该方法将结合许多在生物力学建模和各种生物尺度实验方面经验丰富的研究人员的专业知识，其中一些具有临床专业知识。未来，研究团队将利用该平台建立膝关节结构和负荷状态与软骨细胞应力之间的关系，探索软骨退变的潜在机制。通过记录数据和模型的传播，其他病理的模拟和方法的翻译到其他器官可以由任何感兴趣的研究者进行。预测细胞变形的可能性促进了对从器官到组织到细胞的机械负荷转移方案的充分理解，特别是当作用在人体上的负荷可以通过现成的实验平台测量时。该方案可以确定与这些机制相关的病理的结构和机械因果关系，并提供机械诱导细胞损伤风险的受试者特异性评估。从长远来看，所提出的多尺度建模平台将通过设计直接针对细胞力学的手术、治疗和康复干预措施来促进公共卫生保健，以便在各种生物尺度上恢复机械功能。

DESCRIPTION (provided by applicant): Project Summary Cells of the musculoskeletal system are known to have a biological response to deformation. Deformations, when abnormal in magnitude, duration, and/or frequency content, can lead to cell damage and possible disruption in homeostasis of the extracellular matrix. These mechanisms can be studied in an isolated fashion but connecting mechanical cellular response to organ level mechanics and human movement requires a multiscale approach. At the organ level, physicians perform surgical procedures, investigators try to understand risk of injury, and clinicians prescribe preventive and therapeutic interventions. Many of these operations are aimed at management and prevention of cell damage, and to associate joint level mechanical markers of failure to cell level failure mechanisms. Through human movement, one explores neuromuscular control mechanisms and the influence of physical activity on musculoskeletal tissue properties. At a lower level, mechanical sensation of cell deformations regulate movement control. Physical rehabilitation and exercise regimens are prescribed to promote tissue healing and/or strengthening through cellular regeneration. The knowledge of the mechanical pathway, through which the body level loads are distributed between organs, then within the tissues and further along the extracellular matrix and the cells, is critical for the success of various interventions. However, this information is not established. The goal of this research proposal is to portray that prediction of cell deformations from loads acting on the human body, therefore a clear depiction of the mechanical pathway, is possible, if a multiscale simulation approach is used. Multiresolution models of the knee joint, representative of joint, tissue and cell structure and mechanics, will be developed for this purpose. The knee endures high rates of traumatic injury to its soft tissue structures and it is predominantly affected by osteoarthritis, chronically induced by abnormalities in mechanical loading or how it is transferred to the cartilage. Through multiscale mechanical coupling of these models, a map of cellular deformation in cartilage, ligaments and menisci under a variety of tibiofemoral joint loads will be obtained. Comprehensive mechanical testing at joint, tissue and cell levels will be conducted for parameter estimation and validation, including in vitro loading of the knee joint representative of lifelike loading scenarios. In addition, imaging modalities will capture joint and tissue anatomy, and spatial and deformation related information from cell and extracellular matrix. Advanced computational approaches will be used to obtain model properties and to facilitate multiscale simulations. The approach will combine the expertise of many investigators experienced in biomechanical modeling and experimentation at various biological scales, some with clinical expertise. In future, the research team will utilize this platform to establish the relationship between the structural and loading state of the knee and chondrocyte stresses to explore potential mechanisms of cartilage degeneration. Through documented dissemination of data and models, simulations of other pathologies and translation of the methodology to other organs can be carried out by any interested investigator. PUBLIC HEALTH RELEVANCE: Project Narrative Possibility to predict cell deformations promotes a full understanding of the mechanical load transfer schemes from organ to tissue to cell, particularly when the loads acting on the human body are measurable by readily available experimental platforms. The protocols can identify structural and mechanical causalities of the pathologies associated with these mechanisms, and provide subject-specific assessment of the risk of mechanically induced cell damage. In long term, the proposed multiscale modeling platform will advance public health care through the design of surgical, therapeutic and rehabilitative interventions directly targeted at cell mechanics in order to restore mechanical function at various biological scales.