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.

National Institute of Health (NIH)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BST-E (51))
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Peng, Grace
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Cleveland Clinic Lerner
Other Basic Sciences
Schools of Medicine
United States
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Halloran, Jason P; Sibole, Scott C; Erdemir, Ahmet (2017) The potential for intercellular mechanical interaction: simulations of single chondrocyte versus anatomically based distribution. Biomech Model Mechanobiol :
Sibole, Scott C; Maas, Steve; Halloran, Jason P et al. (2016) Evaluation of a post-processing approach for multiscale analysis of biphasic mechanics of chondrocytes, DOI: 10.1080/10255842.2013.809711. Comput Methods Biomech Biomed Engin 19:ii
Erdemir, Ahmet; Bennetts, Craig; Davis, Sean et al. (2015) Multiscale cartilage biomechanics: technical challenges in realizing a high-throughput modelling and simulation workflow. Interface Focus 5:20140081
Chokhandre, Snehal; Colbrunn, Robb; Bennetts, Craig et al. (2015) A Comprehensive Specimen-Specific Multiscale Data Set for Anatomical and Mechanical Characterization of the Tibiofemoral Joint. PLoS One 10:e0138226
Bennetts, Craig J; Sibole, Scott; Erdemir, Ahmet (2015) Automated generation of tissue-specific three-dimensional finite element meshes containing ellipsoidal cellular inclusions. Comput Methods Biomech Biomed Engin 18:1293-304
de Vries, Stefan A H; van Turnhout, Mark C; Oomens, Cees W J et al. (2014) Deformation thresholds for chondrocyte death and the protective effect of the pericellular matrix. Tissue Eng Part A 20:1870-6
Wilusz, R E; Zauscher, S; Guilak, F (2013) Micromechanical mapping of early osteoarthritic changes in the pericellular matrix of human articular cartilage. Osteoarthritis Cartilage 21:1895-903
Henak, Corinne R; Anderson, Andrew E; Weiss, Jeffrey A (2013) Subject-specific analysis of joint contact mechanics: application to the study of osteoarthritis and surgical planning. J Biomech Eng 135:021003
Sibole, Scott C; Maas, Steve; Halloran, Jason P et al. (2013) Evaluation of a post-processing approach for multiscale analysis of biphasic mechanics of chondrocytes. Comput Methods Biomech Biomed Engin 16:1112-26
Halloran, J P; Sibole, S; van Donkelaar, C C et al. (2012) Multiscale mechanics of articular cartilage: potentials and challenges of coupling musculoskeletal, joint, and microscale computational models. Ann Biomed Eng 40:2456-74

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