Cell-generated mechanical stresses are critical during a number of physiological processes, including embryogenesis, cell migration, cell proliferation and tissue formation. However, there is no method currently available to measure cellular traction forces exerted during adhesion and migration in 3-D scaffolds. This information is critical for understanding the contribution of cell-cell and cell-extracellular matrix (ECM) interactions in processes such as wound healing, cancer metastasis, cardiovascular disease, and chronic inflammation. To partially address this need, a technique called Traction Force Microscopy was developed several years ago to quantify and map the traction field created by a cell on its substrate (1, 2). This technique has provided valuable information about the mechanisms of cell migration and adhesion and has demonstrated key differences in the mechanics of normal and diseased states. However, this currently used technique is limited--- the state-of-the-art is a 2-D calculation of the cell-generated forces on a planar substrate. It is well-established that 2D substrates lack the physiologically realistic environment that a 3D ECM provides cells in vivo. Therefore, to more accurately recapitulate the cellular microenvironment, these measurements need to be done in 3-D, where all sides of the cell are capable of binding to the extracellular matrix, deforming the substrate and using cell-generated traction stresses to migrate. The proposal seeks to develop and build an instrument (hardware) and a computational algorithm (software) that calculates the stresses exerted by cells embedded in 3D matrices for studies of the dynamic processes of cell adhesion and migration in ECMs which mimic the native in vivo environment. We expect that just as 2D Traction Force Microscopy has been widely implemented;our tool will be of wide-spread interest to the large community of scientists interested in mechanism of cell migration and adhesion for a number of different physiological systems and disease conditions.

Public Health Relevance

(provided by applicant): In this proposal, we plan to develop a 4D traction force microscope (hardware and software) that can measure the forces that cells exert against their substrate during adhesion and migration in 3D space and time. Such a device is essential to understand the molecular machinery that drives cell migration in physiological processes such as wound healing, tissue formation, and during the progression of diseases including cancer metastasis and atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory/Developmental Grants (R21)
Project #
8R21GM103388-03
Application #
8213465
Study Section
Special Emphasis Panel (ZRR1-BT-7 (01))
Program Officer
Friedman, Fred K
Project Start
2010-03-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2014-02-28
Support Year
3
Fiscal Year
2012
Total Cost
$182,853
Indirect Cost
$62,707
Name
Cornell University
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
872612445
City
Ithaca
State
NY
Country
United States
Zip Code
14850
Wu, Mingming; Swartz, Melody A (2014) Modeling tumor microenvironments in vitro. J Biomech Eng 136:021011
Feng, Xinzeng; Hall, Matthew S; Wu, Mingming et al. (2014) An adaptive algorithm for tracking 3D bead displacements: application in biological experiments. Meas Sci Technol 25:
Mason, Brooke N; Starchenko, Alina; Williams, Rebecca M et al. (2013) Tuning three-dimensional collagen matrix stiffness independently of collagen concentration modulates endothelial cell behavior. Acta Biomater 9:4635-44
Mason, Brooke N; Reinhart-King, Cynthia A (2013) Controlling the mechanical properties of three-dimensional matrices via non-enzymatic collagen glycation. Organogenesis 9:70-5
Hall, Matthew S; Long, Rong; Feng, Xinzeng et al. (2013) Toward single cell traction microscopy within 3D collagen matrices. Exp Cell Res 319:2396-408