Microfabricated tissue gauges to measure and manipulate forces from 3D microtissues

Physical forces generated by cells drive morphologic changes during development and can feedback to regulate cellular phenotypes. Because these phenomena typically occur within a 3-dimensional (3D) matrix in vivo, we used microelectromechanical systems (MEMS) technology to generate arrays of microti...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2009-06, Vol.106 (25), p.10097-10102
Main Authors: Legant, Wesley R, Pathak, Amit, Yang, Michael T, Deshpande, Vikram S, McMeeking, Robert M, Chen, Christopher S
Format: Article
Language:English
Subjects:
Actins
Animals
Cantilevers
Cell lines
Cells
Collagens
Correlation analysis
Cytoskeleton
Endothelial cells
Extracellular Matrix Proteins - chemistry
Fracture mechanics
Genotype & phenotype
Mechanical stress
Mice
Microarray Analysis
Miniaturization
Morphogenesis
NIH 3T3 Cells
Physical Sciences
Proteins
Stem cells
Stiffness
Studies
Three dimensional imaging
Tissue Culture Techniques
Tissue Embedding - methods
Tissue Engineering
Tissues
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Summary:Physical forces generated by cells drive morphologic changes during development and can feedback to regulate cellular phenotypes. Because these phenomena typically occur within a 3-dimensional (3D) matrix in vivo, we used microelectromechanical systems (MEMS) technology to generate arrays of microtissues consisting of cells encapsulated within 3D micropatterned matrices. Microcantilevers were used to simultaneously constrain the remodeling of a collagen gel and to report forces generated during this process. By concurrently measuring forces and observing matrix remodeling at cellular length scales, we report an initial correlation and later decoupling between cellular contractile forces and changes in tissue morphology. Independently varying the mechanical stiffness of the cantilevers and collagen matrix revealed that cellular forces increased with boundary or matrix rigidity whereas levels of cytoskeletal and extracellular matrix (ECM) proteins correlated with levels of mechanical stress. By mapping these relationships between cellular and matrix mechanics, cellular forces, and protein expression onto a bio-chemo-mechanical model of microtissue contractility, we demonstrate how intratissue gradients of mechanical stress can emerge from collective cellular contractility and finally, how such gradients can be used to engineer protein composition and organization within a 3D tissue. Together, these findings highlight a complex and dynamic relationship between cellular forces, ECM remodeling, and cellular phenotype and describe a system to study and apply this relationship within engineered 3D microtissues.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0900174106