Tension stimulation drives tissue formation in scaffold-free systems



Scaffold-free systems have emerged as viable approaches for engineering load-bearing tissues. However, the tensile properties of engineered tissues have remained far below the values for native tissue. Here, by using self-assembled articular cartilage as a model to examine the effects of intermittent and continuous tension stimulation on tissue formation, we show that the application of tension alone, or in combination with matrix remodelling and synthesis agents, leads to neocartilage with tensile properties approaching those of native tissue. Implantation of tension-stimulated tissues results in neotissues that are morphologically reminiscent of native cartilage. We also show that tension stimulation can be translated to a human cell source to generate anisotropic human neocartilage with enhanced tensile properties. Tension stimulation, which results in nearly sixfold improvements in tensile properties over unstimulated controls, may allow the engineering of mechanically robust biological replacements of native tissue.

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Figure 1: Large-construct generation and uniform-strain validation.
Figure 2: Tissue engineering of neocartilage with enhanced tensile properties.
Figure 3: Under tension stimulation, the TRPV4 ion channel is implicated to initiate matrix remodelling.
Figure 4: The in vivo environment results in neocartilage with morphological structure reminiscent of native articular cartilage.
Figure 5: Translation of tension stimulation to human neocartilage.


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This work was made possible with the support of the National Institutes of Health (NIH) awards R01 AR067821 (National Institute of Arthritis and Musculoskeletal and Skin Diseases), R01 DE015038 (National Institute of Dental and Craniofacial Research) and T32 GM00799 (National Institute of General Medical Sciences) for J.K.L. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. Microarray analysis was made possible by the UC Davis Comprehensive Cancer Center Genomics Shared Resource (NCI P30 CA93373). We also thank L. Cassereau and the Weaver laboratory for assistance with second harmonic generation imaging.

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J.K.L., L.W.H., J.C.H. and K.A.A. were responsible for the design and execution of InTenS and CoTenS studies. N.P. and J.K.L. together conducted all animal work, while N.P., A.A. and L.W.H. performed the human articular chondrocyte experiments. C.A.G. assisted in the design and fabrication of the tensile loading device. J.K.L., L.W.H., N.P., A.A. and C.A.G. collected all data. A.A. performed finite element modelling and analysis. J.K.L. and L.W.H. performed the data analysis. J.K.L., L.W.H., J.C.H. and K.A.A. prepared the manuscript.

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Correspondence to Kyriacos A. Athanasiou.

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Lee, J., Huwe, L., Paschos, N. et al. Tension stimulation drives tissue formation in scaffold-free systems. Nature Mater 16, 864–873 (2017). https://doi.org/10.1038/nmat4917

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