Abstract
Treatment strategies to address pathologies of fibrocartilaginous tissue are in part limited by an incomplete understanding of structure–function relationships in these load-bearing tissues. There is therefore a pressing need to develop micro-engineered tissue platforms that can recreate the highly inhomogeneous tissue microstructures that are known to influence mechanotransductive processes in normal and diseased tissue. Here, we report the quantification of proteoglycan-rich microdomains in developing, ageing and diseased fibrocartilaginous tissues, and the impact of these microdomains on endogenous cell responses to physiologic deformation within a native-tissue context. We also developed a method to generate heterogeneous tissue-engineered constructs (hetTECs) with non-fibrous proteoglycan-rich microdomains engineered into the fibrous structure, and show that these hetTECs match the microstructural, micromechanical and mechanobiological benchmarks of native tissue. Our tissue-engineered platform should facilitate the study of the mechanobiology of developing, homeostatic, degenerating and regenerating fibrous tissues.
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Acknowledgements
The authors would like to thank A. Raj for assistance with fluorescent in situ hybridization, J. Caplan and S. Qu for assistance with confocal microscopy, A. Marcozzi for assistance with histology, and J. Peloquin for finite-element model mesh generation. The research was financially supported by the National Institutes of Health grant R01 EB02425 and the Penn Center of Musculoskeletal Disorders grant P30AR050950. The authors also would like to thank the BioImaging Center at the Delaware Biotechnology Institute for providing resources that contributed to this research.
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W.M.H., S.-J.H., T.P.D., J.F.D., C.M.M., L.J.S., R.L.D., R.L.M. and D.M.E. designed the studies. W.M.H., S.-J.H., T.P.D., J.F.D. and C.M.M. performed the experiments. W.M.H., S.-J.H., T.P.D., J.F.D., C.M.M., L.J.S., R.L.D., R.L.M. and D.M.E. analysed and interpreted the data. W.M.H., S.-J.H., R.L.M. and D.M.E. drafted the manuscript, and all authors edited the final submission.
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Han, W., Heo, SJ., Driscoll, T. et al. Microstructural heterogeneity directs micromechanics and mechanobiology in native and engineered fibrocartilage. Nature Mater 15, 477–484 (2016). https://doi.org/10.1038/nmat4520
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DOI: https://doi.org/10.1038/nmat4520
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