Abstract
Cancer progression involves biomechanical changes within transformed cells and the surrounding extracellular matrix (ECM). The viscoelastic features of fluidity and elasticity that are based on a novel Kelvin–Voigt fractional derivative (KVFD) model were found capable of discriminating normal, benign and malignant breast biopsy tissues on the cellular scale. The improved specificity of KVFD model parameters derives from greater accuracy of fitting the entire approaching force-indentation measurement curve (\(R^{2}\) > 0.99) compared with traditional elastic models (\(R^{2}\) < 0.86). Moreover, model parameters can be interpreted in terms of histopathological features. First, statistical comparisons reveal there are significant differences (p < 0.001) in elasticity E0, fluidity \(\alpha\), and viscosity \(\tau\) among healthy, benign, and malignant groups. Malignant breast tissues show low-value, broad-distributions in E0 and with high fluidity \(\alpha\) as compared with healthy and benign tissues. Second, histograms of E0 and \(\alpha\) provide distinctive features by fitting to Gaussian mixture (GM) models. The histograms of E0 and \(\alpha\) are best fit by two kernels GM for malignant tissues, indicating that the cells are soft but with high fluidity and the ECM is stiff but with low fluidity. However, the data suggest one-kernel GM model for benign tissue and a patched uniform distribution for healthy tissue. Third, using fluidity \(\alpha\) as the test statistic, the area under the receiver operator characteristic curve (AUC) is 0.701 ± 0.012 (p < 0.0001) for control versus malignant and 0.706 ± 0.013 (p < 0.0001) for benign versus malignant group. Variations in tissue fluidity and elasticity offer a concise set of viscoelastic biomarkers that correlate well with histopathological features.
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Acknowledgements
The authors thank Prof. Xin Lv, Dr. Meili Gao and Pathologist Zunzhen Nie for their kind assistance on this work.
Funding
This study was funded by the National Science Fund of China (61871316, 81771854), national key scientific instruments and equipment development project (81827801), and the Fundamental Research Funds for the Central Universities (zdyf2017011).
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All authors contributed to the study conception and design. The KVFD method was developed in Department of Bioengineering, Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana IL, 61801, USA. The experiment was done in The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an 710049, PR China. The development of the KVFD method and design of the experiment was participated by HZ, MFI and MW. The overall structure of the article was designed by HZ and MFI. The construction of KVFD model, the fitting algorithm of KVFD model and the program implementation of the algorithm are completed by HZ. The collection and preparation of experimental samples were completed by LR. The design and execution of mechanical test experiments, the fitting of experimental data with KVFD model and the statistical analysis of samples were completed by YZ. The pathological diagnosis and grading of the samples and the measurement of the epithelial percentage of the samples were completed by KW. Biological explanations of experimental data and statistical results were completed by HZ, HZ, YW and pathological explanations by YG. The first draft of the manuscript was written by HZ and MFI. All authors commented on the previous version of the manuscript, and MFI reviewed and revised it substantially. All the authors read and approved the final manuscript.
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This study was approved by the Institutional Review Board and Ethics Committee of the first affiliated hospital of Xi’an JiaoTong University (XJTU1AF2017LSK-46).
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Zhang, H., Guo, Y., Zhou, Y. et al. Fluidity and elasticity form a concise set of viscoelastic biomarkers for breast cancer diagnosis based on Kelvin–Voigt fractional derivative modeling. Biomech Model Mechanobiol 19, 2163–2177 (2020). https://doi.org/10.1007/s10237-020-01330-7
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DOI: https://doi.org/10.1007/s10237-020-01330-7