For most cancers, metastasis is the point at which disease is no longer curable. Earlier detection of metastasis, when it is undetectable by current clinical methods, may enable better outcomes. We have developed a biomaterial implant that recruits metastatic cancer cells in mouse models of breast cancer. Here, we investigate spectral ultrasound imaging (SUSI) as a non-invasive strategy for detecting metastasis to the implanted biomaterial scaffolds. Our results show that SUSI, which detects parameters related to tissue composition and structure, identified changes at an early time point when tumor cells were recruited to scaffolds in orthotopic breast cancer mouse models. These changes were not associated with acellular components in the scaffolds but were reflected in the cellular composition in the scaffold microenvironment, including an increase in CD31 + CD45-endothelial cell number in tumor bearing mice. In addition, we built a classification model based on changes in SUSI parameters from scaffold measurements to stratify tumor free and tumor bearing status. Combination of a linear discriminant analysis and bagged decision trees model resulted in an area under the curve of 0.92 for receiver operating characteristics analysis. With the potential for early non-invasive detection, SUSI could facilitate clinical translation of the scaffolds for monitoring metastatic disease.
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Thanks to the NIH for their support through 5R01CA173745-06 and R01DE026630. G.G.B. is a recipient of the NSF Graduate Research Fellowship and NRSA F31 CA224982-01. G.G.B., X.H., S.S.R., J.S.J., C.X.D., and L.D.S. conceived the presented hypotheses and experimental designs. G.G.B and X.H. carried out experiments with support from S.S.R, R.M.H, Y.Z., and R.S.O, and completed computational analysis with support from R.S.O. G.G.B., X.H., and L.D.S. wrote the manuscript with support from J.S.J. and C.X.D. L.D.S. supervised the project with support from J.S.J. and C.X.D. All authors discussed the results and reviewed the final manuscript.
Data associated with this manuscript is available through a private repository with password “Bushnell-Hong” at the following link https://1drv.ms/u/s!AmVnzTmi4yrLhI1lf215PCMrJzK7WA?e=S4xYlg. After publication data will be made publicly available.
The authors acknowledge support from the National Institutes of Health NIH-Director’s Transformative Research Award-R01CA173745 and R01CA214384 (to L.D. Shea and J.S. Jeruss) and NIH R01DE026630 (to C. X. Deng and J. P. Stegemann). G.G. Bushnell is a recipient of the NSF Graduate Research Fellowship and NRSA F31 CA224982-01.
Conflict of interest
The scaffold as a platform for metastasis detection is described in a current patent application US20170281798A1 by assignee Northwestern University with inventors Lonnie D. Shea, Samira M. Azarin, Robert M. Gower, Jacqueline S. Jeruss and US2017012556 by assignee Regents of the University of Michigan with inventors Lonnie D. Shea, Shreyas S. Rao, Samira M. Azarin, Jacqueline S. Jeruss, and Grace G. Bushnell.
Associate Editor Agata A. Exner oversaw the review of this article.
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Bushnell, G.G., Hong, X., Hartfield, R.M. et al. High Frequency Spectral Ultrasound Imaging to Detect Metastasis in Implanted Biomaterial Scaffolds. Ann Biomed Eng 48, 477–489 (2020). https://doi.org/10.1007/s10439-019-02366-2