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Towards integration of time-resolved confocal microscopy of a 3D in vitro microfluidic platform with a hybrid multiscale model of tumor angiogenesis

View ORCID ProfileCaleb M. Phillips, View ORCID ProfileErnesto A. B. F. Lima, View ORCID ProfileManasa Gadde, View ORCID ProfileAngela M. Jarrett, Marissa Nichole Rylander, View ORCID ProfileThomas E. Yankeelov
doi: https://doi.org/10.1101/2021.09.29.462293
Caleb M. Phillips
1Oden Institute for Computational Engineering and Sciences, The University of Texas at Austin, Austin, TX, USA
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Ernesto A. B. F. Lima
1Oden Institute for Computational Engineering and Sciences, The University of Texas at Austin, Austin, TX, USA
2Texas Advanced Computing Center, The University of Texas at Austin, Austin, TX, USA
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  • For correspondence: lima@ices.utexas.edu
Manasa Gadde
1Oden Institute for Computational Engineering and Sciences, The University of Texas at Austin, Austin, TX, USA
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  • ORCID record for Manasa Gadde
Angela M. Jarrett
1Oden Institute for Computational Engineering and Sciences, The University of Texas at Austin, Austin, TX, USA
7Livestrong Cancer Institutes, The University of Texas at Austin, Austin, TX, USA
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Marissa Nichole Rylander
1Oden Institute for Computational Engineering and Sciences, The University of Texas at Austin, Austin, TX, USA
3Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, USA
4Department of Mechanical Engineering, The University of Texas at Austin, Austin, TX, USA
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Thomas E. Yankeelov
1Oden Institute for Computational Engineering and Sciences, The University of Texas at Austin, Austin, TX, USA
3Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, USA
5Department of Diagnostic Medicine, The University of Texas at Austin, Austin, TX, USA
6Department of Oncology, The University of Texas at Austin, Austin, TX, USA
7Livestrong Cancer Institutes, The University of Texas at Austin, Austin, TX, USA
8Department of Imaging Physics, The University of Texas at Austin, MD Anderson Cancer Center
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Abstract

The goal of this study is to calibrate a multiscale model of tumor angiogenesis with time-resolved data to allow for systematic testing of mathematical predictions of vascular sprouting. The multi-scale model consists of an agent-based description of tumor and endothelial cell dynamics coupled to a continuum model of vascular endothelial growth factor concentration. First, we calibrate ordinary differential equation models to time-resolved protein expression data to estimate the rates of secretion and consumption of vascular endothelial growth factor by endothelial and tumor cells, respectively. These parameters are then input into the multiscale tumor angiogenesis model, and the remaining model parameters are then calibrated to time resolved confocal microscopy images obtained within a 3D vascularized microfluidic platform. The microfluidic platform mimics a functional blood vessel with a surrounding collagen matrix seeded with inflammatory breast cancer cells, which induce tumor angiogenesis. Once the multi-scale model is fully parameterized, we forecast the spatiotemporal distribution of vascular sprouts at future time points and directly compare the predictions to experimentally measured data. We assess the ability of our model to globally recapitulate angiogenic vasculature density, resulting in an average relative calibration error of 17.7% ± 6.3% and an average prediction error of 20.2% ± 4% and 21.7% ± 3.6% using one and four calibrated parameters, respectively. We then assess the model’s ability to predict local vessel morphology (individualized vessel structure as opposed to global vascular density), initialized with the first time point and calibrated with two intermediate time points. To the best of our knowledge, this represents the first study to integrate well-controlled, experimental data into a mechanism-based, multiscale, mathematical model of angiogenic sprouting to make specific, testable predictions.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted October 01, 2021.
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Towards integration of time-resolved confocal microscopy of a 3D in vitro microfluidic platform with a hybrid multiscale model of tumor angiogenesis
Caleb M. Phillips, Ernesto A. B. F. Lima, Manasa Gadde, Angela M. Jarrett, Marissa Nichole Rylander, Thomas E. Yankeelov
bioRxiv 2021.09.29.462293; doi: https://doi.org/10.1101/2021.09.29.462293
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Towards integration of time-resolved confocal microscopy of a 3D in vitro microfluidic platform with a hybrid multiscale model of tumor angiogenesis
Caleb M. Phillips, Ernesto A. B. F. Lima, Manasa Gadde, Angela M. Jarrett, Marissa Nichole Rylander, Thomas E. Yankeelov
bioRxiv 2021.09.29.462293; doi: https://doi.org/10.1101/2021.09.29.462293

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