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Precise, high-throughput production of multicellular spheroids with a bespoke 3D bioprinter

Robert H. Utama, View ORCID ProfileLakmali Atapattu, Aidan P. O’Mahony, Christopher M. Fife, Jongho Baek, Théophile Allard, Kieran J. O’Mahony, Julio Ribeiro, View ORCID ProfileKatharina Gaus, View ORCID ProfileMaria Kavallaris, View ORCID ProfileJ. Justin Gooding
doi: https://doi.org/10.1101/2020.04.06.028548
Robert H. Utama
1ARC Centre of Excellence in Convergent Bio-Nano Science and Technology and Australian Centre for NanoMedicine, The University of New South Wales, Sydney, NSW 2052, Australia
2School of Chemistry, The University of New South Wales, Sydney, NSW 2052, Australia
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Lakmali Atapattu
1ARC Centre of Excellence in Convergent Bio-Nano Science and Technology and Australian Centre for NanoMedicine, The University of New South Wales, Sydney, NSW 2052, Australia
3Children’s Cancer Institute, Lowy Cancer Research Centre, The University of New South Wales, Sydney, NSW 2052, Australia
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Aidan P. O’Mahony
6Inventia Life Science Pty Ltd, Sydney, New South Wales, Australia
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Christopher M. Fife
1ARC Centre of Excellence in Convergent Bio-Nano Science and Technology and Australian Centre for NanoMedicine, The University of New South Wales, Sydney, NSW 2052, Australia
3Children’s Cancer Institute, Lowy Cancer Research Centre, The University of New South Wales, Sydney, NSW 2052, Australia
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Jongho Baek
4EMBL Australia Node in Single Molecule Science, School of Medical Sciences, The University of New South Wales, Sydney, NSW 2052, Australia
5ARC Centre of Excellence in Advanced Molecular Imaging, The University of New South Wales, Sydney, NSW 2052, Australia
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Théophile Allard
6Inventia Life Science Pty Ltd, Sydney, New South Wales, Australia
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Kieran J. O’Mahony
7OMKO Limited, Tooreen South, Bantry, Co. Cork, Ireland
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Julio Ribeiro
6Inventia Life Science Pty Ltd, Sydney, New South Wales, Australia
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Katharina Gaus
4EMBL Australia Node in Single Molecule Science, School of Medical Sciences, The University of New South Wales, Sydney, NSW 2052, Australia
5ARC Centre of Excellence in Advanced Molecular Imaging, The University of New South Wales, Sydney, NSW 2052, Australia
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  • ORCID record for Katharina Gaus
Maria Kavallaris
1ARC Centre of Excellence in Convergent Bio-Nano Science and Technology and Australian Centre for NanoMedicine, The University of New South Wales, Sydney, NSW 2052, Australia
3Children’s Cancer Institute, Lowy Cancer Research Centre, The University of New South Wales, Sydney, NSW 2052, Australia
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  • For correspondence: m.kavallaris@ccia.unsw.edu.au
J. Justin Gooding
1ARC Centre of Excellence in Convergent Bio-Nano Science and Technology and Australian Centre for NanoMedicine, The University of New South Wales, Sydney, NSW 2052, Australia
2School of Chemistry, The University of New South Wales, Sydney, NSW 2052, Australia
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Abstract

3D in vitro cancer models are important therapeutic and biological discovery tools, yet formation of multicellular spheroids in a throughput and highly controlled manner to achieve robust and statistically relevant data, remains challenging. Here, we developed an enabling technology consisting of a bespoke drop-on-demand 3D bioprinter capable of high-throughput printing of 96-well plates of spheroids. 3D-multicellular spheroids are embedded inside a tissue-like matrix with precise control over size and cell number. Application of 3D bioprinting for high-throughput drug screening was demonstrated with doxorubicin. Measurements showed that IC50 values were sensitive to spheroid size, embedding and how spheroids conform to the embedding, revealing parameters shaping biological responses in these models. Our study demonstrates the potential of 3D bioprinting as a robust high-throughput platform to screen biological and therapeutic parameters.

Significance Statement In vitro 3D cell cultures serve as more realistic models, compared to 2D cell culture, for understanding diverse biology and for drug discovery. Preparing 3D cell cultures with defined parameters is challenging, with significant failure rates when embedding 3D multicellular spheroids into extracellular mimics. Here, we report a new 3D bioprinter we developed in conjunction with bioinks to allow 3D-multicellular spheroids to be produced in a high-throughput manner. High-throughput production of embedded multicellular spheroids allowed entire drug-dose responses to be performed in 96-well plate format with statistically relevant numbers of data points. We have deconvoluted important parameters in drug responses including the impact of spheroid size and embedding in an extracellular matrix mimic on IC50 values.

Competing Interest Statement

A.P.O.M, T.A., K.J.O.M and J.R. are employees and/or consultants of Inventia Life Science Pty Ltd. Inventia Life Science Pty Ltd has an interest in commercializing the technology.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted April 12, 2020.
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Precise, high-throughput production of multicellular spheroids with a bespoke 3D bioprinter
Robert H. Utama, Lakmali Atapattu, Aidan P. O’Mahony, Christopher M. Fife, Jongho Baek, Théophile Allard, Kieran J. O’Mahony, Julio Ribeiro, Katharina Gaus, Maria Kavallaris, J. Justin Gooding
bioRxiv 2020.04.06.028548; doi: https://doi.org/10.1101/2020.04.06.028548
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Precise, high-throughput production of multicellular spheroids with a bespoke 3D bioprinter
Robert H. Utama, Lakmali Atapattu, Aidan P. O’Mahony, Christopher M. Fife, Jongho Baek, Théophile Allard, Kieran J. O’Mahony, Julio Ribeiro, Katharina Gaus, Maria Kavallaris, J. Justin Gooding
bioRxiv 2020.04.06.028548; doi: https://doi.org/10.1101/2020.04.06.028548

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