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A bioprinted human-glioblastoma-on-a-chip for the identification of patient-specific responses to chemoradiotherapy

Nature Biomedical Engineering volume 3, pages 509–519 (2019)Cite this article

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Abstract

Patient-specific ex vivo models of human tumours that recapitulate the pathological characteristics and complex ecology of native tumours could help determine the most appropriate cancer treatment for individual patients. Here, we show that bioprinted reconstituted glioblastoma tumours consisting of patient-derived tumour cells, vascular endothelial cells and decellularized extracellular matrix from brain tissue in a compartmentalized cancer–stroma concentric-ring structure that sustains a radial oxygen gradient, recapitulate the structural, biochemical and biophysical properties of the native tumours. We also show that the glioblastoma-on-a-chip reproduces clinically observed patient-specific resistances to treatment with concurrent chemoradiation and temozolomide, and that the model can be used to determine drug combinations associated with superior tumour killing. The patient-specific tumour-on-a-chip model might be useful for the identification of effective treatments for glioblastoma patients resistant to the standard first-line treatment.

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Fig. 1: Schematic illustration of the bioprinting and use of the patient-specific GBM-on-a-chip for the identification of an optimal drug combination for the patient.
Fig. 2: Preparation and evaluation of the BdECM bioink.
Fig. 3: Working principles of the GBM-on-a-chip and confirmation of reconstituted GBM ecology.
Fig. 4: The synergistic effect of biochemical and biophysical heterogeneities on the pathological progression of GBM-on-a-chip.
Fig. 5: Reproduction of differences in treatment resistance in patient-specific GBMs-on-chips.
Fig. 6: Evaluation of the susceptibility of an individual patient to CCRT with different drug combinations.

Code availability

The computer code for the bioprinting of the GBM-on-a-chip is provided as Supplementary Information.

Data availability

The authors declare that all data supporting the results in this study are available within the paper and its Supplementary information. The source data for the figures in this study are available from figshare (identifier https://doi.org/10.6084/m9.figshare.7392677)51.

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Acknowledgements

This work was supported by the National Research Foundation of Korea (NRF) funded by the Korean government, MSIP (grant nos 2010-0018294, 2015R1A2A2A01005515 and 2018R1A2B2009540). This study was partly supported by the Technology Innovation Program (grant no. 10050154, Business Model Development for Personalized Medicine Based on Integrated Genome and Clinical Information) and by the Bio and Medical Technology Development Program of the NRF funded by the Korean government, MSIP (grant no. 2015M3C7A1028926). We thank J. M. Hong for technical assistance and M. N. Park for helpful discussions.

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Author notes

  1. These authors contributed equally: Hee-Gyeong Yi, Young Hun Jeong.

Authors and Affiliations

  1. Department of Mechanical Engineering, POSTECH, Pohang, Korea

    Hee-Gyeong Yi, Mihyeon Bae & Dong-Woo Cho

  2. School of Mechanical Engineering, Kyungpook National University, Daegu, Korea

    Young Hun Jeong

  3. Department of Neurosurgery, Cancer Research Institute and Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Korea

    Yona Kim, Hyo Eun Moon & Sun Ha Paek

  4. Division of Integrative Biosciences and Biotechnology, POSTECH, Pohang, Korea

    Yeong-Jin Choi

  5. Powder & Ceramics Division, Korea Institute of Materials Science, Changwon, Korea

    Yeong-Jin Choi

  6. Department of Pathology, Seoul National University College of Medicine, Seoul, Korea

    Sung Hye Park

  7. School of Physical Sciences and Engineering, Anderson University, Anderson, IN, USA

    Kyung Shin Kang

  8. Department of Creative IT Engineering, POSTECH, Pohang, Korea

    Jinah Jang

  9. School of Interdisciplinary Bioscience and Bioengineering, POSTECH, Pohang, Korea

    Jinah Jang

  10. Department of Nuclear Medicine and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea

    Hyewon Youn

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Contributions

H.-G.Y., D.-W.C. and S.H.Paek conceived the concept of applying 3D-printing technology to establish the patient-specific GBM-on-a-chip. H.-G.Y. and Y.H.J. devised the working principles of the chip in detail. H.-G.Y. designed and performed most of the experiments. Y.K. performed the bioinformatics analyses and wrote the relevant results and methods. Y.-J.C. assisted with the characterization of the BdECM bioink, 3D printing of the GBMs-on-chips and performed the tumour spheroid invasion study. H.E.M. prepared for the IRB approval process to conduct the experiments using patient-derived GBM cells and organized the clinical information of the patients. S.H.Paek was the physician in charge of the GBM patients. S.H.Park performed the pathological detection and analysis of the patient-derived GBMs. K.S.K. contributed to the discussion for the initial stages of this work. M.B. assisted with the 3D printing and culturing of the GBMs-on-chips. J.J. contributed to the discussion for the revisions of the manuscript. H.Y. provided the genetic analysis data of patient-derived GBM cells. H.-G.Y., Y.H.J., S.H.Paek and D.-W.C. analysed the data. S.H.Paek also analysed the clinical observations and provided the relevant consultation. D.-W.C. provided overall guidance and supervised the project. H.-G.Y. and Y.H.J. wrote and edited the manuscript.

Corresponding authors

Correspondence to Sun Ha Paek or Dong-Woo Cho.

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Competing interests

Patents on the use of BdECM bioink in modelling cancer (patent no. 10-1860798, Korea) and on 3D printing of GBM-on-a-chip (patent no. 10-1803618, Korea) have been registered.

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Supplementary information

Supplementary Information

Supplementary figures, tables, methods and code.

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Supplementary Video 1

Cell-printing of a glioblastoma-on-a-chip.

Supplementary Video 2

Migration of glioblastoma cells to the surrounding matrix.

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Yi, HG., Jeong, Y.H., Kim, Y. et al. A bioprinted human-glioblastoma-on-a-chip for the identification of patient-specific responses to chemoradiotherapy. Nat Biomed Eng 3, 509–519 (2019). https://doi.org/10.1038/s41551-019-0363-x

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