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Bio-3D Printed Organs as Drug Testing Tools

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Kenzan Method for Scaffold-Free Biofabrication

Abstract

Evaluations of side effects and therapeutic efficacy are key steps in drug development. This process is time-consuming and costly and is often discontinued owing to differences in the drug response between animal models and humans, necessitating alternative approaches to animal models. One promising alternative for evaluations of therapeutic efficacy and adverse reactions is human induced pluripotent stem cells (iPS cells). Human iPS cells can differentiate into various cell types. Furthermore, using iPS cells derived from patients, useful human disease models can be established for the development of drugs against a wide range of diseases. Although cells are cultured on a culture dish, spheroids and organoids, which are aggregates of cells with tissue-specific functions, develop to mimic the three-dimensional (3D) cell environment. Bio-3D printing has been developed to generate scaffold-free constructs by using spheroids according to a desired design. The combination of organoids and bio-3D printing is expected to enable the fabrication of constructs with tissue-specific functions for drug testing. In this chapter, we discuss the current status of drug development and tissue engineering techniques as well as the fabrication of spheroids or organoids and applications for drug evaluation. Finally, we discuss the existing challenges and future prospects.

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References

  1. Shanks N, Greek R, Greek J (2009) Are animal models predictive for humans? Philos Ethics Humanit Med 15(4):2

    Article  Google Scholar 

  2. Perel P, Roberts I, Sena E et al (2007) Comparison of treatment effects between animal experiments and clinical trials: systematic review. BMJ 334(7586):197

    Article  Google Scholar 

  3. van der Worp HB, Howells DW, Sena ES et al (2010) Can animal models of disease reliably inform human studies? PLoS Med 7(3):e1000245

    Article  Google Scholar 

  4. Seruga B, Ocana A, Amir E et al (2015) Failures in phase III: causes and consequences. Clin Cancer Res 21(20):4552–4560

    Article  Google Scholar 

  5. Gwathmey JK, Tsaioun K, Hajjar RJ (2009) Cardionomics: a new integrative approach for screening cardiotoxicity of drug candidates. Expert Opin Drug Metab Toxicol 5:647–660

    Article  Google Scholar 

  6. Ferri N, Siegl P, Corsini A et al (2013) Drug attrition during pre-clinical and clinical development: understanding and managing drug-induced cardiotoxicity. Pharmacol Ther 138:470–484

    Article  Google Scholar 

  7. Katarey D, Verma S (2016) Drug-induced liver injury. Clin Med (Lond) 16(Suppl 6):s104–s109

    Article  Google Scholar 

  8. Gao Z, Chen Y, Cai X et al (2017) Predict drug permeability to blood-brain-barrier from clinical phenotypes: drug side effects and drug indications. Bioinformatics 33(6):901–908

    Google Scholar 

  9. Astashkina AI, Mann BK, Prestwich GD et al (2012) Comparing predictive drug nephrotoxicity biomarkers in kidney 3-D primary organoid culture and immortalized cell lines. Biomaterials 33(18):4712–4721

    Article  Google Scholar 

  10. Takahashi K, Tanabe K, Ohnuki M et al (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131(5):861–872

    Article  Google Scholar 

  11. Si-Tayeb K, Noto FK, Nagaoka M et al (2010) Highly efficient generation of human hepatocyte-like cells from induced pluripotent stem cells. Hepatology 51(1):297–305

    Article  Google Scholar 

  12. Zwi L, Caspi O, Arbel G et al (2009) Cardiomyocyte differentiation of human induced pluripotent stem cells. Circulation 120(15):1513–1523

    Article  Google Scholar 

  13. Mungenast AE, Siegert S, Tsai LH (2016) Modeling Alzheimer’s disease with human induced pluripotent stem (iPS) cells. Mol Cell Neurosci 73:13–31

    Article  Google Scholar 

  14. Asakura K, Hayashi S, Ojima A et al (2015) Improvement of acquisition and analysis methods in multi-electrode array experiments with iPS cell-derived cardiomyocytes. J Pharmacol Toxicol Methods 75:17–26

    Article  Google Scholar 

  15. Odawara A, Matsuda N, Ishibashi Y et al (2018) Toxicological evaluation of convulsant and anticonvulsant drugs in human induced pluripotent stem cell-derived cortical neuronal networks using an MEA system. Sci Rep 8(1):10416

    Article  Google Scholar 

  16. Kang SJ, Lee HM, Park YI et al (2016) Chemically induced hepatotoxicity in human stem cell-induced hepatocytes compared with primary hepatocytes and HepG2. Cell Biol Toxicol 32(5):403–417

    Article  Google Scholar 

  17. Pampaloni F, Reynaud EG, Stelzer EH (2007) The third dimension bridges the gap between cell culture and live tissue. Nat Rev Mol Cell Biol 8(10):839–845

    Article  Google Scholar 

  18. Hansen A, Eder A, Bönstrup M et al (2010) Development of a drug screening platform based on engineered heart tissue. Circ Res 107(1):35–44

    Article  Google Scholar 

  19. Kasuya J, Sudo R, Tamogami R et al (2012) Reconstruction of 3D stacked hepatocyte tissues using degradable, microporous poly(d,l-lactide-co-glycolide) membranes. Biomaterials 33(9):2693–2700

    Article  Google Scholar 

  20. Stoppel WL, Kaplan DL, Black LD (2016) Electrical and mechanical stimulation of cardiac cells and tissue constructs. Adv Drug Deliv Rev 96:135–155

    Article  Google Scholar 

  21. Nugraha B, Hong X, Mo X et al (2011) Galactosylated cellulosic sponge for multi-well drug safety testing. Biomaterials 32(29):6982–6994

    Article  Google Scholar 

  22. Lin RZ, Chang HY (2008) Recent advances in three-dimensional multicellular spheroid culture for biomedical research. Biotechnol J 3(9–10):1172–1184

    Article  Google Scholar 

  23. Moldovan NI, Hibino N, Nakayama K (2017) Principles of the Kenzan method for robotic cell spheroid-based three-dimensional bioprinting. Tissue Eng Part B Rev 23(3):237–244

    Article  Google Scholar 

  24. Itoh M, Mukae Y, Kitsuka T et al (2019) Development of an immunodeficient pig model allowing long-term accommodation of artificial human vascular tubes. Nat Commun 10(1):2244

    Article  Google Scholar 

  25. Yurie H, Ikeguchi R, Aoyama T et al (2017) The efficacy of a scaffold-free Bio 3D conduit developed from human fibroblasts on peripheral nerve regeneration in a rat sciatic nerve model. PLoS One 12(2):e0171448

    Article  Google Scholar 

  26. Mitsuzawa S, Ikeguchi R, Aoyama T et al (2019) The efficacy of a scaffold-free bio 3D conduit developed from autologous dermal fibroblasts on peripheral nerve regeneration in a canine ulnar nerve injury model: a preclinical proof-of-concept study. Cell Transplant 28(9–10):1231–1241

    Article  Google Scholar 

  27. Zhang XY, Yanagi Y, Sheng Z et al (2018) Regeneration of diaphragm with bio-3D cellular patch. Biomaterials 167:1–14

    Article  Google Scholar 

  28. Imamura T, Shimamura M, Ogawa T et al (2018) Biofabricated structures reconstruct functional urinary bladders in radiation-injured rat bladders. Tissue Eng Part A 24(21–22):1574–1587

    Article  Google Scholar 

  29. Yamasaki A, Kunitomi Y, Murata D et al (2019) Osteochondral regeneration using constructs of mesenchymal stem cells made by bio three-dimensional printing in mini-pigs. J Orthop Res 37(6):1398–1408

    Article  Google Scholar 

  30. Itoh M, Nakayama K, Noguchi R et al (2015) Scaffold-free tubular tissues created by a Bio-3D printer undergo remodeling and endothelialization when implanted in rat aortae. PLoS One 10(9):e0136681

    Article  Google Scholar 

  31. Yanagi Y, Nakayama K, Taguchi T et al (2017) In vivo and ex vivo methods of growing a liver bud through tissue connection. Sci Rep 7(1):14085

    Article  Google Scholar 

  32. Ong CS, Fukunishi T, Zhang H et al (2017) Biomaterial-free three-dimensional bioprinting of cardiac tissue using human induced pluripotent stem cell derived cardiomyocytes. Sci Rep 7(1):4566

    Article  Google Scholar 

  33. Sutherland RM, McCredie JA, Inch WR (1971) Growth of multicell spheroids in tissue culture as a model of nodular carcinomas. J Natl Cancer Inst 46(1):113–120

    Google Scholar 

  34. Lancaster MA, Knoblich JA (2014) Organogenesis in a dish: modeling development and disease using organoid technologies. Science 345(6194):1247125

    Article  Google Scholar 

  35. Takebe T, Wells JM (2019) Organoids by design. Science 364(6444):956–959

    Article  Google Scholar 

  36. Takebe T, Enomura M, Yoshizawa E et al (2015) Vascularized and complex organ buds from diverse tissues via mesenchymal cell-driven condensation. Cell Stem Cell 16(5):556–565

    Article  Google Scholar 

  37. Takayama K, Kawabata K, Nagamoto Y et al (2013) 3D spheroid culture of hESC/hiPSC-derived hepatocyte-like cells for drug toxicity testing. Biomaterials 34(7):1781–1789

    Article  Google Scholar 

  38. Takebe T, Sekine K, Enomura M et al (2013) Vascularized and functional human liver from an iPSC-derived organ bud transplant. Nature 499(7459):481–484

    Article  Google Scholar 

  39. Heist EK, Ruskin JN (2010) Drug-induced arrhythmia. Circulation 122(14):1426–1435

    Article  Google Scholar 

  40. Beauchamp P, Moritz W, Kelm JM et al (2014) Development and characterization of a scaffold-free 3D spheroid model of iPSC-derived human cardiomyocytes. Tissue Eng Part C Methods 21(8):852–861

    Article  Google Scholar 

  41. Ravenscroft SM, Pointon A, Williams AW et al (2016) Cardiac non-myocyte cells show enhanced pharmacological function suggestive of contractile maturity in stem cell derived cardiomyocyte microtissues. Toxicol Sci 152(1):99–112

    Article  Google Scholar 

  42. Tomlinson L, Lu ZQ, Bentley RA et al (2019) Attenuation of doxorubicin-induced cardiotoxicity in a human in vitro cardiac model by the induction of the NRF-2 pathway. Biomed Pharmacother 112:108637

    Article  Google Scholar 

  43. Shimauchi T, Numaga-Tomita T, Ito T et al (2017) TRPC3-Nox2 complex mediates doxorubicin-induced myocardial atrophy. JCI Insight 2(15). pii: 93358

    Google Scholar 

  44. Ran S, Li Y, Zink D et al (2014) Supervised prediction of drug-induced nephrotoxicity based on interleukin-6 and -8 expression levels. BMC Bioinformatics 15(Suppl 16):S16

    Google Scholar 

  45. Takasato M, Er PX, Becroft M et al (2014) Directing human embryonic stem cell differentiation towards a renal lineage generates a self-organizing kidney. Nat Cell Biol 16(1):118–126

    Article  Google Scholar 

  46. Takasato M, Er PX, Chiu HS et al (2016) Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis. Nature 536(7615):238

    Article  Google Scholar 

  47. Freedman BS, Brooks CR, Lam AQ et al (2015) Modelling kidney disease with CRISPR-mutant kidney organoids derived from human pluripotent epiblast spheroids. Nat Commun 6:8715

    Article  Google Scholar 

  48. Hale LJ, Howden SE, Phipson B et al (2018) 3D organoid-derived human glomeruli for personalised podocyte disease modelling and drug screening. Nat Commun 9(1):5167

    Article  Google Scholar 

  49. Sun T, Hevner RF (2014) Growth and folding of the mammalian cerebral cortex: from molecules to malformations. Nat Rev Neurosci 15(4):217–232

    Article  Google Scholar 

  50. Nakano T, Ando S, Takata N et al (2012) Self-formation of optic cups and storable stratified neural retina from human ESCs. Cell Stem Cell 10(6):771–785

    Article  Google Scholar 

  51. Eiraku M, Watanabe K, Matsuo-Takasaki M (2008) Self-organized formation of polarized cortical tissues from ESCs and its active manipulation by extrinsic signals. Cell Stem Cell 3(5):519–532

    Article  Google Scholar 

  52. Lancaster MA, Renner M, Martin CA et al (2013) Cerebral organoids model human brain development and microcephaly. Nature 501(7467):373–379

    Article  Google Scholar 

  53. Sakaguchi H, Ozaki Y, Ashida T et al (2019) Self-organized synchronous calcium transients in a cultured human neural network derived from cerebral organoids. Stem Cell Rep 13(3):458–473

    Article  Google Scholar 

  54. Ogura T, Sakaguchi H, Miyamoto S et al (2018) Three-dimensional induction of dorsal, intermediate and ventral spinal cord tissues from human pluripotent stem cells. Development 145(16). pii: dev162214

    Google Scholar 

  55. Qian X, Jacob F, Song MM et al (2018) Generation of human brain region-specific organoids using a miniaturized spinning bioreactor. Nat Protoc 13(3):565–580

    Article  Google Scholar 

  56. Nzou G, Wicks RT, Wicks EE et al (2018) Human cortex spheroid with a functional blood brain barrier for high-throughput neurotoxicity screening and disease modeling. Sci Rep 8(1):7413

    Article  Google Scholar 

  57. Gonzalez C, Armijo E, Bravo-Alegria J et al (2018) Modeling amyloid beta and tau pathology in human cerebral organoids. Mol Psychiatry 23(12):2363–2374

    Article  Google Scholar 

  58. Billat PA, Roger E, Faure S et al (2017) Models for drug absorption from the small intestine: where are we and where are we going? Drug Discov Today 22(5):761–775

    Article  Google Scholar 

  59. Fair KL, Colquhoun J, Hannan NRF (2018) Intestinal organoids for modelling intestinal development and disease. Philos Trans R Soc Lond Ser B Biol Sci 373(1750). pii: 20170217

    Google Scholar 

  60. Spence JR, Mayhew CN, Rankin SA et al (2011) Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro. Nature 470(7332):105–109

    Article  Google Scholar 

  61. Panek M, Grabacka M, Pierzchalska M (2018) The formation of intestinal organoids in a hanging drop culture. Cytotechnology 70(3):1085–1095

    Article  Google Scholar 

  62. Lu W, Rettenmeier E, Paszek M et al (2017) Crypt organoid culture as an in vitro model in drug metabolism and cytotoxicity studies. Drug Metab Dispos 45(7):748–754

    Article  Google Scholar 

  63. Kizawa H, Nagao E, Shimamura M et al (2017) Scaffold-free 3D bio-printed human liver tissue stably maintains metabolic functions useful for drug discovery. Biochem Biophys Rep 10:186–191

    Google Scholar 

  64. Taniguchi D, Matsumoto K, Tsuchiya T et al (2018) Scaffold-free trachea regeneration by tissue engineering with bio-3D printing. Interact Cardiovasc Thorac Surg 26(5):745–752

    Article  Google Scholar 

  65. Arai K, Murata D, Verissimo AR et al (2018) Fabrication of scaffold-free tubular cardiac constructs using a Bio-3D printer. PLoS One 13(12):e0209162

    Article  Google Scholar 

  66. van Pel DM, Harada K, Song D et al (2018) Modelling glioma invasion using 3D bioprinting and scaffold-free 3D culture. J Cell Commun Signal 12(4):723–730

    Article  Google Scholar 

  67. Birey F, Andersen J, Makinson CD et al (2017) Assembly of functionally integrated human forebrain spheroids. Nature 545(7652):54–59

    Article  Google Scholar 

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Authors and Affiliations

  1. Center for Regenerative Medicine Research, Faculty of Medicine, Saga University, Saga, Japan

    Kenichi Arai & Koichi Nakayama

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  1. Kenichi Arai
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  2. Koichi Nakayama
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Correspondence to Kenichi Arai .

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  1. Center of Regenerative Medicine Research, Faculty of Medicine, Saga University, Saga, Japan

    Koichi Nakayama

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Arai, K., Nakayama, K. (2021). Bio-3D Printed Organs as Drug Testing Tools. In: Nakayama, K. (eds) Kenzan Method for Scaffold-Free Biofabrication. Springer, Cham. https://doi.org/10.1007/978-3-030-58688-1_12

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  • DOI: https://doi.org/10.1007/978-3-030-58688-1_12

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