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Challenges in Bio-fabrication of Organoid Cultures

  • Weijie Peng
  • Pallab Datta
  • Yang Wu
  • Madhuri Dey
  • Bugra Ayan
  • Amer Dababneh
  • Ibrahim T. Ozbolat
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1107)

Abstract

Three-dimensional (3D) organoids have shown advantages in cell culture over traditional two-dimensional (2D) culture, and have great potential in various applications of tissue engineering. However, there are limitations in current organoid fabrication technologies, such as uncontrolled size, poor reproductively, and inadequate complexity of organoids. In this chapter, we present the existing techniques and discuss the major challenges for 3D organoid biofabrication. Future perspectives on organoid bioprinting are also discussed, where bioprinting technologies are expected to make a major contribution in organoid fabrication, such as realizing mass production and constructing complex heterotypic tissues, and thus further advance the translational application of organoids in tissue engineering and regenerative medicine as well drug testing and pharmaceutics.

Keywords

3D culture Bioprinting Organoids Regenerative medicine Tissue engineering 

Abbreviations

2D

two-dimensional

3D

three-dimensional

adMSCs

Adipose-derived mesenchymal stem cells

ASCs

adipose-derived stem cell

BioLP

biological laser printing

CXCL

CXC ligand

CXCR

CXC receptor

DBB

droplet-based bioprinting

DPCs

dental pulp cells

EBB

extrusion-based bioprinting

ES

embryonic stem

HA

hyaluronic acid

HER2

human epidermal growth receptor

HGF

hepatocyte growth factor

HIF

hypoxia-inducible factor

HTC

hydrogel tissue constructs

HUVECs

human umbilical vein endothelial cells

LBB

laser-based bioprinting

MAPK

mitogen activate protein kinase

MAPLE-DW

matrix assisted pulsed laser evaporation-direct write

MCS

multicellular spheroids

MSCs

mesenchymal stem cells

pHEMA

poly (2-hydroxethyl methacrylate)

PI3K

phosphoinositide 3-kinase

PNIPAAm

poly (N-isopropylacrylamide)

PVA

polyvinyl alcohol

REF-52

Rat embryo fibroblasts

RGD

arginylglycylaspartic acid

SDF

stromal cell-derived factor

SPIONs

superparamagnetic iron oxide nanoparticles

TCD

tissue culture dish

TE

tissue engineering

TNFα

tumor necrosis factor

VEGF

vascular endothelial growth factor

Notes

Acknowledgements

This work has been supported by National Science Foundation Awards # 1624515, National Institutes of Health Grant #R21 CA224422-01A1, an ENGINE grant from Penn State, Diabetes in Action Research and Education Foundation grant # 426, a Wells Fargo grant, the China Scholarship Council 201308360128 and the Oversea Sailing Project from Jiangxi Association for Science and Technology. The authors also acknowledge Indian Council of Medical Research, Government of India, for financial assistance to P.D. The authors are grateful to the support from the Turkish Ministry of National Education for providing graduate scholarship to B.A.

References

  1. Abbasalizadeh S, Larijani MR, Samadian A, Baharvand H (2012) Bioprocess development for mass production of size-controlled human pluripotent stem cell aggregates in stirred suspension bioreactor. Tissue Eng Part C Methods 18(11):831–851Google Scholar
  2. Achilli TM, Meyer J, Morgan JR (2012) Advances in the formation, use and understanding of multi-cellular spheroids. Expert Opin Biol Ther 12(10):1347–1360Google Scholar
  3. Agastin S, Giang UB, Geng Y, Delouise LA, King MR (2011) Continuously perfused microbubble array for 3D tumor spheroid model. Biomicrofluidics 5(3):039901/1–039901/12Google Scholar
  4. Astashkina A, Mann B, Grainger DW (2012) A critical evaluation of in vitro cell culture models for high-throughput drug screening and toxicity. Pharmacol Ther 134(1):82–106.  https://doi.org/10.1016/j.pharmthera.2012.01.001 Elsevier Inc.Google Scholar
  5. Bartosh TJ, Ylöstalo JH, Mohammadipoor A, Bazhanov N, Coble K, Claypool K, Lee RH, Choi H, Prockop DJ (2010) Aggregation of human mesenchymal stromal cells (MSCs) into 3D spheroids enhances their antiinflammatory properties. Proc Natl Acad Sci 107(31):13724–13729Google Scholar
  6. Bhang SH, Cho S-W, La W-G, Lee T-J, Yang HS, Sun A-Y, Baek S-H, Rhie J-W, Kim B-S (2011) Angiogenesis in ischemic tissue produced by spheroid grafting of human adipose-derived stromal cells. Biomaterials 32(11):2734–2747Google Scholar
  7. Blakely AM, Manning KL, Tripathi A, Morgan JR (2015) Bio-pick, place, and perfuse: a new instrument for three-dimensional tissue engineering. Tissue Eng Part C Methods 21(7):737–746.  https://doi.org/10.1089/ten.tec.2014.0439 Google Scholar
  8. Bratt-Leal AM, Carpenedo RL, Ungrin MD, Zandstra PW, McDevitt TC (2011) Incorporation of biomaterials in multicellular aggregates modulates pluripotent stem cell differentiation. Biomaterials 32(1):48–56Google Scholar
  9. Chang TT, Hughes-Fulford M (2008) Monolayer and spheroid culture of human liver hepatocellular carcinoma cell line cells demonstrate distinct global gene expression patterns and functional phenotypes. Tissue Eng A 15(3):559–567Google Scholar
  10. Chen P, Güven S, Usta OB, Yarmush ML, Demirci U (2015) Biotunable acoustic node assembly of organoids. Adv Healthc Mater 4(13):1937–1943.  https://doi.org/10.1002/adhm.201500279 Google Scholar
  11. Clevers H (2016) Modeling development and disease with organoids. Cell 165(7):1586–1597.  https://doi.org/10.1016/j.cell.2016.05.082 Google Scholar
  12. Datta P, Ayan B, Ozbolat IT (2017) Bioprinting for vascular and vascularized tissue biofabrication. Acta Biomater 51:1.  https://doi.org/10.1016/j.actbio.2017.01.035 Google Scholar
  13. de Ridder L, Cornelissen M, de Ridder D (2000) Autologous spheroid culture: a screening tool for human brain tumour invasion. Crit Rev Oncol Hematol 36(2–3):107–122Google Scholar
  14. Dean DM, Napolitano AP, Youssef J, Morgan JR (2007) Rods, tori, and honeycombs: the directed self-assembly of microtissues with prescribed microscale geometries. FASEB J 21(14):4005–4012Google Scholar
  15. Dissanayaka WL, Zhu L, Hargreaves KM, Jin L, Zhang C (2015) In vitro analysis of scaffold-free prevascularized microtissue spheroids containing human dental pulp cells and endothelial cells. J Endod 41(5):663–670Google Scholar
  16. Edmondson R, Broglie JJ, Adcock AF, Yang L (2014) Three-dimensional cell culture systems and their applications in drug discovery and cell-based biosensors. Assay Drug Dev Technol 12(4):207–218.  https://doi.org/10.1089/adt.2014.573 Google Scholar
  17. Eglen RM, Randle DH (2015) Drug discovery Goes three-dimensional: goodbye to flat high-throughput screening? Assay Drug Dev Technol 13(5):262–265.  https://doi.org/10.1089/adt.2015.647 Google Scholar
  18. Fatehullah A, Tan SH, Barker N (2016) Organoids as an in vitro model of human development and disease. Nat Cell Biol 18(3):246–254 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights ReservedGoogle Scholar
  19. Fonoudi H, Ansari H, Abbasalizadeh S, Larijani MR, Kiani S, Hashemizadeh S, Zarchi AS, Bosman A, Blue GM, Pahlavan S (2015) A universal and robust integrated platform for the scalable production of human cardiomyocytes from pluripotent stem cells. Stem Cells Transl Med 4(12):1482–1494Google Scholar
  20. Frey O, Misun PM, Fluri DA, Hengstler JG, Hierlemann A (2014) Reconfigurable microfluidic hanging drop network for multi-tissue interaction and analysis. Nat Commun 5:1–11Google Scholar
  21. Fu CY, Tseng SY, Yang SM, Hsu L, Liu CH, Chang HY (2014) A microfluidic chip with a U-shaped microstructure array for multicellular spheroid formation, culturing and analysis. Biofabrication 6(1):015009/1–015009/9Google Scholar
  22. Gudupati H, Dey M, Ozbolat I (2016) A comprehensive review on droplet-based bioprinting: past, present and future. Biomaterials 102:20–42.  https://doi.org/10.1016/j.biomaterials.2016.06.012 Elsevier Ltd.Google Scholar
  23. Hölzl K, Lin S, Tytgat L, Van Vlierberghe S, Gu L, Ovsianikov A (2016) Bioink properties before, during and after 3D bioprinting. Biofabrication 8(3):32002Google Scholar
  24. Hospodiuk M, Dey M, Sosnoski D, Ozbolat IT (2017) The bioink: a comprehensive review on bioprintable materials. Biotechnol Adv 35(2):217–239.  https://doi.org/10.1016/j.biotechadv.2016.12.006 Elsevier Inc.Google Scholar
  25. Hospodiuk M, Dey M, Ayan B, Sosnoski D, Moncal KK, Wu Y, Ozbolat IT (2018) Sprouting angiogenesis in engineered pseudo islets. Biofabrication 10:035003Google Scholar
  26. Hsiao AY, Torisawa YS, Tung YC, Sud S, Taichman RS, Pienta KJ, Takayama S (2009) Microfluidic system for formation of PC-3 prostate cancer co-culture spheroids. Biomaterials 30(16):3020–3027Google Scholar
  27. Huang CP, Lu J, Seon H, Lee AP, Flanagan LA, Kim HY, Putnam AJ, Jeon NL (2009) Engineering microscale cellular niches for three-dimensional multicellular co-cultures. Lab Chip 9(12):1740–1748Google Scholar
  28. Ingram M, Techy GB, Saroufeem R, Yazan O, Narayan KS, Goodwin TJ, Spaulding GF (1997) Three-dimensional growth patterns of various human tumor cell lines in simulated microgravity of a NASA bioreactor. In Vitro Cell Dev Biol Anim 33(6):459–466Google Scholar
  29. Itoh M, Nakayama K, Noguchi R, Kamohara K, Furukawa K, Uchihashi K, Toda S, Oyama JI, Node K, Morita S (2015) Scaffold-free tubular tissues created by a bio-3D printer undergo remodeling and endothelialization when implanted in rat aortae. PLoS One 10(9):1–15.  https://doi.org/10.1371/journal.pone.0136681 Google Scholar
  30. Jakab K, Norotte C, Francoise M, Murphy K, Vunjak-Novakovic G, Forgacs F (2010) Tissue engineering by self-assembly and bio-printing of living cells. Biofabrication 2(2):022001/1–022001/14Google Scholar
  31. Jakab K, Norotte C, Damon B, Marga F, Neagu A, Besch-Williford CL, Kachurin A, Church KH, Park H, Mironov V, Markwald R, Vunjak-Novakovic G, Forgacs G (2008) Tissue engineering by self-assembly of cells printed into topologically defined structures. Tissue Eng Part A 14(3):413–421Google Scholar
  32. Jin HJ, Cho YH, Gu JM, Kim J, Oh YS (2011) A multicellular spheroid formation and extraction chip using removable cell trapping barriers. Lab Chip 11(1):115–119Google Scholar
  33. John M, Albert P, Andrew O, Aaron J (1977) A simplified method for production and growth of multicellular tumor spheroids. Cancer Res 37(1):3639–3643Google Scholar
  34. Karlsson H, Fryknäs M, Larsson R, Nygren P (2012) Loss of cancer drug activity in colon cancer HCT-116 cells during spheroid formation in a new 3-D spheroid cell culture system. Exp Cell Res 318(13):1577–1585Google Scholar
  35. Keller GM (1995) In vitro differentiation of embryonic stem cells. Curr Opin Cell Biol 7(6):862–869Google Scholar
  36. Kelm JM, Fussenegger M (2004) Microscale tissue engineering using gravity-enforced cell assembly. Trends Biotechnol 22(4):195–202Google Scholar
  37. Kelm JM, Timmins NE, Brown CJ, Fussenegger M, Nielsen LK (2003) Method for generation of homogeneous multicellular tumor spheroids applicable to a wide variety of cell types. Biotechnol Bioeng 83(2):173–180Google Scholar
  38. Kelm JM, Ehler E, Nielsen LK, Schlatter S, Perriard JC, Fussenegger M (2004) Design of artificial myocardial microtissues. Tissue Eng 10(1–2):201–214Google Scholar
  39. Kim JB (2005) Three-dimensional tissue culture models in cancer biology. Semin Cancer Biol 15(5):365–377Google Scholar
  40. Kim JA, Choi JH, Kim M, Rhee WJ, Son B, Jung HK, Park TH (2013) High-throughput generation of spheroids using magnetic nanoparticles for three-dimensional cell culture. Biomaterials 34(34):8555–8563.  https://doi.org/10.1016/j.biomaterials.2013.07.056 Elsevier Ltd.Google Scholar
  41. Kimlin LC, Casagrande G, Virador VM (2013) In vitro three-dimensional (3D) models in cancer research: an update. Mol Carcinog 52(3):167–182Google Scholar
  42. Kwon SH, Bhang SH, Jang H-K, Rhim T, Kim B-S (2015) Conditioned medium of adipose-derived stromal cell culture in three-dimensional bioreactors for enhanced wound healing. J Surg Res 194(1):8–17Google Scholar
  43. L’Heureux N, Pâquet S, Labbé R, Germain L, Auger FA (1998) A completely biological tissue-engineered human blood vessel. FASEB J 12(1):47–56Google Scholar
  44. Lam VY, Wakatsuki T (2011) Hydrogel tissue construct-based high-content compound screening. J Biomol Screen 16(1):120–128.  https://doi.org/10.1177/1087057110388269 Google Scholar
  45. Lam CRI, Wong HK, Nai S, Chua CK, Tan NS, Tan LP (2014) A 3D biomimetic model of tissue stiffness Interface for Cancer drug testing. Mol Pharm 11(7):2016–2021.  https://doi.org/10.1021/mp500059q Google Scholar
  46. Landry J, Bernier D, Ouellet C, Goyette R, Marceau N (1985) Spheroidal aggregate culture of rat liver cells: histotypic reorganization, biomatrix deposition, and maintenance of functional activities. J Cell Biol 101(3):914–923Google Scholar
  47. Laschke MW, Menger MD (2017) Life is 3D: boosting spheroid function for tissue engineering. Trends Biotechnol 35(2):133–144Google Scholar
  48. Laschke MW, Giebels C, Menger MD (2011) Vasculogenesis: a new piece of the endometriosis puzzle. Hum Reprod Update 17(5):628–636Google Scholar
  49. Laschke MW, Schank TE, Scheuer C, Kleer S, Schuler S, Metzger W, Eglin D, Alini M, Menger MD (2013) Three-dimensional spheroids of adipose-derived mesenchymal stem cells are potent initiators of blood vessel formation in porous polyurethane scaffolds. Acta Biomater 9(6):6876–6884Google Scholar
  50. Lee K-W, Lee SK, Joh J-W, Kim S-J, Lee B-B, Kim K-W, Lee KU (2004) Influence of pancreatic islets on spheroid formation and functions of hepatocytes in hepatocyte—pancreatic islet spheroid culture. Tissue Eng 10(7–8):965–977Google Scholar
  51. Lee BH, Kim MH, Lee JH, Seliktar D, Cho N-J, Tan LP (2015) Modulation of Huh7. 5 spheroid formation and functionality using modified PEG-based hydrogels of different stiffness. PLoS One 10(2):e0118123Google Scholar
  52. Leung BM, Lesher-Perez SC, Matsuoka T, Moraes C, Takayama S (2015) Media additives to promote spheroid circularity and compactness in hanging drop platform. Biomater Sci 3(2):336–344Google Scholar
  53. Lin RZ, Chou LF, Chien CC, Chang HY (2006) Dynamic analysis of hepatoma spheroid formation: roles of E-cadherin and beta1-integrin. Cell Tissue Res 324(3):411–422Google Scholar
  54. Lu H-F, Chua K-N, Zhang P-C, Lim W-S, Ramakrishna S, Leong KW, Mao H-Q (2005) Three-dimensional co-culture of rat hepatocyte spheroids and NIH/3T3 fibroblasts enhances hepatocyte functional maintenance. Acta Biomater 1(4):399–410Google Scholar
  55. Manley P, Lelkes P (2006) A novel real-time system to monitor cell aggregation and trajectories in rotating wall vessel bioreactors. J Biotechnol 125(3):416–424Google Scholar
  56. Marga F, Neagu A, Kosztin I, Forgacs G (2007) Developmental biology and tissue engineering. Birth Defects Res C Embryo Today 81(4):320–328Google Scholar
  57. McAllister TN, Maruszewski M, Garrido SA, Wystrychowski W, Dusserre N, Marini A, Zagalski K, Fiorillo A, Avila H, Manglano X, Antonelli J, Kocher A, Zembala M, Cierpka L, de la Fuente LM, L’Heureux N (2009) Effectiveness of haemodialysis access with an autologous tissue-engineered vascular graft: a multicentre cohort study. Lancet 373(9673):1440–1446.  https://doi.org/10.1016/S0140-6736(09)60248-8 Google Scholar
  58. Metzger W, Sossong D, Bächle A, Pütz N, Wennemuth G, Pohlemann T, Oberringer M (2011) The liquid overlay technique is the key to formation of co-culture spheroids consisting of primary osteoblasts, fibroblasts and endothelial cells. Cytotherapy 13(8):1000–1012Google Scholar
  59. Mineda K, Feng J, Ishimine H, Takada H, Kuno S, Kinoshita K, Kanayama K, Kato H, Mashiko T, Hashimoto I (2015) Therapeutic potential of human adipose-derived stem/stromal cell microspheroids prepared by three-dimensional culture in non-cross-linked hyaluronic acid gel. Stem Cells Transl Med 4(12):1511–1522Google Scholar
  60. Mironov V, Visconti P, Kasyanov V, Forgacs G, Drake J, Markwald R (2009) Organ printing: tissue spheroids as building blocks. Biomaterials 30(12):2164–2174Google Scholar
  61. Mironov V, Khesuani YD, Bulanova EA, Koudan EV, Parfenov VA, Knyazeva AD, Mitryashkin AN, Replyanski N, Kasyanov VA, Pereira DASF (2016) Patterning of tissue spheroids biofabricated from human fibroblasts on the surface of electrospun polyurethane matrix using 3D bioprinter. Int J Bioprint 2(1):45–52.  https://doi.org/10.18063/IJB.2016.01.007 Google Scholar
  62. Murakami S, Ijima H, Ono T, Kawakami K (2004) Development of co-culture system of hepatocytes with bone marrow cells for expression and maintenance of hepatic functions. Int J Artif Organs 27(2):118–126Google Scholar
  63. Napolitano AP, Chai P, Dean DM, Morgan JR (2007) Dynamics of the self-assembly of complex cellular aggregates on micro-molded nonadhesive hydrogels. Tissue Eng 13(8):2087–2094Google Scholar
  64. Norotte C, Marga F, Niklason L, Forgacs G (2010) Scaffold-free vascular tissue engineering using bioprinting. Biomaterials 30(30):5910–5917.  https://doi.org/10.1016/j.biomaterials.2009.06.034.Scaffold-Free Google Scholar
  65. Ozbolat IT, Hospodiuk M (2016) Current advances and future perspectives in extrusion-based bioprinting. Biomaterials 76:321–343.  https://doi.org/10.1016/j.biomaterials.2015.10.076 Elsevier Ltd.Google Scholar
  66. Ozbolat IT, Yu Y (2013) Bioprinting toward organ fabrication: challenges and future trends. IEEE Trans Biomed Eng 60(691–699):691–699.  https://doi.org/10.1109/TBME.2013.2243912 Google Scholar
  67. Ozbolat IT, Peng W, Ozbolat V (2016) Application areas of 3D bioprinting. Drug Discov Today 21:1257.  https://doi.org/10.1016/j.drudis.2016.04.006 Elsevier Ltd.Google Scholar
  68. Ozbolat IT, Moncal KK, Gudapati H (2017) Evaluation of bioprinter technologies. Addit Manuf 13:179–200.  https://doi.org/10.1016/j.addma.2016.10.003 Google Scholar
  69. Park KH, Na K, Sung WK, Sung YJ, Kyu HP, Chung HM (2005) Phenotype of hepatocyte spheroids behavior within thermo-sensitive poly(NiPAAm-co-PEG-g-GRGDS) hydrogel as a cell delivery vehicle. Biotechnol Lett 27(15):1081–1086.  https://doi.org/10.1007/s10529-005-8453-0 Google Scholar
  70. Peng W, Unutmaz D, Ozbolat IT (2016) Bioprinting towards physiologically relevant tissue models for pharmaceutics. Trends Biotechnol 34(9):722–732.  https://doi.org/10.1016/j.tibtech.2016.05.013 Google Scholar
  71. Peng W, Datta P, Ayan B, Ozbolat V, Sosnoski D (2017) Acta Biomaterialia 3D bioprinting for drug discovery and development in pharmaceutics. Acta Biomater 57:26–46.  https://doi.org/10.1016/j.actbio.2017.05.025 Acta Materialia Inc.Google Scholar
  72. Pickl M, Ries CH (2009) Comparison of 3D and 2D tumor models reveals enhanced HER2 activation in 3D associated with an increased response to trastuzumab. Oncogene 28(3):461–468Google Scholar
  73. Qihao Z, Xigu C, Guanghui C, Weiwei Z (2007) Spheroid formation and differentiation into hepatocyte-like cells of rat mesenchymal stem cell induced by co-culture with liver cells. DNA Cell Biol 26(7):497–503Google Scholar
  74. Rezende RA, Pereira FDAS, Kasyanov V, Kemmoku DT, Maia I, da Silva JVL, Mironov V (2013) Scalable biofabrication of tissue spheroids for organ printing. Procedia CIRP 5(1):276–281Google Scholar
  75. Richard M, Kim C, Daniel J, Daniel K, Robert S (2001) Dynamics of spheroid self-assembly in liquid-overlay culture of DU 145 human prostate Cancer cells. Biotechnol Bioeng 72(6):579–591Google Scholar
  76. Robert L (2007) Editorial: tissue engineering: perspectives, challenges, and future directions. Tissue Eng 13(1):1–2Google Scholar
  77. Sachlos E, Czernuszka JT (2003) Making tissue engineering scaffolds work. Review: the application of solid freeform fabrication technology to the production of tissue engineering scaffolds. Eur Cell Mater 30(5):29–39Google Scholar
  78. Santini MT, Rainaldi G, Indovina PL (1998) Multicellular tumour spheroids in radiation biology. Int J Radiat Bio 75(7):787–799Google Scholar
  79. Sebastian A, Buckle AM, Markx GH (2007) Tissue engineering with electric fields: immobilization of mammalian cells in multilayer aggregates using dielectrophoresis. Biotechnol Bioeng 98(3):694–700.  https://doi.org/10.1002/bit.21416 Google Scholar
  80. Shearier E, Xing Q, Qian Z, Zhao F (2016) Physiologically low oxygen enhances biomolecule production and stemness of mesenchymal stem cell spheroids. Tissue Eng Part C Methods 22(4):360–369Google Scholar
  81. Shi Y, Ma J, Zhang X, Li H, Jiang L, Qin J (2015) Hypoxia combined with spheroid culture improves cartilage specific function in chondrocytes. Integr Biol 7(3):289–297Google Scholar
  82. Skardal A, Smith L, Bharadwaj S, Atala A, Soker S, Zhang Y (2012) Tissue specific synthetic ECM hydrogels for 3D in vitro maintenance of hepatocyte function. Biomaterials 33:4565.  https://doi.org/10.1016/j.biomaterials.2012.03.034 Google Scholar
  83. Skiles ML, Sahai S, Rucker L, Blanchette JO (2013) Use of culture geometry to control hypoxia-induced vascular endothelial growth factor secretion from adipose-derived stem cells: optimizing a cell-based approach to drive vascular growth. Tissue Eng A 19(21–22):2330–2338Google Scholar
  84. Stampella A, Papi A, Rizzitelli G, Costantini M, Colosi C, Barbetta A, Massimi M, Devirgiliis LC, Dentini M (2013) Synthesis and characterization of a novel poly(vinyl alcohol) 3D platform for the evaluation of hepatocytes’ response to drug administration. J Mater Chem B 1(24):3083–3098.  https://doi.org/10.1039/c3tb20432d Google Scholar
  85. Sutherland RM (1988) Cell and environment interactions in tumor microregions: the multicell spheroid model. Science 240(4849):177–184Google Scholar
  86. Takezawa T, Yamazaki M, Mori Y, Yonaha T, Yoshizato K (1992) Morphological and immuno-cytochemical characterization of a hetero-spheroid composed of fibroblasts and hepatocytes. J Cell Sci 101(3):495–501Google Scholar
  87. Tan PHS, Chia SS, Toh SL, Goh JCH, Nathan SS (2014) The dominant role of IL-8 as an Angiogenic driver in a three-dimensional physiological tumor construct for drug testing. Tissue Eng A 20(11–12):1758–1766.  https://doi.org/10.1089/ten.tea.2013.0245 Google Scholar
  88. Thomas RJ, Bhandari R, Barrett DA, Bennett AJ, Fry JR, Powe D, Thomson BJ, Shakesheff KM (2005) The effect of three-dimensional co-culture of hepatocytes and hepatic stellate cells on key hepatocyte functions in vitro. Cells Tissues Organs 181(2):67–79Google Scholar
  89. Timmins NE, Nielsen LK (2007) Generation of multicellular tumor spheroids by the hanging-drop method. Methods Mol Med 140(1):141–151Google Scholar
  90. Timmins NE, Dietmair S, Nielsen LK (2004) Hanging-drop multicellular spheroids as a model of tumour angiogenesis. Angiogenesis 7(2):97–103Google Scholar
  91. Timothy R, Frank A (2014) Bioprocessing of tissues using cellular spheroids. J Bioprocess Biotechniques 4(2):1000e112/1–1000e112/4Google Scholar
  92. Toh YC, Zhang C, Zhang J, KY M, Chang S, Samper VD, Noort D, Hutmacher DW, Yu H (2007) A novel 3D mammalian cell perfusion-culture system in microfluidic channels. Lab Chip 7(3):302Google Scholar
  93. Tseng T-C, Hsu S (2014) Substrate-mediated nanoparticle/gene delivery to MSC spheroids and their applications in peripheral nerve regeneration. Biomaterials 35(9):2630–2641Google Scholar
  94. Tung YC, Hsiao AY, Allen SG, Torisawa YS, Ho M, Takayama S (2011) High-throughput 3D spheroid culture and drug testing using a 384 hanging drop array. Analyst 136(3):473–478.  https://doi.org/10.1039/c0an00609b Google Scholar
  95. Vosough M, Omidinia E, Kadivar M, Shokrgozar M-A, Pournasr B, Aghdami N, Baharvand H (2013) Generation of functional hepatocyte-like cells from human pluripotent stem cells in a scalable suspension culture. Stem Cells Dev 22(20):2693–2705Google Scholar
  96. Walser R, Metzger W, Görg A, Pohlemann T, Menger MD, Laschke MW (2013) Generation of co-culture spheroids as vascularisation units for bone tissue engineering. Eur Cell Mater 26:222–233Google Scholar
  97. Wartenberg M, Dönmez F, Ling FC, Acker H, Hescheler J, Sauer H (2001) Tumor-induced angiogenesis studied in confrontation cultures of multicellular tumor spheroids and embryoid bodies grown from pluripotent embryonic stem cells. FASEB J 15(6):995–1005Google Scholar
  98. Whatley BR, Li X, Zhang N, Wen X (2014) Magnetic-directed patterning of cell spheroids. J Biomed Mater Res A 102(5):1537–1547.  https://doi.org/10.1002/jbm.a.34797 Google Scholar
  99. Wittig C, Laschke MW, Scheuer C, Menger MD (2013) Incorporation of bone marrow cells in pancreatic pseudoislets improves posttransplant vascularization and endocrine function. PLoS One 8(7):e69975Google Scholar
  100. Wu LY, Di Carlo D, Lee LP (2008) Microfluidic self-assembly of tumor spheroids for anticancer drug discovery. Biomed Microdevices 10(2):197–202Google Scholar
  101. Xinaris C, Brizi V, Remuzzi G (2015) Organoid models and applications in biomedical research. Nephron 130(3):191–199.  https://doi.org/10.1159/000433566 Google Scholar
  102. Xu Y, Shi T, Xu A and Zhang L (2015) 3D spheroid culture enhances survival and therapeutic capacities of MSCs injected into ischemic kidney. J Cell Mol MedGoogle Scholar
  103. Yang S, Leong KF, Du Z, Chua CK (2001) The design of Scaffolds for use in tissue engineering. Tissue Eng 7(6):679–689Google Scholar
  104. Yeh H-Y, Liu B-H, Sieber M, Hsu S (2014) Substrate-dependent gene regulation of self-assembled human MSC spheroids on chitosan membranes. BMC Genomics 15(1):10Google Scholar
  105. Yin X, Mead BE, Safaee H, Langer R, Karp JM, Levy O (2016) Stem cell organoid engineering. Cell Stem Cell 18(1):25–38.  https://doi.org/10.1016/j.stem.2015.12.005 Google Scholar
  106. Yu Y, Moncal KK, Li J, Peng W, Rivero I, Martin JA, Ozbolat IT (2016) Three-dimensional bioprinting using self-assembling scalable scaffold-free “tissue strands” as a new bioink. Sci Rep. Nature Publishing Group 6(1):28714.  https://doi.org/10.1038/srep28714

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Weijie Peng
    • 1
    • 2
    • 3
  • Pallab Datta
    • 4
  • Yang Wu
    • 3
    • 5
  • Madhuri Dey
    • 5
    • 6
  • Bugra Ayan
    • 3
    • 5
  • Amer Dababneh
    • 7
  • Ibrahim T. Ozbolat
    • 3
    • 5
    • 8
    • 9
  1. 1.Jiangxi Academy of Medical ScienceHospital of Nanchang UniversityNanchangChina
  2. 2.Department of PharmacologyNanchang UniversityNanchangChina
  3. 3.Engineering Science and Mechanics DepartmentPenn State UniversityUniversity ParkUSA
  4. 4.Centre for Healthcare Science and TechnologyIndian Institute of Engineering Science and Technology ShibpurHowrahIndia
  5. 5.The Huck Institutes of the Life SciencesPenn State UniversityUniversity ParkUSA
  6. 6.Department of ChemistryPenn State UniversityUniversity ParkUSA
  7. 7.Center for Computer-Aided Design, College of EngineeringUniversity of IowaIowa CityUSA
  8. 8.Biomedical Engineering DepartmentPenn State UniversityUniversity ParkUSA
  9. 9.Materials Research InstitutePenn State UniversityUniversity ParkUSA

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