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Published Online: 15 May 2014

Three-Dimensional Cell Culture Systems and Their Applications in Drug Discovery and Cell-Based Biosensors

Publication: ASSAY and Drug Development Technologies
Volume 12, Issue Number 4

Abstract

Three-dimensional (3D) cell culture systems have gained increasing interest in drug discovery and tissue engineering due to their evident advantages in providing more physiologically relevant information and more predictive data for in vivo tests. In this review, we discuss the characteristics of 3D cell culture systems in comparison to the two-dimensional (2D) monolayer culture, focusing on cell growth conditions, cell proliferation, population, and gene and protein expression profiles. The innovations and development in 3D culture systems for drug discovery over the past 5 years are also reviewed in the article, emphasizing the cellular response to different classes of anticancer drugs, focusing particularly on similarities and differences between 3D and 2D models across the field. The progression and advancement in the application of 3D cell cultures in cell-based biosensors is another focal point of this review.

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References

1.
Birgersdotter A, Sandberg R, Ernberg I: Gene expression perturbation in vitro—a growing case for three-dimensional (3D) culture systems. Semin Cancer Biol 2005;15:405–412.
2.
Weaver VM, Petersen OW, Wang F, et al.: Reversion of the malignant phenotype of human breast cells in three-dimensional culture and in vivo by integrin blocking antibodies. J Cell Biol 1997;137:231–245.
3.
Bhadriraju K, Chen CS: Engineering cellular microenvironments to improve cell-based drug testing. Drug Discov Today 2002;7:612–620.
4.
DiMasi JA, Grabowski HG: Economics of new oncology drug development. J Clin Oncol 2007;25:209–216.
5.
Breslin S, O'Driscoll L: Three-dimensional cell culture: the missing link in drug discovery. Drug Discov Today 2013;18:240–249.
6.
Hopkins AL: Network pharmacology: the next paradigm in drug discovery. Nat Chem Biol 2008;4:682–690.
7.
Kola I: The state of innovation in drug development. Clin Pharmacol Ther 2008;83:227–230.
8.
Baharvand H, Hashemi SM, Kazemi Ashtiani S, Farrokhi A: Differentiation of human embryonic stem cells into hepatocytes in 2D and 3D culture systems in vitro. Int J Dev Biol 2006;50:645–652.
9.
Benya PD, Shaffer JD: Dedifferentiated chondrocytes reexpress the differentiated collagen phenotype when cultured in agarose gels. Cell 1982;30:215–224.
10.
Nelson CM, Bissell MJ: Modeling dynamic reciprocity: engineering three-dimensional culture models of breast architecture, function, and neoplastic transformation. Semin Cancer Bio. 2005;15:342–352.
11.
Shield K, Ackland ML, Ahmed N, Rice GE: Multicellular spheroids in ovarian cancer metastases: biology and pathology. Gynecol Oncol 2009;113:143–148.
12.
Zietarska M, Maugard CM, Filali-Mouhim A, et al.: Molecular description of a 3D in vitro model for the study of epithelial ovarian cancer (EOC). Mol Carcinog 2007;46:872–885.
13.
Lee J, Cuddihy MJ, Kotov NA: Three-dimensional cell culture matrices: state of the art. Tissue Eng Part B Rev 2008;14:61–86.
14.
Justice BA, Badr NA, Felder RA: 3D cell culture opens new dimensions in cell-based assays. Drug Discov Today 2009;14:102–107.
15.
Reininger-Mack A, Thielecke H, Robitzki AA: 3D-biohybrid systems: applications in drug screening. Trends Biotechnol 2002;20:56–61.
16.
Sun T, Jackson S, Haycock JW, MacNeil S: Culture of skin cells in 3D rather than 2D improves their ability to survive exposure to cytotoxic agents. J Biotechnol 2006;122:372–381.
17.
Gurski L, Petrelli N, Jia X, Farach-Carson M: Three-dimensional matrices for anti-cancer drug testing and development. Oncol Issues 2010;25:20–25.
18.
Tibbitt MW, Anseth KS: Hydrogels as extracellular matrix mimics for 3D cell culture. Biotechnol Bioeng 2009;103:655–663.
19.
Rimann M, Graf-Hausner U: Synthetic 3D multicellular systems for drug development. Curr Opin Biotechnol 2012;23:803–809.
20.
Huang H, Ding Y, Sun XS, Nguyen TA: Peptide hydrogelation and cell encapsulation for 3D culture of MCF-7 breast cancer cells. PLoS One 2013;8:e59482.
21.
Huh D, Hamilton GA, Ingber DE: From 3D cell culture to organs-on-chips. Trends Cell Biol 2011;21:745–754.
22.
Kim D-H, Provenzano PP, Smith CL, Levchenko A: Matrix nanotopography as a regulator of cell function. J Cell Biol 2012;197:351–360.
23.
Chen W, Villa-Diaz LG, Sun Y, et al.: Nanotopography influences adhesion, spreading, and self-renewal of human embryonic stem cells. ACS Nano 2012;6:4094–4103.
24.
Kim JB: Three-dimensional tissue culture models in cancer biology. Semin Cancer Biol 2005;15:365–377.
25.
Khaitan D, Chandna S, Arya MB, Dwarakanath BS: Establishment and characterization of multicellular spheroids from a human glioma cell line; Implications for tumor therapy. J Transl Med 2006;4:1–13.
26.
Mehta G, Hsiao AY, Ingram M, Luker GD, Takayama S: Opportunities and challenges for use of tumor spheroids as models to test drug delivery and efficacy. J Control Release 2012;164:192–204.
27.
Chitcholtan K, Sykes P, Evans J: The resistance of intracellular mediators to doxorubicin and cisplatin are distinct in 3D and 2D endometrial cancer. J Transl Med 2012;10:1–16.
28.
Fallica B, Maffei JS, Villa S, Makin G, Zaman M: Alteration of cellular behavior and response to PI3K pathway inhibition by culture in 3D collagen gels. PLoS One 2012;7:e48024.
29.
Luca AC, Mersch S, Deenen R, et al.: Impact of the 3D microenvironment on phenotype, gene expression, and EGFR inhibition of colorectal cancer cell lines. PLoS One 2013;8:e59689.
30.
Wong S, El-Gamal A, Griffin P, Nishi Y, Pease F, Plummer J: Monolithic 3D integrated circuits. Paper presented at VLSI Technology, Systems and Applications 2007 (VLSI-TSA 2007), Hsinchu, Taiwan, April 23–25, 2007.
31.
Maria OM, Maria O, Liu Y, Komarova SV, Tran SD: Matrigel improves functional properties of human submandibular salivary gland cell line. Int J Biochem Cell Biol 2011;43:622–631.
32.
Wang X, Sun L, Maffini MV, Soto A, Sonnenschein C, Kaplan DL: A complex 3D human tissue culture system based on mammary stromal cells and silk scaffolds for modeling breast morphogenesis and function. Biomaterials 2010;31:3920–3929.
33.
Hongisto V, Jernstrom S, Fey V, et al.: High-throughput 3D screening reveals differences in drug sensitivities between culture models of JIMT1 breast cancer cells. PLoS One 2013;8:e77232.
34.
Gurski LA, Jha AK, Zhang C, Jia X, Farach-Carson MC: Hyaluronic acid-based hydrogels as 3D matrices for in vitro evaluation of chemotherapeutic drugs using poorly adherent prostate cancer cells. Biomaterials 2009;30:6076–6085.
35.
Kenny PA, Lee GY, Myers CA, et al.: The morphologies of breast cancer cell lines in three-dimensional assays correlate with their profiles of gene expression. Mol Oncol 2007;1:84–96.
36.
Sodunke TR, Turner KK, Caldwell SA, McBride KW, Reginato MJ, Noh HM: Micropatterns of Matrigel for three-dimensional epithelial cultures. Biomaterials 2007;28:4006–4016.
37.
Chitcholtan K, Asselin E, Parent S, Sykes PH, Evans JJ: Differences in growth properties of endometrial cancer in three dimensional (3D) culture and 2D cell monolayer. Exper Cell Res 2013;319:75–87.
38.
Härmä V, Virtanen J, Mäkelä R, et al.: A comprehensive panel of three-dimensional models for studies of prostate cancer growth, invasion and drug responses. PLoS One 2010;5:e10431.
39.
Lin RZ, Chang HY: Recent advances in three-dimensional multicellular spheroid culture for biomedical research. Biotechnol J 2008;3:1172–1184.
40.
Price KJ, Tsykin A, Giles KM, et al.: Matrigel basement membrane matrix influences expression of microRNAs in cancer cell lines. Biochem Biophys Res Commun 2012;427:343–348.
41.
Loessner D, Stok KS, Lutolf MP, Hutmacher DW, Clements JA, Rizzi SC: Bioengineered 3D platform to explore cell–ECM interactions and drug resistance of epithelial ovarian cancer cells. Biomaterials 2010;31:8494–8506.
42.
Kiss DL, Windus LCE, Avery VM: Chemokine receptor expression on integrin-mediated stellate projections of prostate cancer cells in 3D culture. Cytokine 2013;64:122–130.
43.
Li H, Fan X, Houghton J: Tumor microenvironment: the role of the tumor stroma in cancer. J Cell Biochem 2007;101:805–815.
44.
Pageau SC, Sazonova OV, Wong JY, Soto AM, Sonnenschein C: The effect of stromal components on the modulation of the phenotype of human bronchial epithelial cells in 3D culture. Biomaterials 2011;32:7169–7180.
45.
Shen FH, Werner BC, Liang H, et al.: Implications of adipose-derived stromal cells in a 3D culture system for osteogenic differentiation: an in vitro and in vivo investigation. Spine J 2013;13:32–43.
46.
Matsuda N, Shimizu T, Yamato M, Okano T: Tissue engineering based on cell sheet technology. Adv Mater 2007;19:3089–3099.
47.
Kawaguchi N, Hatta K, Nakanishi T: 3D-culture system for heart regeneration and cardiac medicine. Biomed Res Int 2013;2013:895967.
48.
Tsuda Y, Kikuchi A, Yamato M, Chen G, Okano T: Heterotypic cell interactions on a dually patterned surface. Biochem Biophys Res Commun 2006;348:937–944.
49.
Harimoto M, Yamato M, Hirose M, et al.: Novel approach for achieving double-layered cell sheets co-culture: overlaying endothelial cell sheets onto monolayer hepatocytes utilizing temperature-responsive culture dishes. J Biomed Mater Res 2002;62:464–470.
50.
Baker BM, Chen CS: Deconstructing the third dimension—how 3D culture microenvironments alter cellular cues. J Cell Sci 2012;125:3015–3024.
51.
Xu X, Gurski LA, Zhang C, Harrington DA, Farach-Carson MC, Jia X: Recreating the tumor microenvironment in a bilayer, hyaluronic acid hydrogel construct for the growth of prostate cancer spheroids. Biomaterials 2012;33:9049–9060.
52.
Yip D, Cho CH: A multicellular 3D heterospheroid model of liver tumor and stromal cells in collagen gel for anti-cancer drug testing. Biochem Biophys Res Commun 2013;433:327–332.
53.
Trédan O, Galmarini CM, Patel K, Tannock IF: Drug resistance and the solid tumor microenvironment. J Nat Cancer Inst 2007;99:1441–1454.
54.
Szot CS, Buchanan CF, Freeman JW, Rylander MN: 3D in vitro bioengineered tumors based on collagen I hydrogels. Biomaterials 2011;32:7905–7912.
55.
DiMasi JA, Hansen RW, Grabowski HG: The price of innovation: new estimates of drug development costs. J Health Econ 2003;22:151–185.
56.
Karlsson H, Fryknäs M, Larsson R, Nygren P: Loss of cancer drug activity in colon cancer HCT-116 cells during spheroid formation in a new 3-D spheroid cell culture system. Exper Cell Res 2012;318:1577–1585.
57.
Walker DM, Boey G, McDonald LA: The pathology of oral cancer. Pathology 2003;35:376–383.
58.
Sodek KL, Ringuette MJ, Brown TJ: Compact spheroid formation by ovarian cancer cells is associated with contractile behavior and an invasive phenotype. Int J Cancer 2009;124:2060–2070.
59.
News GEaB. Top 10 Clinical Trial Failures of 2013. Top 10 Clinical Trial Failures of 2013. www.genengnews.com/insight-and-intelligenceand153/top-10-clinical-trial-failures-of-2013/77900029/?page=1 (last accessed on February 3, 2014).
60.
Hingorani P, Zhang W, Piperdi S, et al.: Preclinical activity of palifosfamide lysine (ZIO-201) in pediatric sarcomas including oxazaphosphorine-resistant osteosarcoma. Cancer Chemother Pharmacol 2009;64:733–740.
61.
Genmab. Zalutumumab. www.genmab.com/partnering/licensing-opportunities/products (last accessed on April 7, 2014).
62.
Ivaska J, Nevo J: Assessing risk of metastases and/or ddfs of patients with neoplasms, screening of patients responding to cancer therapy and such therapy. WO Patent App. PCT/FI2009/050,555. December 30, 2009.
63.
Wen Z, Liao Q, Hu Y, You L, Zhou L, Zhao Y: A spheroid-based 3-D culture model for pancreatic cancer drug testing, using the acid phosphatase assay. Braz J Med Biol Res 2013;46:634–642.
64.
Tung Y-C, Hsiao AY, Allen SG, Torisawa Y-s, Ho M, Takayama S: High-throughput 3D spheroid culture and drug testing using a 384 hanging drop array. Analyst 2011;136:473–478.
65.
Swietach P, Hulikova A, Patiar S, Vaughan-Jones RD, Harris AL: Importance of intracellular pH in determining the uptake and efficacy of the weakly basic chemotherapeutic drug, doxorubicin. PLoS One 2012;7:e35949.
66.
Nam J-M, Onodera Y, Bissell MJ, Park CC: Breast cancer cells in three-dimensional culture display an enhanced radioresponse after coordinate targeting of integrin α5β1 and fibronectin. Cancer Res 2010;70:5238–5248.
67.
Michaylira CZ, Wong GS, Miller CG, et al.: Periostin, a cell adhesion molecule, facilitates invasion in the tumor microenvironment and annotates a novel tumor-invasive signature in esophageal cancer. Cancer Res 2010;70:5281–5292.
68.
Kondo J, Endo H, Okuyama H, et al.: Retaining cell–cell contact enables preparation and culture of spheroids composed of pure primary cancer cells from colorectal cancer. Proc Natl Acad Sci USA 2011;108:6235–6240.
69.
Praveen K, Streiner N, Vo M, Anderes K, Yokota K, Ikeya T: Evaluation of Cell-able spheroid culture system for culturing patient derived primary tumor cells. Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research. Cancer Res 2012;72(8 Suppl):5270 [Abstract].
70.
Fiebig H: Oncotest. www.oncotest.com/id-3d-assays.html (last accessed on April 11, 2014).
71.
Vinci M, Gowan S, Boxall F, et al.: Advances in establishment and analysis of three-dimensional tumor spheroid-based functional assays for target validation and drug evaluation. BMC Biol 2012;10:29.
72.
Lai Y, Asthana A, Kisaalita WS: Biomarkers for simplifying HTS 3D cell culture platforms for drug discovery: the case for cytokines. Drug Discov Today 2011;16:293–297.
73.
Albrecht C, Helmreich M, Tichy B, et al.: Impact of 3D-culture on the expression of differentiation markers and hormone receptors in growth plate chondrocytes as compared to articular chondrocytes. Int J Mol Med 2009;23:347–355.
74.
Mishra DK, Sakamoto JH, Thrall MJ, et al.: Human lung cancer cells grown in an ex vivo 3D lung model produce matrix metalloproteinases not produced in 2D culture. PLoS One 2012;7:e45308.
75.
Yamada KM, Cukierman E: Modeling tissue morphogenesis and cancer in 3D. Cell 2007;130:601–610.
76.
Bohunicky B, Mousa SA: Biosensors: the new wave in cancer diagnosis. Nanotechnol Sci Appl 2010;4:1–10.
77.
Lei KF, Wu MH, Hsu CW, Chen YD: Real-time and non-invasive impedimetric monitoring of cell proliferation and chemosensitivity in a perfusion 3D cell culture microfluidic chip. Biosens Bioelectron 2014;51:16–21.
78.
Jeong SH, Lee DW, Kim S, Kim J, Ku B: A study of electrochemical biosensor for analysis of three-dimensional (3D) cell culture. Biosens Bioelectron 2012;35:128–133.
79.
Daus AW, Layer PG, Thielemann C: A spheroid-based biosensor for the label-free detection of drug-induced field potential alterations. Sensor Actuat B-Chem 2012;165:53–58.
80.
Zhou L, Huang G, Wang S, et al.: Advances in cell-based biosensors using three-dimensional cell-encapsulating hydrogels. Biotechnol J 2011;6:1466–1476.
81.
Wu M-H, Chang Y-H, Liu Y-T, et al.: Development of high throughput microfluidic cell culture chip for perfusion 3-dimensional cell culture-based chemosensitivity assay. Sensor Actuat B-Chem 2011;155:397–407.
82.
Zhang X, Yang ST: High-throughput 3-D cell-based proliferation and cytotoxicity assays for drug screening and bioprocess development. J Biotechnol 2011;151:186–193.
83.
Ben-Yoav H, Melamed S, Freeman A, Shacham-Diamand Y, Belkin S: Whole-cell biochips for bio-sensing: integration of live cells and inanimate surfaces. Crit Rev Biotechnol 2011;31:337–353.
84.
Ong S-M, Zhang C, Toh Y-C, et al.: A gel-free 3D microfluidic cell culture system. Biomaterials 2008;29:3237–3244.
85.
Lin SP, Kyriakides TR, Chen JJ: On-line observation of cell growth in a three-dimensional matrix on surface-modified microelectrode arrays. Biomaterials 2009;30:3110–3117.
86.
Tan W, Desai TA: Layer-by-layer microfluidics for biomimetic three-dimensional structures. Biomaterials 2004;25:1355–1364.
87.
Kim MS, Yeon JH, Park JK: A microfluidic platform for 3-dimensional cell culture and cell-based assays. Biomed Microdevices 2007;9:25–34.
88.
Kloss D, Kurz R, Jahnke HG, et al.: Microcavity array (MCA)-based biosensor chip for functional drug screening of 3D tissue models. Biosens Bioelectron 2008;23:1473–1480.
89.
Thielecke H, Mack A, Robitzki A: A multicellular spheroid-based sensor for anti-cancer therapeutics. Biosens Bioelectron 2001;16:261–269.
90.
Hildebrandt C, Buth H, Cho S, Impidjati, Thielecke H: Detection of the osteogenic differentiation of mesenchymal stem cells in 2D and 3D cultures by electrochemical impedance spectroscopy. J Biotechnol 2010;148:83–90.
91.
Wang J, Wu C, Hu N, Zhou J, Du L, Wang P: Microfabricated electrochemical cell-based biosensors for analysis of living cells in vitro. Biosensors 2012;2:127–170.
92.
Ngoepe M, Choonara Y, Tyagi C, et al.: Integration of biosensors and drug delivery technologies for early detection and chronic management of illness. Sensors 2013;13:7680–7713.
93.
Souiri M, Gammoudi I, Mora L, et al.: A novel 3-D nano-assembly bacteria based biosensor for enhanced detection of heavy metal pollutants. J Environ Sci Eng 2012;1:924–935.
94.
Torisawa Y-s, Shiku H, Yasukawa T, Nishizawa M, Matsue T: Multi-channel 3-D cell culture device integrated on a silicon chip for anticancer drug sensitivity test. Biomaterials 2005;26:2165–2172.
95.
Lei KF, Wu MH, Hsu CW: Electrical impendance determination of cancer cell viability in a 3-dimensional cell culture microfluidic chip. Int J Electrochem Sci 2012;7:12817–12828.
96.
Banerjee P, Lenz D, Robinson JP, Rickus JL, Bhunia AK: A novel and simple cell-based detection system with a collagen-encapsulated B-lymphocyte cell line as a biosensor for rapid detection of pathogens and toxins. Lab Invest 2008;88:196–206.
97.
Nguyen TA, Yin TI, Reyes D, Urban GA: Microfluidic chip with integrated electrical cell-impedance sensing for monitoring single cancer cell migration in three-dimensional matrixes. Anal Chem 2013;85:11068–11076.

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cover image ASSAY and Drug Development Technologies
ASSAY and Drug Development Technologies
Volume 12Issue Number 4May 2014
Pages: 207 - 218
PubMed: 24831787

History

Published online: 15 May 2014
Published in print: May 2014

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Rasheena Edmondson
Biomanufacturing Research Institute and Technology Enterprises (BRITE), and Department of Pharmaceutical Sciences, North Carolina Central University, Durham, North Carolina.
Jessica Jenkins Broglie
Biomanufacturing Research Institute and Technology Enterprises (BRITE), and Department of Pharmaceutical Sciences, North Carolina Central University, Durham, North Carolina.
Audrey F. Adcock
Biomanufacturing Research Institute and Technology Enterprises (BRITE), and Department of Pharmaceutical Sciences, North Carolina Central University, Durham, North Carolina.
Liju Yang
Biomanufacturing Research Institute and Technology Enterprises (BRITE), and Department of Pharmaceutical Sciences, North Carolina Central University, Durham, North Carolina.

Notes

Address correspondence to:Liju Yang, PhDDepartment of Pharmaceutical Sciences and Biomanufacturing Research Institute and Technology Enterprises (BRITE)North Carolina Central UniversityDurham, NC 27707E-mail: [email protected]

Disclosure Statement

No competing financial interests exist.

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