Abstract
Mammalian cells grow within a complex three-dimensional (3D) microenvironment where multiple cells are organized and surrounded by extracellular matrix (ECM). The quantity and types of ECM components, alongside cell-to-cell and cell-to-matrix interactions dictate cellular differentiation, proliferation and function in vivo. To mimic natural cellular activities, various 3D tissue culture models have been established to replace conventional two dimensional (2D) culture environments. Allowing for both characterization and visualization of cellular activities within possibly bulky 3D tissue models presents considerable challenges due to the increased thickness and subsequent light scattering features of such 3D models. In this chapter, state-of-the-art methodologies used to establish 3D tissue models are discussed, first with a focus on both scaffold-free and scaffold-based 3D tissue model formation. Following on, multiple 3D live cell imaging systems, mainly optical imaging modalities, are introduced. Their advantages and disadvantages are discussed, with the aim of stimulating more research in this highly demanding research area.
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References
Baker BM, Chen CS (2012) Deconstructing the third dimension: how 3D culture microenvironments alter cellular cues. J Cell Sci 125(Pt 13):3015–3024
Thomas CH, Collier JH, Sfeir CS, Healy KE (2002) Engineering gene expression and protein synthesis by modulation of nuclear shape. Proc Natl Acad Sci 99(4):1972–1977
Vergani L, Grattarola M, Nicolini C (2004) Modifications of chromatin structure and gene expression following induced alterations of cellular shape. Int J Biochem Cell Biol 36(8):1447–1461
Nam KH, Smith AS, Lone S, Kwon S, Kim DH (2015) Biomimetic 3D tissue models for advanced high-throughput drug screening. J Lab Autom 20(3):201–215
Cukierman E, Pankov R, Yamada KM (2002) Cell interactions with three-dimensional matrices. Curr Opin Cell Biol 14(5):633–639
Knight E, Przyborski S (2015) Advances in 3D cell culture technologies enabling tissue-like structures to be created in vitro. J Anat 227(6):746–756
Wang W, Itaka K, Ohba S, Nishiyama N, Chung U-I, Yamasaki Y et al (2009) 3D spheroid culture system on micropatterned substrates for improved differentiation efficiency of multipotent mesenchymal stem cells. Biomaterials 30(14):2705–2715
Deegan AJ, Aydin HM, Hu B, Konduru S, Kuiper JH, Yang Y (2014) A facile in vitro model to study rapid mineralization in bone tissues. Biomed Eng Online 13(1):136
Hildebrandt C, Büth H, Thielecke H (2011) A scaffold-free in vitro model for osteogenesis of human mesenchymal stem cells. Tissue Cell 43:91–100
Berrier AL, Yamada KM (2007) Cell–matrix adhesion. J Cell Physiol 213(3):565–573
Kanczler JA, Ginty PJ, Barry JJA, Clarke NMP, Howdle SM, Shakesheff KM et al (2008) The effect of mesenchymal populations and vascular endothelial growth factor delivered from biodegradable polymer scaffolds on bone formation. Biomaterials 29(12):1892–1900
Rouwkema J, Rivron NC, van Blitterswijk CA (2008) Vascularization in tissue engineering. Trends Biotechnol 26:434–441
Fuchs S, Hofmann A, Kirkpatrick C (2007) Microvessel-like structures from outgrowth endothelial cells from human peripheral blood in 2-dimensional and 3-dimensional co-cultures with osteoblastic lineage cells. Tissue Eng 13(10):2577–2588
Melero-Martin JM, De Obaldia ME, Kang SY, Khan ZA, Yuan L, Oettgen P et al (2008) Engineering robust and functional vascular networks in vivo with human adult and cord blood-derived progenitor cells. Circ Res 103(2):194–202
Fuchs S, Ghanaati S, Orth C, Barbeck M, Kolbe M, Hofmann A et al (2009) Contribution of outgrowth endothelial cells from human peripheral blood on in vivo vascularization of bone tissue engineered constructs based on starch polycaprolactone scaffolds. Biomaterials 30(4):526–534
Tsigkou O, Pomerantseva I, Spencer JA, Redondo PA, Hart AR, O’Doherty E et al (2010) Engineered vascularized bone grafts. Proc Natl Acad Sci 107(8):3311–3316
Saleh FA, Whyte M, Genever PG (2011) Effects of endothelial cells on human mesenchymal stem cell activity in a three-dimensional in vitro model. Eur Cell Mater 22:242–257. discussion 57
Morimoto Y, Kato-Negishi M, Onoe H, Takeuchi S (2013) Three-dimensional neuron–muscle constructs with neuromuscular junctions. Biomaterials 34(37):9413–9419
Giacomelli E, Bellin M, Sala L, van Meer BJ, Tertoolen LG, Orlova VV et al (2017) Three-dimensional cardiac microtissues composed of cardiomyocytes and endothelial cells co-differentiated from human pluripotent stem cells. Development 144(6):1008–1017
Mannhardt I, Breckwoldt K, Letuffe-Brenière D, Schaaf S, Schulz H, Neuber C et al (2016) Human engineered heart tissue: analysis of contractile force. Stem Cell Rep 7(1):29–42
Howard D, Buttery LD, Shakesheff KM, Roberts SJ (2008) Tissue engineering: strategies, stem cells and scaffolds. J Anat 213(1):66–72
Baharvand H, Hashemi SM, Kazemi Ashtiani S, Farrokhi A (2006) Differentiation of human embryonic stem cells into hepatocytes in 2D and 3D culture systems in vitro. Int J Dev Biol 50(7):645–652
Willerth SM, Arendas KJ, Gottlieb DI, Sakiyama-Elbert SE (2006) Optimization of fibrin scaffolds for differentiation of murine embryonic stem cells into neural lineage cells. Biomaterials 27(36):5990–6003
Gerecht S, Burdick JA, Ferreira LS, Townsend SA, Langer R, Vunjak-Novakovic G (2007) Hyaluronic acid hydrogel for controlled self-renewal and differentiation of human embryonic stem cells. Proc Natl Acad Sci U S A 104(27):11298–11303
O'Brien FJ (2011) Biomaterials & amp; scaffolds for tissue engineering. Mater Today 14(3):88–95
Yang Y, El Haj AJ (2006) Biodegradable scaffolds--delivery systems for cell therapies. Expert Opin Biol Ther 6(5):485–498
Jafari M, Paknejad Z, Rad MR, Motamedian SR, Eghbal MJ, Nadjmi N et al (2017) Polymeric scaffolds in tissue engineering: a literature review. J Biomed Mater Res B Appl Biomater 105(2):431–459
Dabbs DJ (2013) Diagnostic immunohistochemistry e-book. Elsevier Health Sciences, Amsterdam
Ramos-Vara JA (2005) Technical aspects of immunohistochemistry. Vet Pathol 42(4):405–426
Pusztaszeri MP, Seelentag W, Bosman FT (2006) Immunohistochemical expression of endothelial markers CD31, CD34, von Willebrand factor, and Fli-1 in normal human tissues. J Histochem Cytochem 54(4):385–395
Gantenbein-Ritter B, Sprecher CM, Chan S, Illien-Junger S, Grad S (2011) Confocal imaging protocols for live/dead staining in three-dimensional carriers. Methods Mol Biol 740:127–140
Clegg RM, Murchie AI, Lilley DM (1993) The four-way DNA junction: a fluorescence resonance energy transfer study. Braz J Med Biol Res 26(4):405–416
Deniz AA, Laurence TA, Beligere GS, Dahan M, Martin AB, Chemla DS et al (2000) Single-molecule protein folding: diffusion fluorescence resonance energy transfer studies of the denaturation of chymotrypsin inhibitor 2. Proc Natl Acad Sci U S A 97(10):5179–5184
Chennell G, Willows RJW, Warren SC, Carling D, French PMW, Dunsby C et al (2016) Imaging of metabolic status in 3D cultures with an improved AMPK FRET biosensor for FLIM. Sensors 16(8):1312
Dmitriev RI, Borisov SM, Dussmann H, Sun S, Muller BJ, Prehn J et al (2015) Versatile conjugated polymer nanoparticles for high-resolution O2 imaging in cells and 3D tissue models. ACS Nano 9(5):5275–5288
Elttayef A, Dmitriev R, Kelly C, Yang Y (2017) Fabrication and characterisation of pseudoislets with different size and cell-cell contact. Abstract booklet of TCES annual conference, Manchester, UK
Yang Y, Bagnaninchi PO, Wood MA, El Haj AJ, Guyot E, Dubois A et al (2005) Monitoring cell profile in tissue engineering by optical coherence tomography. Proc SPIE 5695:51–57
Yang Y, Dubois A, Qin XP, Li J, El Haj A, Wang RK (2006) Investigation of optical coherence tomography as an imaging modality in tissue engineering. Phys Med Biol 51(7):1649–1659
Izatt JA, Swanson EA, Fujimoto JG, Hee MR, Owen GM (1994) Optical coherence microscopy in scattering media. Opt Lett 19(8):590–592
Tan W, Vinegoni C, Norman JJ, Desai TA, Boppart SA (2007) Imaging cellular responses to mechanical stimuli within three-dimensional tissue constructs. Microsc Res Tech 70(4):361–371
Appel AA, Anastasio MA, Larson JC, Brey EM (2013) Imaging challenges in biomaterials and tissue engineering. Biomaterials 34(28):6615–6630
Martín-Badosa E, Amblard D, Nuzzo S, Elmoutaouakkil A, Vico L, Peyrin F (2003) Excised bone structures in mice: imaging at three-dimensional synchrotron radiation micro CT. Radiology 229(3):921–928
Kallai I, Mizrahi O, Tawackoli W, Gazit Z, Pelled G, Gazit D (2011) Microcomputed tomography-based structural analysis of various bone tissue regeneration models. Nat Protoc 6(1):105–110
Taiani JT, Buie HR, Campbell GM, Manske SL, Krawetz RJ, Rancourt DE et al (2014) Embryonic stem cell therapy improves bone quality in a model of impaired fracture healing in the mouse; tracked temporally using in vivo micro-CT. Bone 64:263–272
Lienemann PS, Metzger S, Kivelio AS, Blanc A, Papageorgiou P, Astolfo A et al (2015) Longitudinal in vivo evaluation of bone regeneration by combined measurement of multi-pinhole SPECT and micro-CT for tissue engineering. Sci Rep 5:10238
Tower RJ, Campbell GM, Muller M, Gluer CC, Tiwari S (2015) Utilizing time-lapse micro-CT-correlated bisphosphonate binding kinetics and soft tissue-derived input functions to differentiate site-specific changes in bone metabolism in vivo. Bone 74:171–181
Jones AC, Milthorpe B, Averdunk H, Limaye A, Senden TJ, Sakellariou A et al (2004) Analysis of 3D bone ingrowth into polymer scaffolds via micro-computed tomography imaging. Biomaterials 25(20):4947–4954
Porter BD, Lin AS, Peister A, Hutmacher D, Guldberg RE (2007) Noninvasive image analysis of 3D construct mineralization in a perfusion bioreactor. Biomaterials 28(15):2525–2533
Cartmell S, Huynh K, Lin A, Nagaraja S, Guldberg R (2004) Quantitative microcomputed tomography analysis of mineralization within three-dimensional scaffolds in vitro. J Biomed Mater Res A 69A(1):97–104
Young S, Kretlow JD, Nguyen C, Bashoura AG, Baggett LS, Jansen JA et al (2008) Microcomputed tomography characterization of neovascularization in bone tissue engineering applications. Tissue Eng B Rev 14(3):295–306
Nagata M, Oi A, Sakai W, Tsutsumi N (2012) Synthesis and properties of biodegradable network poly(ether-urethane)s from L-lysine triisocyanate and poly(alkylene glycol)s. J Appl Polym Sci 126(S2):E358–EE64
Giunchedi P, Conti B, Scalia S, Conte U (1998) In vitro degradation study of polyester microspheres by a new HPLC method for monomer release determination. J Control Release 56(1–3):53–62
Proikakis CS, Mamouzelos NJ, Tarantili PA, Andreopoulos AG (2006) Swelling and hydrolytic degradation of poly(d,l-lactic acid) in aqueous solutions. Polym Degrad Stab 91(3):614–619
Artzi N, Oliva N, Puron C, Shitreet S, Artzi S, Bon Ramos A et al (2011) In vivo and in vitro tracking of erosion in biodegradable materials using non-invasive fluorescence imaging. Nat Mater 10(9):704–709
Bardsley K, Wimpenny I, Yang Y, El Haj AJ (2016) Fluorescent, online monitoring of PLGA degradation for regenerative medicine applications. RSC Adv 6(50):44364–44370
Cunha-Reis C, El Haj AJ, Yang X, Yang Y (2013) Fluorescent labeling of chitosan for use in non-invasive monitoring of degradation in tissue engineering. J Tissue Eng Regen Med 7(1):39–50
Wolbank S, Pichler V, Ferguson JC, Meinl A, van Griensven M, Goppelt A et al (2015) Non-invasive in vivo tracking of fibrin degradation by fluorescence imaging. J Tissue Eng Regen Med 9(8):973–976
Bardsley K, Wimpenny I, Wechsler R, Shachaf Y, Yang Y, El Haj AJ (2016) Defining a turnover index for the correlation of biomaterial degradation and cell based extracellular matrix synthesis using fluorescent tagging techniques. Acta Biomater 45:133–142
Muiznieks LD, Keeley FW (2013) Molecular assembly and mechanical properties of the extracellular matrix: a fibrous protein perspective. Biochim Biophys Acta 1832(7):866–875
Kim S-H, Turnbull J, Guimond S (2011) Extracellular matrix and cell signalling: the dynamic cooperation of integrin, proteoglycan and growth factor receptor. J Endocrinol 209(2):139–151
Kozel BA, Rongish BJ, Czirok A, Zach J, Little CD, Davis EC et al (2006) Elastic fiber formation: a dynamic view of extracellular matrix assembly using timer reporters. J Cell Physiol 207(1):87–96
Bardsley K, Yang Y, El Haj AJ (2017) Fluorescent labeling of collagen production by cells for noninvasive imaging of extracellular matrix deposition. Tissue Eng Part C Method 23(4):228–236
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Bardsley, K., Deegan, A.J., El Haj, A., Yang, Y. (2017). Current State-of-the-Art 3D Tissue Models and Their Compatibility with Live Cell Imaging. In: Dmitriev, R. (eds) Multi-Parametric Live Cell Microscopy of 3D Tissue Models. Advances in Experimental Medicine and Biology, vol 1035. Springer, Cham. https://doi.org/10.1007/978-3-319-67358-5_1
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DOI: https://doi.org/10.1007/978-3-319-67358-5_1
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