Modelling tissues in 3D: the next future of pharmaco-toxicology and food research?

The development and validation of reliable in vitro methods alternative to conventional in vivo studies in experimental animals is a well-recognised priority in the fields of pharmaco-toxicology and food research. Conventional studies based on two-dimensional (2-D) cell monolayers have demonstrated their significant limitations: the chemically and spatially defined three-dimensional (3-D) network of extracellular matrix components, cell-to-cell and cell-to-matrix interactions that governs differentiation, proliferation and function of cells in vivo is, in fact, lost under the simplified 2-D condition. Being able to reproduce specific tissue-like structures and to mimic functions and responses of real tissues in a way that is more physiologically relevant than what can be achieved through traditional 2-D cell monolayers, 3-D cell culture represents a potential bridge to cover the gap between animal models and human studies. This article addresses the significance and the potential of 3-D in vitro systems to improve the predictive value of cell-based assays for safety and risk assessment studies and for new drugs development and testing. The crucial role of tissue engineering and of the new microscale technologies for improving and optimising these models, as well as the necessity of developing new protocols and analytical methods for their full exploitation, will be also discussed.

[1]  James P. Freyer,et al.  The Use of 3-D Cultures for High-Throughput Screening: The Multicellular Spheroid Model , 2004, Journal of biomolecular screening.

[2]  Keith E. Mostov,et al.  Building epithelial architecture: insights from three-dimensional culture models , 2002, Nature Reviews Molecular Cell Biology.

[3]  R. Weinberg,et al.  Species- and cell type-specific requirements for cellular transformation. , 2004, Cancer cell.

[4]  L. Griffith,et al.  Functional behavior of primary rat liver cells in a three-dimensional perfused microarray bioreactor. , 2002, Tissue engineering.

[5]  Masayuki Yamato,et al.  Engineering functional two- and three-dimensional liver systems in vivo using hepatic tissue sheets , 2007, Nature Medicine.

[6]  R. Kerbel,et al.  Cell adhesion and drug resistance in cancer , 1997, Current opinion in oncology.

[7]  Holger Gerhardt,et al.  Spatially restricted patterning cues provided by heparin-binding VEGF-A control blood vessel branching morphogenesis. , 2002, Genes & development.

[8]  David B. Edelman,et al.  A cultural renaissance: in vitro cell biology embraces three-dimensional context , 2005, Experimental Neurology.

[9]  J. Zimmerberg,et al.  Multilineage Differentiation of Rhesus Monkey Embryonic Stem Cells in Three‐Dimensional Culture Systems , 2003, Stem cells.

[10]  M. Gómez-Lechón,et al.  Long‐term expression of differentiated functions in hepatocytes cultured in three‐dimensional collagen matrix , 1998, Journal of cellular physiology.

[11]  Keiran S. M. Smalley,et al.  Life ins't flat: Taking cancer biology to the next dimension , 2006, In Vitro Cellular & Developmental Biology - Animal.

[12]  K. Yoshizato,et al.  EXPRESSION OF HUMAN PHASE II ENZYMES IN CHIMERIC MICE WITH HUMANIZED LIVER , 2005, Drug Metabolism and Disposition.

[13]  C. Mark Ott,et al.  Studying Host–Pathogen Interactions in 3-D: Organotypic Models for Infectious Disease and Drug Development , 2007, Journal of Neuroimmune Pharmacology.

[14]  Schwachöfer Jh Multicellular tumor spheroids in radiotherapy research (review). , 1990 .

[15]  J. Schwachöfer Multicellular tumor spheroids in radiotherapy research (review). , 1990, Anticancer research.

[16]  M. Bissell,et al.  Designer microenvironments for the analysis of cell and tissue function. , 1990, Current opinion in cell biology.

[17]  G. Gilani,et al.  Need for accurate and standardized determination of amino acids and bioactive peptides for evaluating protein quality and potential health effects of foods and dietary supplements. , 2008, Journal of AOAC International.

[18]  Lotfi Senhadji,et al.  ICA and biomedical applications , 2010 .

[19]  R Hetzer,et al.  New pulsatile bioreactor for fabrication of tissue-engineered patches. , 2001, Journal of biomedical materials research.

[20]  A. Bader,et al.  A Novel Full‐Scale Flat Membrane Bioreactor Utilizing Porcine Hepatocytes: Cell Viability and Tissue‐Specific Functions , 2000, Biotechnology progress.

[21]  T. Goodwin,et al.  Prospects for use of microgravity‐based bioreactors to study three‐dimensional host—tumor interactions in human neoplasia , 1993, Journal of cellular biochemistry.

[22]  D. Beebe,et al.  Cell culture models in microfluidic systems. , 2008, Annual review of analytical chemistry.

[23]  JONG BIN Kim,et al.  Three-dimensional tissue culture models in cancer biology. , 2005, Seminars in cancer biology.

[24]  I. Mian,et al.  Tissue architecture: the ultimate regulator of breast epithelial function. , 2003, Current opinion in cell biology.

[25]  Kenneth M. Yamada,et al.  Three-dimensional microenvironments modulate fibroblast signaling responses. , 2007, Advanced drug delivery reviews.

[26]  F Meuwly,et al.  Packed-bed bioreactors for mammalian cell culture: bioprocess and biomedical applications. , 2007, Biotechnology advances.

[27]  M. Bissell,et al.  The plasticity of human breast carcinoma cells is more than epithelial to mesenchymal conversion , 2001, Breast Cancer Research.

[28]  Kenneth M. Yamada,et al.  The matrix reorganized: extracellular matrix remodeling and integrin signaling. , 2006, Current opinion in cell biology.

[29]  J. G. Hengstler,et al.  Alternative methods to safety studies in experimental animals: role in the risk assessment of chemicals under the new European Chemicals Legislation (REACH) , 2008, Archives of Toxicology.

[30]  Heather Sheardown,et al.  Building in vitro models of organs. , 2005, International review of cytology.

[31]  Michael Fischer,et al.  Drug testing on 3D in vitro tissues trapped on a microcavity chip. , 2008, Lab on a chip.

[32]  H. Kuiper,et al.  Safety and nutritional assessment of GM plants and derived food and feed: the role of animal feeding trials. , 2008, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[33]  G. Andrei Three-dimensional culture models for human viral diseases and antiviral drug development. , 2006, Antiviral research.

[34]  Keith E. Mostov,et al.  Rac1 orientates epithelial apical polarity through effects on basolateral laminin assembly , 2001, Nature Cell Biology.

[35]  Mina J. Bissell The organizing principle: microenvironmental influences in the normal and malignant breast , 2010 .

[36]  L. Griffith,et al.  Capturing complex 3D tissue physiology in vitro , 2006, Nature Reviews Molecular Cell Biology.

[37]  B. Hinz,et al.  Myofibroblasts and mechano-regulation of connective tissue remodelling , 2002, Nature Reviews Molecular Cell Biology.

[38]  K. Jensen,et al.  Cells on chips , 2006, Nature.

[39]  C. Larabell,et al.  Reversion of the Malignant Phenotype of Human Breast Cells in Three-Dimensional Culture and In Vivo by Integrin Blocking Antibodies , 1997, The Journal of cell biology.

[40]  N. Kotov,et al.  Three-dimensional cell culture matrices: state of the art. , 2008, Tissue engineering. Part B, Reviews.

[41]  H Green,et al.  Growth of cultured human epidermal cells into multiple epithelia suitable for grafting. , 1979, Proceedings of the National Academy of Sciences of the United States of America.

[42]  D M Klaus,et al.  Clinostats and bioreactors. , 2007, Gravitational and space biology bulletin : publication of the American Society for Gravitational and Space Biology.

[43]  D. Bojanic,et al.  Keynote review: in vitro safety pharmacology profiling: an essential tool for successful drug development. , 2005, Drug discovery today.

[44]  Mina J Bissell,et al.  Normal and tumor-derived myoepithelial cells differ in their ability to interact with luminal breast epithelial cells for polarity and basement membrane deposition. , 2010, Journal of cell science.

[45]  Kenneth M. Yamada,et al.  Modeling Tissue Morphogenesis and Cancer in 3D , 2007, Cell.

[46]  M. Bissell The differentiated state of normal and malignant cells or how to define a "normal" cell in culture. , 1981, International review of cytology.

[47]  M. Zegers,et al.  Morphological and biochemical analysis of Rac1 in three-dimensional epithelial cell cultures. , 2006, Methods in enzymology.

[48]  D E H Tee,et al.  Book Review: Culture of Animal Cells: A Manual of Basic Technique , 1984 .

[49]  Tobias Schmelzle,et al.  Engineering tumors with 3D scaffolds , 2007, Nature Methods.

[50]  F. Balis,et al.  Evolution of anticancer drug discovery and the role of cell-based screening. , 2002, Journal of the National Cancer Institute.

[51]  D. Lauffenburger,et al.  Fusing Tissue Engineering and Systems Biology Toward Fulfilling Their Promise , 2008 .

[52]  M J Bissell,et al.  Extracellular matrix-dependent tissue-specific gene expression in mammary epithelial cells requires both physical and biochemical signal transduction. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[53]  Sophie Lelièvre,et al.  beta4 integrin-dependent formation of polarized three-dimensional architecture confers resistance to apoptosis in normal and malignant mammary epithelium. , 2002, Cancer cell.

[54]  Anirban Datta,et al.  Epithelial polarity and tubulogenesis in vitro. , 2003, Trends in cell biology.

[55]  E. Hay,et al.  SECRETION OF COLLAGEN BY CORNEAL EPITHELIUM , 1973, The Journal of cell biology.

[56]  F. Pampaloni,et al.  The third dimension bridges the gap between cell culture and live tissue , 2007, Nature Reviews Molecular Cell Biology.

[57]  P. Lelkes,et al.  Growing tissues in microgravity , 1998, Nature Medicine.

[58]  Mina J Bissell,et al.  Modeling tissue-specific signaling and organ function in three dimensions , 2003, Journal of Cell Science.

[59]  M J Bissell,et al.  Tissue phenotype depends on reciprocal interactions between the extracellular matrix and the structural organization of the nucleus. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[60]  R. Hoffman,et al.  To do tissue culture in two or three dimensions? that is the question , 1993, Stem cells.

[61]  Deepika Walpita,et al.  Studying actin-dependent processes in tissue culture , 2002, Nature Reviews Molecular Cell Biology.

[62]  A. Khademhosseini,et al.  Microscale technologies for tissue engineering and biology. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[63]  Genee Y. Lee,et al.  The morphologies of breast cancer cell lines in three‐dimensional assays correlate with their profiles of gene expression , 2007, Molecular oncology.

[64]  Elizabeth Jones,et al.  Living in three dimensions , 2007, Cell Biochemistry and Biophysics.

[65]  R. Ian Freshney,et al.  Culture of Animal Cells: A Manual of Basic Technique and Specialized Applications , 2010 .

[66]  Portonovo S. Ayyaswamy,et al.  Optimal conditions for simulating microgravity employing NASA designed rotating wall vessels , 2007 .

[67]  A. W. Hubbard,et al.  Human keratinocyte cultures in an in vitro approach for the assessment of surfactant-induced irritation. , 1998, Toxicology in vitro : an international journal published in association with BIBRA.

[68]  Harmeet Singh,et al.  Computational fluid dynamics for improved bioreactor design and 3D culture. , 2008, Trends in biotechnology.

[69]  Michael P. Sheetz,et al.  Basic mechanism of three-dimensional collagen fibre transport by fibroblasts , 2005, Nature Cell Biology.

[70]  Jonathan Bard,et al.  COLLAGEN SUBSTRATA FOR STUDIES ON CELL BEHAVIOR , 1972, The Journal of cell biology.

[71]  Millie Hughes-Fulford,et al.  Monolayer and spheroid culture of human liver hepatocellular carcinoma cell line cells demonstrate distinct global gene expression patterns and functional phenotypes. , 2009, Tissue engineering. Part A.

[72]  Nancy Cheng,et al.  Mature human hepatocytes from ex vivo differentiation of alginate-encapsulated hepatoblasts. , 2008, Tissue engineering. Part A.

[73]  Donald E. Ingber,et al.  How does extracellular matrix control capillary morphogenesis? , 1989, Cell.

[74]  Kenneth M. Yamada,et al.  Cell biology: Survival in three dimensions , 2002, Nature.

[75]  R. Kerbel,et al.  Intrinsic or acquired drug resistance and metastasis: Are they linked phenotypes? , 1994, Journal of cellular biochemistry.

[76]  M J Bissell,et al.  How does the extracellular matrix direct gene expression? , 1982, Journal of theoretical biology.

[77]  Cynthia A. Reinhart-King,et al.  Tensional homeostasis and the malignant phenotype. , 2005, Cancer cell.

[78]  Yukinori Endo,et al.  A Rac switch regulates random versus directionally persistent cell migration , 2005, The Journal of cell biology.

[79]  S. Boyce,et al.  Principles and practices for treatment of cutaneous wounds with cultured skin substitutes. , 2002, American journal of surgery.

[80]  L. Samson,et al.  A microscale in vitro physiological model of the liver: predictive screens for drug metabolism and enzyme induction. , 2005, Current drug metabolism.

[81]  R. Sandberg,et al.  Gene expression perturbation in vitro--a growing case for three-dimensional (3D) culture systems. , 2005, Seminars in cancer biology.

[82]  Erik Sahai,et al.  Differing modes of tumour cell invasion have distinct requirements for Rho/ROCK signalling and extracellular proteolysis , 2003, Nature Cell Biology.

[83]  Matthew J. Paszek,et al.  The Tension Mounts: Mechanics Meets Morphogenesis and Malignancy , 2004, Journal of Mammary Gland Biology and Neoplasia.

[84]  Kimmo Louekari Status and Prospects of In Vitro Tests in Risk Assessment , 2004, Alternatives to laboratory animals : ATLA.

[85]  Ivan Martin,et al.  Three‐dimensional culture of melanoma cells profoundly affects gene expression profile: A high density oligonucleotide array study , 2005, Journal of cellular physiology.

[86]  M. Fournier,et al.  Transcriptome profiling in clinical breast cancer: From 3D culture models to prognostic signatures , 2006, Journal of cellular physiology.

[87]  W. Cefalu,et al.  Efficacy of dietary supplementation with botanicals on carbohydrate metabolism in humans. , 2008, Endocrine, metabolic & immune disorders drug targets.

[88]  Kenneth M. Yamada,et al.  Taking Cell-Matrix Adhesions to the Third Dimension , 2001, Science.

[89]  Carlos E Semino,et al.  Functional differentiation of hepatocyte-like spheroid structures from putative liver progenitor cells in three-dimensional peptide scaffolds. , 2003, Differentiation; research in biological diversity.

[90]  Wei Sun,et al.  Effects of dispensing pressure and nozzle diameter on cell survival from solid freeform fabrication-based direct cell writing. , 2008, Tissue engineering. Part A.

[91]  Patrick Vermette,et al.  Bioreactors for tissue mass culture: design, characterization, and recent advances. , 2005, Biomaterials.

[92]  Robert Combes,et al.  Toxicity testing: creating a revolution based on new technologies. , 2005, Trends in biotechnology.

[93]  Christopher S. Chen,et al.  Engineering cellular microenvironments to improve cell-based drug testing. , 2002, Drug discovery today.

[94]  Gregory T. Grochoski,et al.  How Safe is Vitamin E Supplementation? , 2008, Critical reviews in food science and nutrition.

[95]  T G Hammond,et al.  Optimized suspension culture: the rotating-wall vessel. , 2001, American journal of physiology. Renal physiology.

[96]  D. Wolf,et al.  Cell culture for three-dimensional modeling in rotating-wall vessels: an application of simulated microgravity. , 1992, Journal of tissue culture methods : Tissue Culture Association manual of cell, tissue, and organ culture procedures.

[97]  Eric J Kunkel,et al.  Systems biology in drug discovery. , 2006, Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference.