Computer simulations of in vitro morphogenesis

One of the most important challenges of contemporary biology is understanding how cells assemble into tissues. The complexity of morphogenesis calls for computational tools able to identify the dominant mechanisms involved in shaping tissues. This narrative review presents individual-based computational models that proved useful in simulating phenomena of interest in tissue engineering (TE), a research field that aims to create tissue replacements in the laboratory. First, we briefly describe morphogenetic mechanisms. Then, we present several computational models of cellular and subcellular resolution, along with applications that illustrate their potential to address problems of TE. Finally, we analyze experiments that may be used to validate computational models of tissue constructs made of cohesive cells. Our analysis shows that the models available in the literature are not exploited to their full potential. We argue that, upon validation, a computational model can be used to optimize cell culture conditions and to design new experiments.

[1]  Adrian Neagu,et al.  Role of physical mechanisms in biological self-organization. , 2005, Physical review letters.

[2]  Roger R. Markwald,et al.  Computational modeling of epithelial-mesenchymal transformations , 2010, Biosyst..

[3]  E. Palsson,et al.  A three-dimensional model of cell movement in multicellular systems , 2001, Future Gener. Comput. Syst..

[4]  John L. Semple,et al.  Review: In Vitro, in Vivo, in Silico: Computational Systems in Tissue Engineering and Regenerative Medicine , 2005 .

[5]  M. Holcombe,et al.  The epitheliome: agent-based modelling of the social behaviour of cells. , 2004, Bio Systems.

[6]  M. S. Steinberg,et al.  Differential adhesion in morphogenesis: a modern view. , 2007, Current opinion in genetics & development.

[7]  Mark Taylor,et al.  Computational modelling of cell spreading and tissue regeneration in porous scaffolds. , 2007, Biomaterials.

[8]  Charles J Lumsden,et al.  In vitro, in vivo, in silico: computational systems in tissue engineering and regenerative medicine. , 2005, Tissue engineering.

[9]  M. S. Steinberg,et al.  Adhesion in development: an historical overview. , 1996, Developmental biology.

[10]  Roberto Mayor,et al.  Keeping in touch with contact inhibition of locomotion , 2010, Trends in cell biology.

[11]  R. Huiskes,et al.  Biophysical stimuli on cells during tissue differentiation at implant interfaces , 1997 .

[12]  P J Prendergast,et al.  Biophysical stimuli on cells during tissue differentiation at implant interfaces , 1997 .

[13]  Michael Levin,et al.  What lies at the interface of regenerative medicine and developmental biology? , 2007, Development.

[14]  Karoly Jakab,et al.  Tissue engineering by self-assembly and bio-printing of living cells , 2010, Biofabrication.

[15]  S. Carter,et al.  Haptotaxis and the Mechanism of Cell Motility , 1967, Nature.

[16]  Douglas A Lauffenburger,et al.  Microarchitecture of three-dimensional scaffolds influences cell migration behavior via junction interactions. , 2008, Biophysical journal.

[17]  H. Augustin,et al.  Tensional forces in fibrillar extracellular matrices control directional capillary sprouting. , 1999, Journal of cell science.

[18]  Matthias Hermes,et al.  Prediction and validation of cell alignment along microvessels as order principle to restore tissue architecture in liver regeneration , 2010, Proceedings of the National Academy of Sciences.

[19]  Dirk Drasdo,et al.  Individual-based and continuum models of growing cell populations: a comparison , 2009, Journal of mathematical biology.

[20]  Roeland M. H. Merks,et al.  Contact-Inhibited Chemotaxis in De Novo and Sprouting Blood-Vessel Growth , 2005, PLoS Comput. Biol..

[21]  Lisa Willis,et al.  Integrated simulation with experimentation is a powerful tool for understanding diatom valve morphogenesis , 2012, Biosyst..

[22]  Liesbet Geris,et al.  Mathematical Modelling of Cell Adhesion in Tissue Engineering using Continuum Models , 2010 .

[23]  Timothy J. Newman,et al.  Correlating Cell Behavior with Tissue Topology in Embryonic Epithelia , 2011, PloS one.

[24]  Malcolm S. Steinberg,et al.  Reconstruction of Tissues by Dissociated Cells , 1963 .

[25]  W. Hennink,et al.  Organ printing: the future of bone regeneration? , 2011, Trends in biotechnology.

[26]  Lacramioara Stoicu-Tivadar,et al.  Cell seeding of Tissue Engineering Scaffolds studied by Monte Carlo simulations , 2011, MIE.

[27]  Sara Checa,et al.  Effect of cell seeding and mechanical loading on vascularization and tissue formation inside a scaffold: a mechano-biological model using a lattice approach to simulate cell activity. , 2010, Journal of biomechanics.

[28]  Jens-Peer Kuska,et al.  Spatial Organization of Mesenchymal Stem Cells In Vitro—Results from a New Individual Cell-Based Model with Podia , 2011, PloS one.

[29]  K Schulten,et al.  VMD: visual molecular dynamics. , 1996, Journal of molecular graphics.

[30]  Abbas Mgharbel,et al.  Measuring accurately liquid and tissue surface tension with a compression plate tensiometer , 2009, HFSP journal.

[31]  Adrian Neagu,et al.  Relating biophysical properties across scales. , 2007, Current topics in developmental biology.

[32]  Jacques G. Amar,et al.  The Monte Carlo method in science and engineering , 2006, Computing in Science & Engineering.

[33]  G. Forgacs,et al.  Surface tensions of embryonic tissues predict their mutual envelopment behavior. , 1996, Development.

[34]  Margherita Cioffi,et al.  Potential and Bottlenecks of Bioreactors in 3D Cell Culture and Tissue Manufacturing , 2009, Advanced materials.

[35]  Alessandro Giacomello,et al.  Cardiac tissue engineering using tissue printing technology and human cardiac progenitor cells. , 2012, Biomaterials.

[36]  Steinberg,et al.  Liquid properties of embryonic tissues: Measurement of interfacial tensions. , 1994, Physical review letters.

[37]  M. S. Steinberg,et al.  Reconstruction of tissues by dissociated cells. Some morphogenetic tissue movements and the sorting out of embryonic cells may have a common explanation. , 1963, Science.

[38]  Adrian Neagu,et al.  Computational Modeling of Tissue Self-Assembly , 2006 .

[39]  Adrian Neagu,et al.  Organ printing: fiction or science. , 2004, Biorheology.

[40]  Alison P McGuigan,et al.  Vascularized Organoid Engineered by Modular Assembly Enables Blood Perfusion , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[41]  P. Hogeweg,et al.  Modelling Morphogenesis: From Single Cells to Crawling Slugs. , 1997, Journal of theoretical biology.

[42]  Richard O. Hynes,et al.  Integrins: Versatility, modulation, and signaling in cell adhesion , 1992, Cell.

[43]  A. Neagu,et al.  The influence of cell-substrate and cell-medium interfacial tension on the cell spreading , 2011, 2011 15th IEEE International Conference on Intelligent Engineering Systems.

[44]  Jeffrey R Morgan,et al.  Directed self-assembly of large scaffold-free multi-cellular honeycomb structures , 2011, Biofabrication.

[45]  L. Griffith,et al.  Tissue Engineering--Current Challenges and Expanding Opportunities , 2002, Science.

[46]  M. Dembo,et al.  Cell movement is guided by the rigidity of the substrate. , 2000, Biophysical journal.

[47]  Glazier,et al.  Simulation of the differential adhesion driven rearrangement of biological cells. , 1993, Physical review. E, Statistical physics, plasmas, fluids, and related interdisciplinary topics.

[48]  Françoise Brochard-Wyart,et al.  Spreading dynamics and wetting transition of cellular aggregates , 2011, Proceedings of the National Academy of Sciences.

[49]  P. Friedl,et al.  Collective cell migration in morphogenesis, regeneration and cancer , 2009, Nature Reviews Molecular Cell Biology.

[50]  Lacramioara Stoicu-Tivadar,et al.  Optimal Energetic Conditions for Cell Seeding of Scaffolds , 2012 .

[51]  D. Beysens,et al.  Cell sorting is analogous to phase ordering in fluids. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[52]  R Langer,et al.  Dynamic Cell Seeding of Polymer Scaffolds for Cartilage Tissue Engineering , 1998, Biotechnology progress.

[53]  J. Vacanti,et al.  Tissue engineering : Frontiers in biotechnology , 1993 .

[54]  Patrick J. Prendergast,et al.  Computational techniques for selection of biomaterial scaffolds for tissue engineering , 2011 .

[55]  L G Griffith,et al.  Who's got pull around here? Cell organization in development and tissue engineering , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[56]  Lacramioara Stoicu-Tivadar,et al.  Cell spreading on biocompatible materials studied by computer simulations , 2011, 2011 6th IEEE International Symposium on Applied Computational Intelligence and Informatics (SACI).

[57]  Koichi Masuda,et al.  Chapter 62: TISSUE ENGINEERING FOR REGENERATION AND REPLACEMENT OF THE INTERVERTEBRAL DISC , 2006 .

[58]  Josep A Planell,et al.  Simulation of tissue differentiation in a scaffold as a function of porosity, Young's modulus and dissolution rate: application of mechanobiological models in tissue engineering. , 2007, Biomaterials.

[59]  Roeland M. H. Merks,et al.  Modeling Morphogenesis in silico and in vitro: Towards Quantitative, Predictive, Cell-based Modeling , 2009 .

[60]  D. Lauffenburger,et al.  Cell Migration: A Physically Integrated Molecular Process , 1996, Cell.

[61]  T. Newman,et al.  Emergent cell and tissue dynamics from subcellular modeling of active biomechanical processes , 2011, Physical biology.

[62]  François Graner,et al.  The role of fluctuations and stress on the effective viscosity of cell aggregates , 2009, Proceedings of the National Academy of Sciences.

[63]  Adrian Neagu,et al.  Experimental evaluation of apparent tissue surface tension based on the exact solution of the Laplace equation , 2007, 0706.3678.

[64]  Dawn C. Walker,et al.  The virtual cellça candidate co-ordinator for ‘middle-out’ modelling of biological systems , 2009 .

[65]  A. B. Bortz,et al.  A new algorithm for Monte Carlo simulation of Ising spin systems , 1975 .

[66]  Richard O Hynes,et al.  Integrins Bidirectional, Allosteric Signaling Machines , 2002, Cell.

[67]  Jesús A. Izaguirre,et al.  A framework for three-dimensional simulation of morphogenesis , 2005, IEEE/ACM Transactions on Computational Biology and Bioinformatics.

[68]  Robert Langer,et al.  Three-dimensional biomaterials for the study of human pluripotent stem cells , 2011, Nature Methods.

[69]  A. Harris,et al.  Behavior of cultured cells on substrata of variable adhesiveness. , 1973, Experimental cell research.

[70]  Adrian Neagu,et al.  Kinetic Monte Carlo and cellular particle dynamics simulations of multicellular systems. , 2011, Physical review. E, Statistical, nonlinear, and soft matter physics.

[71]  D. Drasdo,et al.  A single-cell-based model of tumor growth in vitro: monolayers and spheroids , 2005, Physical biology.

[72]  Vladimir Mironov,et al.  Relating cell and tissue mechanics: Implications and applications , 2008, Developmental dynamics : an official publication of the American Association of Anatomists.

[73]  J. Kohn,et al.  Tissue spreading on implantable substrates is a competitive outcome of cell–cell vs. cell–substratum adhesivity , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[74]  T. Newman,et al.  Modeling cell rheology with the Subcellular Element Model , 2008, Physical biology.

[75]  Ivan Merelli,et al.  A data integration approach for cell cycle analysis oriented to model simulation in systems biology , 2007, BMC Systems Biology.

[76]  Stefan Hoehme,et al.  A cell-based simulation software for multi-cellular systems , 2010, Bioinform..

[77]  Adrian Neagu,et al.  Fusion of uniluminal vascular spheroids: A model for assembly of blood vessels , 2010, Developmental dynamics : an official publication of the American Association of Anatomists.

[78]  James A. Glazier,et al.  A Multi-cell, Multi-scale Model of Vertebrate Segmentation and Somite Formation , 2011, PLoS Comput. Biol..

[79]  J. Pérez-Pomares,et al.  Tissue fusion and cell sorting in embryonic development and disease: biomedical implications , 2006, BioEssays : news and reviews in molecular, cellular and developmental biology.

[80]  T. Newman,et al.  Modeling multicellular systems using subcellular elements. , 2005, Mathematical biosciences and engineering : MBE.

[81]  J. Southgate,et al.  Agent-based computational modeling of wounded epithelial cell monolayers , 2004, IEEE Transactions on NanoBioscience.

[82]  M. Loeffler,et al.  Modeling the effect of deregulated proliferation and apoptosis on the growth dynamics of epithelial cell populations in vitro. , 2005, Biophysical journal.

[83]  Glazier,et al.  Simulation of biological cell sorting using a two-dimensional extended Potts model. , 1992, Physical review letters.

[84]  Francesca Ungaro,et al.  Controlled drug delivery in tissue engineering. , 2008, Advanced drug delivery reviews.

[85]  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.

[86]  James A. Glazier,et al.  Magnetization to Morphogenesis: A Brief History of the Glazier-Graner-Hogeweg Model , 2007 .

[87]  C. Anthony Hunt,et al.  Simulating Properties of In Vitro Epithelial Cell Morphogenesis , 2006, PLoS Comput. Biol..

[88]  P. Hogeweg,et al.  How amoeboids self-organize into a fruiting body: Multicellular coordination in Dictyostelium discoideum , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[89]  Vladimir Mironov,et al.  Organ printing: computer-aided jet-based 3D tissue engineering. , 2003, Trends in biotechnology.

[90]  Hans G Othmer,et al.  How cellular movement determines the collective force generated by the Dictyostelium discoideum slug. , 2004, Journal of theoretical biology.

[91]  Markus Loeffler,et al.  Tumorigenesis and Neoplastic Progression Individual Cell-Based Models of Tumor-Environment Interactions Multiple Effects of CD 97 on Tumor Invasion , 2006 .

[92]  P. Hogeweg,et al.  Modelling Morphogenesis: From Single Cells to Crawling Slugs. , 1997, Journal of theoretical biology.

[93]  B. Gumbiner,et al.  Cell Adhesion: The Molecular Basis of Tissue Architecture and Morphogenesis , 1996, Cell.

[94]  H. Othmer,et al.  A model for individual and collective cell movement in Dictyostelium discoideum. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[95]  J. Galle,et al.  From single cells to tissue architecture—a bottom-up approach to modelling the spatio-temporal organisation of complex multi-cellular systems , 2009, Journal of mathematical biology.

[96]  Shayn M. Peirce,et al.  Combining experiments with multi-cell agent-based modeling to study biological tissue patterning , 2007, Briefings Bioinform..

[97]  Lorenzo Moroni,et al.  3D-Fiber Deposition for Tissue Engineering and Organ Printing Applications , 2010 .

[98]  M. Sefton,et al.  Tissue engineering. , 1998, Journal of cutaneous medicine and surgery.

[99]  Jesús A. Izaguirre,et al.  COMPUCELL, a multi-model framework for simulation of morphogenesis , 2004, Bioinform..

[100]  H. Kleinman,et al.  New method for modeling connective-tissue cell migration: improved accuracy on motility parameters. , 2007, Biophysical journal.

[101]  James A Glazier,et al.  Multicell simulations of development and disease using the CompuCell3D simulation environment. , 2009, Methods in molecular biology.

[102]  V. Mironov,et al.  Engineering biological structures of prescribed shape using self-assembling multicellular systems. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[103]  Ali Khademhosseini,et al.  Microengineered hydrogels for tissue engineering. , 2007, Biomaterials.

[104]  Jean Paul Thiery,et al.  Johnson-Kendall-Roberts theory applied to living cells. , 2005, Physical review letters.

[105]  S. Hollister Porous scaffold design for tissue engineering , 2005, Nature materials.

[106]  Robert Langer,et al.  Principles of tissue engineering , 2014 .