1932

Abstract

Multiscale modeling of muscular-skeletal systems—the materials and structures that help organisms support themselves and move—is a rapidly growing field of study that has contributed key elements to the understanding of these systems, especially from a multiscale perspective. The systems, including materials such as bone and muscle, have hierarchical structures ranging from the nano- to the macroscale, and it is difficult to understand their macroscopic behaviors, both physiological and pathological, without knowledge of their hierarchical structures and properties. In this review, we discuss the methods of multiscale modeling. Through a series of case studies about key materials in muscular-skeletal systems, we describe how different methods can bridge the gap between hierarchical structures and their roles in the systems’ mechanical properties. In particular, we emphasize the importance of the quality of minerals in bone. Finally, we discuss biomimetic material designs facilitated by additive manufacturing technology.

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2017-06-21
2024-06-21
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Literature Cited

  1. Arnould-Taylor W. 1.  1998. A Textbook of Anatomy and Physiology Cheltenham, UK: Stanley Thornes [Google Scholar]
  2. Taga G. 2.  1995. A model of the neuro-musculo-skeletal system for human locomotion. Biol. Cybern. 73:97–111 [Google Scholar]
  3. Frank CB. 3.  2004. Ligament structure, physiology and function. J. Musculoskelet. Neuronal Interact. 4:199–201 [Google Scholar]
  4. Kannus P. 4.  2000. Structure of the tendon connective tissue. Scand. J. Med. Sci. Sports 10312–20 [Google Scholar]
  5. Fox AJS, Bedi A, Rodeo SA. 5.  2009. The basic science of articular cartilage: structure, composition, and function. Sports Health 1:461–68 [Google Scholar]
  6. Clarke B. 6.  2008. Normal bone anatomy and physiology. Clin. J. Am. Soc. Nephrol. 3:S131–39 [Google Scholar]
  7. Olszta MJ, Cheng X, Jee SS, Kumar R, Kim Y-Y. 7.  et al. 2007. Bone structure and formation: a new perspective. Mater. Sci. Eng. Rep. 58:77–116 [Google Scholar]
  8. Launey ME, Buehler MJ, Ritchie RO. 8.  2010. On the mechanistic origins of toughness in bone. Annu. Rev. Mater. Res. 40:25–53 [Google Scholar]
  9. Cassidy JJ, Hiltner A, Baer E. 9.  1989. Hierarchical structure of the intervertebral disc. Connect. Tissue Res. 23:75–88 [Google Scholar]
  10. Screen HRC, Lee DA, Bader DL, Shelton JC. 10.  2004. An investigation into the effects of the hierarchical structure of tendon fascicles on micromechanical properties. Proc. Inst. Mech. Eng. H 218:109–19 [Google Scholar]
  11. Keaveny TM, Hayes WC. 11.  1993. A 20-year perspective on the mechanical properties of trabecular bone. J. Biomech. Eng. 115:534–42 [Google Scholar]
  12. Danielsen CC, Andreassen TT. 12.  1988. Mechanical properties of rat tail tendon in relation to proximal–distal sampling position and age. J. Biomech. 21:207–12 [Google Scholar]
  13. Escoffier C, de Rigal J, Rochefort A, Vasselet R, Lévêque J-L, Agache PG. 13.  1989. Age-related mechanical properties of human skin: an in vivo study. J. Investig. Dermatol. 93:353–57 [Google Scholar]
  14. Reznikov N, Shahar R, Weiner S. 14.  2014. Three-dimensional structure of human lamellar bone: the presence of two different materials and new insights into the hierarchical organization. Bone 59:93–104 [Google Scholar]
  15. Reznikov N, Shahar R, Weiner S. 15.  2014. Bone hierarchical structure in three dimensions. Acta Biomater 10:3815–26 [Google Scholar]
  16. Meyers MA, Chen P-Y, Lin AY-M, Seki Y. 16.  2008. Biological materials: structure and mechanical properties. Prog. Mater. Sci. 53:1–206 [Google Scholar]
  17. Giesa T, Pugno NM, Wong JY, Kaplan DL, Buehler MJ. 17.  2014. What's inside the box? Length scales that govern fracture processes of polymer fibers. Adv. Mater. 26:412–17 [Google Scholar]
  18. Gao H, Ji B, Jäger IL, Arzt E, Fratzl P. 18.  2003. Materials become insensitive to flaws at nanoscale: lessons from nature. PNAS 100:5597–600 [Google Scholar]
  19. Kielty CM, Sherratt MJ, Shuttleworth CA. 19.  2002. Elastic fibres. J. Cell Sci. 115:2817–28 [Google Scholar]
  20. Fratzl P, Weinkamer R. 20.  2007. Nature's hierarchical materials. Prog. Mater. Sci. 52:1263–334 [Google Scholar]
  21. Fratzl P. 21.  2008. Collagen: structure and mechanics. An introduction. Collagen: Structure and Mechanics P Fratzl 1–13 Boston: Springer [Google Scholar]
  22. Landi E, Celotti G, Logroscino G, Tampieri A. 22.  2003. Carbonated hydroxyapatite as bone substitute. J. Eur. Ceram. Soc. 23:2931–37 [Google Scholar]
  23. Rey C, Collins B, Goehl T, Dickson IR, Glimcher MJ. 23.  1989. The carbonate environment in bone mineral: a resolution-enhanced Fourier transform infrared spectroscopy study. Calcif. Tissue Int. 45:157–64 [Google Scholar]
  24. Buehler M, Keten S. 24.  2010. Colloquium: failure of molecules, bones, and the Earth itself. Rev. Mod. Phys. 82:1459–87 [Google Scholar]
  25. Keylock CJ, Constantinescu G, Hardy RJ. 25.  2012. The application of computational fluid dynamics to natural river channels: eddy resolving versus mean flow approaches. Geomorphology 179:1–20 [Google Scholar]
  26. Monaghan JJ. 26.  2005. Smoothed particle hydrodynamics. Rep. Prog. Phys. 68:1703 [Google Scholar]
  27. Matsumoto M, Saito S, Ohmine I. 27.  2002. Molecular dynamics simulation of the ice nucleation and growth process leading to water freezing. Nature 416:409–13 [Google Scholar]
  28. Senftle TP, Hong S, Islam MM, Kylasa SB, Zheng Y. 28.  et al. 2016. The ReaxFF reactive-force field: development, applications and future directions. NPJ Comput. Mater. 2:15011 [Google Scholar]
  29. Ng M-F, Zhou L, Yang S-W, Sim LY, Tan VBC, Wu P. 29.  2007. Theoretical investigation of silicon nanowires: methodology, geometry, surface modification, and electrical conductivity using a multiscale approach. Phys. Rev. B 76:155435 [Google Scholar]
  30. Hafner J, Wolverton C, Ceder G. 30.  2006. Toward computational materials design: the impact of density functional theory on materials research. MRS Bull 31:659–68 [Google Scholar]
  31. Hamed E, Lee Y, Jasiuk I. 31.  2010. Multiscale modeling of elastic properties of cortical bone. Acta Mech 213:131–54 [Google Scholar]
  32. Zeng QH, Yu AB, Lu GQ. 32.  2008. Multiscale modeling and simulation of polymer nanocomposites. Prog. Polym. Sci. 33:191–269 [Google Scholar]
  33. Xiang Gu G, Su I, Sharma S, Voros JL, Qin Z, Buehler MJ. 33.  2016. Three-dimensional printing of bio-inspired composites. J. Biomech. Eng. 138:021006–16 [Google Scholar]
  34. Murphy SV, Atala A. 34.  2014. 3D bioprinting of tissues and organs. Nat. Biotechnol. 32:773–85 [Google Scholar]
  35. Libonati F, Gu GX, Qin Z, Vergani L, Buehler MJ. 35.  2016. Bone-inspired materials by design: toughness amplification observed using 3D printing and testing.. Adv. Eng. Mater. 18:1354–63 [Google Scholar]
  36. Sugita Y, Okamoto Y. 36.  1999. Replica-exchange molecular dynamics method for protein folding. Chem. Phys. Lett. 314:141–51 [Google Scholar]
  37. Georgescu IM, Ashhab S, Nori F. 37.  2014. Quantum simulation. Rev. Mod. Phys. 86:153–85 [Google Scholar]
  38. Hohenberg P, Kohn W. 38.  1964. Inhomogeneous electron gas. Phys. Rev. B 136:864–71 [Google Scholar]
  39. Kohn W, Sham LJ. 39.  1965. Self-consistent equations including exchange and correlation effects. Phys. Rev. A 140:1133–38 [Google Scholar]
  40. Perdew JP, Burke K, Ernzerhof M. 40.  1996. Generalized gradient approximation made simple. Phys. Rev. Lett. 77:3865–68 [Google Scholar]
  41. Szabó A, Ostlund NS. 41.  1996. Modern Quantum Chemistry: Introduction to Advanced Electronic Structure Theory Mineola, NY: Dover [Google Scholar]
  42. van der Kamp MW, Shaw KE, Woods CJ, Mulholland AJ. 42.  2008. Biomolecular simulation and modelling: status, progress and prospects. J. R. Soc. Interface 5:S173–90 [Google Scholar]
  43. Alder BJ, Wainwright TE. 43.  1959. Studies in molecular dynamics. I. General method. J. Chem. Phys. 31:459–66 [Google Scholar]
  44. Rahman A. 44.  1964. Correlations in the motion of atoms in liquid argon. Phys. Rev. A 136:405–11 [Google Scholar]
  45. MacKerell AD Jr., Bashford D, Bellott M, Dunbrack RL Jr., Evanseck JD. 45.  et al. 1998. All-atom empirical potential for molecular modeling and dynamics studies of proteins. J. Phys. Chem. B 102:3586–616 [Google Scholar]
  46. Cornell WD, Cieplak P, Bayly CI, Gould IR, Merz KM. 46.  et al. 1995. A second generation force field for the simulation of proteins, nucleic acids, and organic molecules. J. Am. Chem. Soc. 117:5179–97 [Google Scholar]
  47. Christen M, Hünenberger PH, Bakowies D, Baron R, Bürgi R. 47.  et al. 2005. The GROMOS software for biomolecular simulation: GROMOS05. J. Comput. Chem. 26:1719–51 [Google Scholar]
  48. Lindorff-Larsen K, Maragakis P, Piana S, Eastwood MP, Dror RO. 48.  et al. 2012. Systematic validation of protein force fields against experimental data. PLOS ONE 7:e32131 [Google Scholar]
  49. Verlet L. 49.  1967. Computer “experiments” on classical fluids. I. Thermodynamical properties of Lennard-Jones molecules. Phys. Rev. 159:98–103 [Google Scholar]
  50. Nosé S. 50.  1984. A unified formulation of the constant temperature molecular dynamics methods. J. Chem. Phys. 81:511–10 [Google Scholar]
  51. Hoover WG. 51.  1985. Canonical dynamics: equilibrium phase-space distributions. Phys. Rev. A 31:1695–97 [Google Scholar]
  52. Martyna GJ, Klein ML, Tuckerman M. 52.  1992. Nosé–Hoover chains: the canonical ensemble via continuous dynamics. J. Chem. Phys. 97:2635–10 [Google Scholar]
  53. Andersen HC. 53.  1983. Rattle: a “velocity” version of the shake algorithm for molecular dynamics calculations. J. Comput. Phys. 52:24–34 [Google Scholar]
  54. Jung GS, Qin Z, Buehler MJ. 54.  2015. Mechanical properties and failure of biopolymers: atomistic reactions to macroscale response. Top. Curr. Chem. 369:317–43 [Google Scholar]
  55. Buehler MJ. 55.  2007. Hierarchical chemo-nanomechanics of proteins: entropic elasticity, protein unfolding and molecular fracture. J. Mech. Mater. Struct. 2:1019–57 [Google Scholar]
  56. van Duin ACT, Dasgupta S, Lorant F, Goddard WA. 56.  2001. ReaxFF: a reactive force field for hydrocarbons. J. Phys. Chem. A 105:9396–409 [Google Scholar]
  57. Buehler MJ, van Duin ACT, Goddard WA. 57.  2006. Multiparadigm modeling of dynamical crack propagation in silicon using a reactive force field. Phys. Rev. Lett. 96:095505 [Google Scholar]
  58. Marrink SJ, Risselada HJ, Yefimov S, Tieleman DP, de Vries AH. 58.  2007. The MARTINI force field: coarse grained model for biomolecular simulations. J. Phys. Chem. B 111:7812–24 [Google Scholar]
  59. Marrink SJ, Tieleman DP. 59.  2013. Perspective on the MARTINI model. Chem. Soc. Rev. 42:6801–22 [Google Scholar]
  60. Griffith AA. 60.  1921. The phenomena of rupture and flow in solids. Philos. Trans. R. Soc. A 221:163–98 [Google Scholar]
  61. Irwin GR. 61.  1957. Analysis of stresses and strains near the end of a crack traversing a plate. J. Appl. Mech. 24:361–64 [Google Scholar]
  62. Jung GS, Qin Z, Buehler MJ. 62.  2015. Molecular mechanics of polycrystalline graphene with enhanced fracture toughness. Extreme Mech. Lett. 2:52–59 [Google Scholar]
  63. Plimpton S. 63.  1995. Fast parallel algorithms for short-range molecular dynamics. J. Comput. Phys. 117:1–19 [Google Scholar]
  64. Bowers KJ, Dror RO, Shaw DE. 64.  2006. The midpoint method for parallelization of particle simulations. J. Chem. Phys. 124:184109 [Google Scholar]
  65. Kessel A, Ben-Tal N. 65.  2011. Introduction to Proteins: Structure, Function, and Motion Boca Raton, FL: CRC [Google Scholar]
  66. He D, Miao M, Sitarz EE, Muiznieks LD, Reichheld S. 66.  et al. 2012. Polymorphisms in the human tropoelastin gene modify in vitro self-assembly and mechanical properties of elastin-like polypeptides. PLOS ONE 7:e46130 [Google Scholar]
  67. Miao M, Cirulis JT, Lee S, Keeley FW. 67.  2005. Structural determinants of cross-linking and hydrophobic domains for self-assembly of elastin-like polypeptides. Biochemistry 44:14367–75 [Google Scholar]
  68. Yeo GC, Tarakanova A, Baldock C, Wise SG, Buehler MJ, Weiss AS. 68.  2016. Subtle balance of tropoelastin molecular shape and flexibility regulates dynamics and hierarchical assembly. Sci. Adv. 2:e1501145 [Google Scholar]
  69. Tirion MM. 69.  1996. Large amplitude elastic motions in proteins from a single-parameter, atomic analysis. Phys. Rev. Lett. 77:1905–8 [Google Scholar]
  70. Hinsen K. 70.  1998. Analysis of domain motions by approximate normal mode calculations. Proteins Struct. Funct. Bioinform. 33:417–29 [Google Scholar]
  71. Bahar I, Rader AJ. 71.  2005. Coarse-grained normal mode analysis in structural biology. Curr. Opin. Struct. Biol. 15:586–92 [Google Scholar]
  72. Frederix PWJM, Scott GG, Abul-Haija YM, Kalafatovic D, Pappas CG. 72.  et al. Exploring the sequence space for (tri-)peptide self-assembly to design and discover new hydrogels. Nat. Chem. 7:30–37 [Google Scholar]
  73. Seo M, Rauscher S, Pomès R, Tieleman DP. 73.  2012. Improving internal peptide dynamics in the coarse-grained MARTINI model: toward large-scale simulations of amyloid- and elastin-like peptides. J. Chem. Theory Comput. 8:1774–85 [Google Scholar]
  74. Orgel JPRO, Irving TC, Miller A, Wess TJ. 74.  2006. Microfibrillar structure of type I collagen in situ. PNAS 103:9001–5 [Google Scholar]
  75. Gautieri A, Buehler MJ, Redaelli A. 75.  2009. Deformation rate controls elasticity and unfolding pathway of single tropocollagen molecules. J. Mech. Behav. Biomed. Mater 2130–37 [Google Scholar]
  76. Sasaki N, Odajima S. 76.  1996. Stress–strain curve and Young's modulus of a collagen molecule as determined by the X-ray diffraction technique. J. Biomech. 29:655–58 [Google Scholar]
  77. Chang S-W, Shefelbine SJ, Buehler MJ. 77.  2012. Structural and mechanical differences between collagen homo- and heterotrimers: relevance for the molecular origin of brittle bone disease. Biophys. J. 102:640–48 [Google Scholar]
  78. Depalle B, Qin Z, Shefelbine SJ, Buehler MJ. 78.  2015. Influence of cross-link structure, density and mechanical properties in the mesoscale deformation mechanisms of collagen fibrils. J. Mech. Behav. Biomed. Mater 521–13 [Google Scholar]
  79. Buehler MJ. 79.  2007. Molecular nanomechanics of nascent bone: fibrillar toughening by mineralization. Nanotechnology 18:295102 [Google Scholar]
  80. Buehler MJ. 80.  2006. Nature designs tough collagen: explaining the nanostructure of collagen fibrils. PNAS 103:12285–90 [Google Scholar]
  81. Gautieri A, Russo A, Vesentini S, Redaelli A, Buehler MJ. 81.  2010. Coarse-grained model of collagen molecules using an extended MARTINI force field. J. Chem. Theory Comput. 6:1210–18 [Google Scholar]
  82. Birk DE, Zycband E. 82.  1994. Assembly of the tendon extracellular matrix during development. J. Anat. 184:457–63 [Google Scholar]
  83. Iozzo RV, Schaefer L. 83.  2015. Proteoglycan form and function: a comprehensive nomenclature of proteoglycans. Matrix Biol 42:11–55 [Google Scholar]
  84. Knudson CB, Knudson W. 84.  2001. Cartilage proteoglycans. Semin. Cell Dev. Biol. 12:69–78 [Google Scholar]
  85. Redaelli A, Vesentini S, Soncini M, Vena P, Mantero S, Montevecchi FM. 85.  2003. Possible role of decorin glycosaminoglycans in fibril to fibril force transfer in relative mature tendons—a computational study from molecular to microstructural level. J. Biomech. 36:1555–69 [Google Scholar]
  86. Viswanath B, Raghavan R, Ramamurty U, Ravishankar N. 86.  2007. Mechanical properties and anisotropy in hydroxyapatite single crystals. Scr. Mater. 57:361–64 [Google Scholar]
  87. Misra A, Ching WY. 87.  2013. Theoretical nonlinear response of complex single crystal under multi-axial tensile loading. Sci. Rep. 3:1488 [Google Scholar]
  88. Kuhn L, Eppell SJ, Tong W, Glimcher MJ, Katz JL. 88.  2003. Size and shape of mineralites in young bovine bone measured by atomic force microscopy. Calcif. Tissue Int. 72:592–98 [Google Scholar]
  89. Fratzl P, Paris O, Klaushofer K, Landis WJ. 89.  1996. Bone mineralization in an osteogenesis imperfecta mouse model studied by small-angle X-ray scattering. J. Clin. Investig. 97:396–402 [Google Scholar]
  90. Qin Z, Gautieri A, Nair AK, Inbar H, Buehler MJ. 90.  2012. Thickness of hydroxyapatite nanocrystal controls mechanical properties of the collagen–hydroxyapatite interface. Langmuir 28:1982–92 [Google Scholar]
  91. Meneghini C, Dalconi MC, Nuzzo S, Mobilio S, Wenk RH. 91.  2003. Rietveld refinement on X-ray diffraction patterns of bioapatite in human fetal bones. Biophys. J. 84:2021–29 [Google Scholar]
  92. Pastenes ES, Reyes-Gasga J. 92.  2001. Computer simulation of selected and convergent beam electron diffraction patterns for hydroxyapatite. Rev. Latinoam. Metal. Mater. 21:69–73 [Google Scholar]
  93. Yerramshetty JS, Akkus O. 93.  2008. The associations between mineral crystallinity and the mechanical properties of human cortical bone. Bone 42:476–82 [Google Scholar]
  94. Farlay D, Panczer G, Rey C, Delmas P, Boivin G. 94.  2010. Mineral maturity and crystallinity index are distinct characteristics of bone mineral. J. Bone Miner. Metab. 28:433–45 [Google Scholar]
  95. Almora-Barrios N, de Leeuw NH. 95.  2010. Modelling the interaction of a Hyp-Pro-Gly peptide with hydroxyapatite surfaces in aqueous environment. CrystEngComm 12:960–67 [Google Scholar]
  96. Nair AK, Gautieri A, Chang S-W, Buehler MJ. 96.  2013. Molecular mechanics of mineralized collagen fibrils in bone. Nat. Commun. 4:1724 [Google Scholar]
  97. Duchstein P, Zahn D. 97.  2010. Atomistic modeling of apatite–collagen composites from molecular dynamics simulations extended to hyperspace. J. Mol. Model. 17:73–79 [Google Scholar]
  98. Depalle B, Qin Z, Shefelbine SJ, Buehler MJ. 98.  2016. Large deformation mechanisms, plasticity, and failure of an individual collagen fibril with different mineral content. J. Bone Miner. Res. 31:380–90 [Google Scholar]
  99. Schwarcz HP. 99.  2015. The ultrastructure of bone as revealed in electron microscopy of ion-milled sections. Semin. Cell Dev. Biol. 46:44–50 [Google Scholar]
  100. Schwarcz HP, McNally EA, Botton GA. 100.  2014. Dark-field transmission electron microscopy of cortical bone reveals details of extrafibrillar crystals. J. Struct. Biol. 188:240–48 [Google Scholar]
  101. Reisinger AG, Pahr DH, Zysset PK. 101.  2010. Sensitivity analysis and parametric study of elastic properties of an unidirectional mineralized bone fibril array using mean field methods. Biomech. Model. Mechanobiol. 9:499–510 [Google Scholar]
  102. Jonvaux J, Hoc T, Budyn É. 102.  2012. Analysis of micro fracture in human Haversian cortical bone undercompression. Int. J. Numer. Methods Biomed. Eng 28974–98 [Google Scholar]
  103. Patel P. 103.  2013. Micro 3-D printer creates tiny structures in seconds. MIT Technology Review March 5. https://www.technologyreview.com/s/511856/micro-3-d-printer-creates-tiny-structures-in-seconds/ [Google Scholar]
  104. Dimas LS, Bratzel GH, Eylon I, Buehler MJ. 104.  2013. Tough composites inspired by mineralized natural materials: computation, 3D printing, and testing. Adv. Funct. Mater. 23:4629–38 [Google Scholar]
  105. Grunenfelder LK, Suksangpanya N, Salinas C, Milliron G, Yaraghi N. 105.  et al. 2014. Bio-inspired impact-resistant composites. Acta Biomater 10:3997–4008 [Google Scholar]
  106. Martin JJ, Fiore BE, Erb RM. 106.  Designing bioinspired composite reinforcement architectures via 3D magnetic printing. Nat. Commun. 6:8641 [Google Scholar]
  107. Józsa L, Kannus P. 107.  1997. Histopathological findings in spontaneous tendon ruptures. Scand. J. Med. Sci. Sports 7113–18 [Google Scholar]
  108. 108. Boundless 2016. Connective tissue is found throughout the body, providing support and shock absorption for tissues and bones. Boundless Biology May 26. https://www.boundless.com/biology/textbooks/boundless-biology-textbook/the-animal-body-basic-form-and-function-33/animal-primary-tissues-193/connective-tissues-loose-fibrous-and-cartilage-738-11968/ [Google Scholar]
  109. Phillips ATM, Villette CC, Modenese L. 109.  2015. Femoral bone mesoscale structural architecture prediction using musculoskeletal and finite element modelling. Int. Biomech. 2:43–61 [Google Scholar]
  110. Coleman SP, Spearot DE, Capolungo L. 110.  2013. Virtual diffraction analysis of Ni [010] symmetric tilt grain boundaries. Model. Simul. Mater. Sci. Eng. 21:055020 [Google Scholar]
  111. Bres EF, Cherns D, Vincent R, Morniroli JP. 111.  1993. Space-group determination of human tooth-enamel crystals. Acta Crystallogr. B 49:56–62 [Google Scholar]
  112. Dalconi MC, Meneghini C, Nuzzo S, Wenk R, Mobilio S. 112.  2003. Structure of bioapatite in human foetal bones: an X-ray diffraction study. Nucl. Instrum. Methods B 200:406–10 [Google Scholar]
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