Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

A materials science vision of extracellular matrix mineralization

Nature Reviews Materials volume 1, Article number: 16041 (2016) Cite this article

Subjects

Abstract

From an engineering perspective, skeletal tissues are remarkable structures because they are lightweight, stiff and tough, yet produced at ambient conditions. The biomechanical success of skeletal tissues is largely attributable to the process of biomineralization — a tightly regulated, cell-driven formation of billions of inorganic nanocrystals formed from ions found abundantly in body fluids. In this Review, we discuss nature's strategies to produce and sustain appropriate biomechanical properties in mineralizing (by the promotion of mineralization) and non-mineralizing (by the inhibition of mineralization) tissues. We review how perturbations of biomineralization are controlled over a continuum that spans from the desirable (or defective in disease) mineralization of the skeleton to pathological cardiovascular mineralization, and to mineralization of bioengineered constructs. A materials science vision of mineralization is presented with an emphasis on the micro- and nanostructure of mineralized tissues recently revealed by state-of-the-art analytical methods, and on how biomineralization-inspired designs are influencing the field of synthetic materials.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Physiological regulation of mineralization.
Figure 2: Cyclic loading in the cardiovascular system and the effects of mineralization.
Figure 3: Correlative combinations of materials-based analytical tools for the multiscale interrogation of bone.
Figure 4: Unanswered questions for the pathological mineralization of cardiovascular tissues and the physiological mineralization of bone.

Similar content being viewed by others

References

  1. Pearce, P. Structure in Nature is a Strategy for Design (MIT Press, 1980).

    Google Scholar 

  2. Thompson, D. W. On Growth and Form (Cambridge Univ. Press, 1942). This monograph describes the natural phenomena of an organism's growth, development and morphology from a mathematical perspective and rationalizes the miracles of adaptation and diversity — a must-read for a bioengineer.

    Google Scholar 

  3. Campbell, A. K. Calcium as an intracellular regulator. Proc. Nutr. Soc. 49, 51–56 (1990).

    Article  CAS  Google Scholar 

  4. Penido, M. G. M. G. & Alon, U. S. Phosphate homeostasis and its role in bone health. Pediatr. Nephrol. 27, 2039–2048 (2012).

    Article  Google Scholar 

  5. Hunter, G. K., Kyle, C. L. & Goldberg, H. A. Modulation of crystal formation by bone phosphoproteins: structural specificity of the osteopontin-mediated inhibition of hydroxyapatite formation. Biochem. J. 300, 723–728 (1994).

    Article  CAS  Google Scholar 

  6. Addison, W. N., Masica, D. L., Gray, J. J. & McKee, M. D. Phosphorylation-dependent inhibition of mineralization by osteopontin ASARM peptides is regulated by PHEX cleavage. J. Bone Miner. Res. 25, 695–705 (2010).

    Article  CAS  Google Scholar 

  7. Goldstein, D. A. Clinical Methods: The History, Physical, and Laboratory Examinations (Butterworth-Heinemann, 1990).

    Google Scholar 

  8. Magalhaes, M. C. F., Marques, P. A. A. P. & Correira, R. N. in Biomineralization: Medical Aspects of Solubility (eds Köenigsberger, E. & Köenigsberger, L. ) (Wiley, 2006).

    Google Scholar 

  9. Moreno, E. C., Gregory, T. M. & Brown, W. E. Preparation and solubility of hydroxyapatite. J. Res. Natl. Bur. Stand., Sect. A 72A, 773–782 (1968).

    Article  Google Scholar 

  10. Elliott, J. C. Calcium phosphate biominerals. Rev. Geochem. Miner. 48, 427–453 (2002).

    Article  CAS  Google Scholar 

  11. Elliott, J. C. Hydroxyapatites and nonstoichiometric apatites. Studies Inorg. Chem. 18, 111–189 (1994).

    Article  Google Scholar 

  12. Habraken, W. J. E. M. et al. Ion-association complexes unite classical and non-classical theories for the biomimetic nucleation of calcium phosphate. Nat. Commun. 4, 1507 (2013).

    Article  CAS  Google Scholar 

  13. De Yoreo, J. J. et al. Crystallization by particle attachment in synthetic, biogenic, and geologic environments. Science 349, aaa6760 (2015).

    Article  CAS  Google Scholar 

  14. Hodge, A. J. & Petruska, J. A. in Aspects of Protein Structure (ed. Ramachandran, G. N. ) 289–300 (Academic Press, 1963).

    Google Scholar 

  15. Saito, M. & Marumo, K. Collagen cross-links as a determinant of bone quality: a possible explanation for bone fragility in aging, osteoporosis, and diabetes mellitus. Osteoporos. Int. 21, 195–214 (2010).

    Article  CAS  Google Scholar 

  16. Eyre, D. R., Dickson, I. R. & Van Ness, K. Collagen cross-linking in human bone and articular cartilage. Biochem. J. 252, 495–500 (1988).

    Article  CAS  Google Scholar 

  17. Fratzl, P. Collagen: Structure and Mechanics (Springer, 2008).

    Book  Google Scholar 

  18. Fratzl, P. & Weinkamer, R. Nature's hierarchical materials. Prog. Mater. Sci. 52, 1263–1334 (2007). A comprehensive overview of natural materials, focusing on those that exhibit hierarchical organization in the structure.

    Article  CAS  Google Scholar 

  19. Reznikov, N., Shahar, R. & Weiner, S. Bone hierarchical structure in three dimensions. Acta Biomater. 10, 3815–2826 (2014).

    Article  Google Scholar 

  20. Yamauchi, M., Chandler, G. S. & Katz, E. P. in Chemistry and Biology of Mineralized Tissues (eds Slavkin, H. & Price, P. ) 39–46 (Elsevier, 1992).

    Google Scholar 

  21. Fleisch, H., Russell, R. G. G. & Straumann, F. Effect of pyrophosphate on hydroxyapatite and its implications in calcium homeostasis. Nature 5065, 901–903 (1966).

    Article  Google Scholar 

  22. Omelon, S. et al. Control of vertebrate skeletal mineralization by polyphosphates. PLoS ONE 4, e5634 (2009).

    Article  CAS  Google Scholar 

  23. Omelon, S., Ariganello, M., Bonucci, E., Grynpas, M. & Nanci, A. A review of phosphate mineral nucleation in biology and geobiology. Calcif. Tissue Int. 93, 382–396 (2013).

    Article  CAS  Google Scholar 

  24. Jahnen-Dechent, W., Schaefer, C., Ketteler, M. & McKee, M. D. Mineral chaperones: a role for fetuin-A and osteopontin in the inhibition and regression of pathologic calcification. J. Mol. Med. 86, 379–389 (2008).

    Article  CAS  Google Scholar 

  25. Jahnen-Dechent, W., Heiss, A., Schaefer, C. & Ketteler, M. Fetuin A regulation of calcified matrix metabolism. Circ. Res. 108, 1494–1509 (2011).

    Article  CAS  Google Scholar 

  26. Millan, J. L. Alkaline phosphatases. Structure, substrate specificity and functional relatedness to other members of a large superfamily of enzymes. Purinergic Signal. 2, 335–341 (2006).

    Article  CAS  Google Scholar 

  27. George, A. & Veis, A. Phosphorylated proteins and control over apatite nucleation, crystal growth, and inhibition. Chem. Rev. 108, 4670–4693 (2008).

    Article  CAS  Google Scholar 

  28. Nudelman, F. et al. The role of collagen in bone apatite formation in the presence of hydroxyapatite nucleation inhibitors. Nat. Mater. 9, 1004–1009 (2010).

    Article  CAS  Google Scholar 

  29. Wang, Y. et al. The predominant role of collagen in the nucleation, growth, structure and orientation of bone apatite. Nat. Mater. 11, 724–733 (2012). In this paper, the interaction of organic phases, inorganic phases and water are discussed with an emphasis on self-assembly processes and the role of water in biomineralization.

    Article  CAS  Google Scholar 

  30. McKee, M. D. & Nanci, A. Osteopontin: an interfacial extracellular matrix protein in mineralized tissues. Connect. Tissue Res. 35, 197–205 (1996).

    Article  CAS  Google Scholar 

  31. McKee, M. D. & Nanci, A. Osteopontin at mineralized tissue interfaces in bone, teeth and osseointegrated implants: ultrastructural distribution and implications for mineralized tissue formation, turnover and repair. Microsc. Res. Tech. 33, 141–164 (1996).

    Article  CAS  Google Scholar 

  32. McKee, M. D., Zalzal, S. & Nanci, A. Extracellular matrix in tooth cementum and mantle dentin: localization of osteopontin and other noncollagenous proteins, plasma proteins, and glycoconjugates by electron microscopy. Anat. Rec. 245, 293–312 (1996).

    Article  CAS  Google Scholar 

  33. Kavukcuoglu, N. B., Denhardt, D. T., Guzelsu, N. & Mann, A. B. Osteopontin deficiency and aging on nanomechanics of mouse bone. J. Biomed. Mater. Res. A 83, 136–144 (2007).

    Article  CAS  Google Scholar 

  34. Boskey, A. L., Spevak, L., Paschalis, E., Doty, S. B. & McKee, M. D. Osteopontin deficiency increases mineral content and mineral crystallinity in mouse bone. Calcif. Tissue Int. 71, 145–154 (2002).

    Article  CAS  Google Scholar 

  35. Luo, G. et al. Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature 386, 78–81 (1997).

    Article  CAS  Google Scholar 

  36. Schinke, T., McKee, M. D. & Karsenty, G. Extracellular matrix calcification: where is the action? Nat. Genet. 21, 150–151 (1999).

    Article  CAS  Google Scholar 

  37. Gorski, J. P. Is all bone the same? Distinctive distributions and properties of non-collagenous matrix proteins in lamellar versus woven bone imply the existence of different underlying osteogenic mechanisms. Crit. Rev. Oral Biol. Med. 9, 201–223 (1998).

    Article  CAS  Google Scholar 

  38. Boskey, A. L. Biomineralization: conflicts, challenges and opportunities. J. Cell. Biochem. Suppl. 30–31, 83–91 (1998).

    Article  Google Scholar 

  39. Veis, A. in Biomineralization: Reviews in Mineralogy and Geochemistry (eds Dove, P. M., De Yoreo, J. J. & Weiner, S. ) 249–290 (Mineralogical Society of America, 2003).

    Book  Google Scholar 

  40. Barros, N. M. T. et al. Proteolytic processing of osteopontin by PHEX and accumulation of osteopontin fragments in Hyp mouse bone, the murine model of X-linked hypophosphatemia. J. Bone Miner. Res. 28, 688–699 (2013).

    Article  CAS  Google Scholar 

  41. Posner, A. S., Betts, F. & Blumenthal, N. C. Properties of nucleating systems. Metab. Bone Dis. Relat. Res. 1, 179–183 (1978).

    Article  CAS  Google Scholar 

  42. Betts, F., Blumenthal, N. C. & Posner, A. S. Bone mineralization. J. Cryst. Growth 53, 63–73 (1981).

    Article  CAS  Google Scholar 

  43. Mahamid, J. et al. Bone mineralization proceeds through intracellular calcium phosphate loaded vesicles: a cryo-electron microscopy study. J. Struct. Biol. 174, 527–535 (2011).

    Article  CAS  Google Scholar 

  44. Politi, Y., Arad, T., Klein, E., Weiner, S. & Addadi, L. Sea urchin spine calcite forms via a transient amorphous calcium carbonate phase. Science 306, 1161–1164 (2004).

    Article  CAS  Google Scholar 

  45. Mahamid, J., Sharir, A., Addadi, L. & Weiner, S. Amorphous calcium phosphate is a major component of the forming fin bones of zebrafish: indications for an amorphous precursor phase. Proc. Natl Acad. Sci. USA 105, 12748–12753 (2008). This state-of-the-art cryo-electron microscopy study of bone formation and maturation in situ clearly illustrates the dynamics of biomineralization via the disordered mineral precursor stage.

    Article  Google Scholar 

  46. Boonrungsiman, S. et al. The role of intracellular calcium phosphate in osteoblast-mediated bone apatite formation. Proc. Natl Acad. Sci. USA 109, 14170–14175 (2012).

    Article  Google Scholar 

  47. Akiva, A. et al. On the pathway of mineral deposition in larval zebrafish caudal fin bone. Bone 75, 192–200 (2015).

    Article  CAS  Google Scholar 

  48. Kerschnitzki, M. et al. Transport of membrane-bound mineral particles in blood vessels during chicken embryonic bone development. Bone 83, 65–72 (2016).

    Article  CAS  Google Scholar 

  49. Currey, J. D. Bones: Structure and Mechanics (Princeton Univ. Press, 2002).

    Google Scholar 

  50. Wagermaier, W., Klaushofer, K. & Fratzl, P. Fragility of bone material controlled by internal interfaces. Calcif. Tissue Int. 97, 201–212 (2015). This paper overviews the role of interfaces at multiple size scales that provide appropriate bone toughness and provides a paradigm shift from the common-place notion of ‘strength’ towards an accurate vision of the bone quality determinants.

    Article  CAS  Google Scholar 

  51. Martin, R. B., Burr, D. B. & Sharkey, N. A. Skeletal Tissue Mechanics (Springer, 1998).

    Book  Google Scholar 

  52. Helfrich, M. H. Osteoclast diseases. Microsc. Res. Tech. 61, 514–532 (2003).

    Article  Google Scholar 

  53. Golub, E. E. Role of matrix vesicles in biomineralization. Biochim. Biophys. Acta 1790, 1592–1598 (2009).

    Article  CAS  Google Scholar 

  54. Landis, W. J., Hodgens, K. J., Arena, J., Song, M. J. & McEwen, B. F. Structural relations between collagen and mineral in bone as determined by high voltage electron microscopic tomography. Microsc. Res. Tech. 33, 192–202 (1996).

    Article  CAS  Google Scholar 

  55. Weiner, S. & Price, P. Disaggregation of bone into crystals. Calcif. Tissue Int. 39, 365–375 (1986).

    Article  CAS  Google Scholar 

  56. Moradian-Oldak, J., Weiner, S., Addadi, L., Landis, W. J. & Traub, W. Electron imaging and diffraction study of individual crystals of bone, mineralized tendon and synthetic carbonate apatite. Connect. Tissue Res. 25, 219–228 (1991).

    Article  CAS  Google Scholar 

  57. Wang, Y. et al. Water-mediated structuring of bone apatite. Nat. Mater. 12, 1144–1153 (2013).

    Article  CAS  Google Scholar 

  58. Ennos, R. Solid Biomechanics (Princeton Univ. Press, 2012).

    Google Scholar 

  59. Wainwright, S. A., Biggs, W. D., Currey, J. D. & Gosline, J. M. Mechanical Design in Organisms (Princeton Univ. Press, 1976). An insightful monograph recommended for junior scientists working in the fields of (bio)materials and (bio)engineering. Nature's answers to engineering problems are presented in the context of basic physics and converted into a source of inspiration for materials design.

    Google Scholar 

  60. Gordon, J. E. Structures: Or Why Things Don't Fall Down (Da Capo Press, 2003). This witty textbook explains memorable real-life examples of engineering issues in an entertaining manner yet with adamant logic: recommended for life scientists tackling the fields of engineering and materials science.

    Google Scholar 

  61. Nikitovic, D. et al. The biology of small leucine-rich proteoglycans in bone pathophysiology. J. Biol. Chem. 287, 33926–33933 (2012).

    Article  CAS  Google Scholar 

  62. Allen, M. R. et al. Changes in skeletal collagen cross-links and matrix hydration in high- and low-turnover chronic kidney disease. Osteoporos. Int. 26, 977–985 (2015).

    Article  CAS  Google Scholar 

  63. Bertinetti, L. et al. Osmotically driven tensile stress in collagen-based mineralized tissues. J. Mech. Behav. Biomed. Mater. 52, 14–21 (2015).

    Article  CAS  Google Scholar 

  64. Masic, A. et al. Osmotic pressure induces tensile forces in tendon collagen. Nat. Commun. 6, 5942 (2015).

    Article  CAS  Google Scholar 

  65. Maroudas, A. Balance between swelling pressure and collagen tension in normal and degenerate cartilage. Nature 260, 808–809 (1976).

    Article  CAS  Google Scholar 

  66. Timmins, P. A. & Wall, J. C. Bone water. Calcif. Tissue Res. 23, 1–5 (1977).

    Article  CAS  Google Scholar 

  67. Forien, J. B. et al. Compressive residual strains in mineral nanoparticles as a possible origin of enhanced crack resistance in human tooth dentin. Nano Lett. 15, 3729–3734 (2015).

    Article  CAS  Google Scholar 

  68. Kaartinen, M. T., El-Maadawy, S., Rasanen, N. H. & McKee, M. D. Tissue transglutaminase and its substrates in bone. J. Bone Miner. Res. 17, 2161–2173 (2002).

    Article  CAS  Google Scholar 

  69. Gupta, H. S. et al. Cooperative deformation of mineral and collagen in bone at the nanoscale. Proc. Natl Acad. Sci. USA 103, 17741–17746 (2006).

    Article  CAS  Google Scholar 

  70. Hoo, R. P. et al. Cooperation of length scales and orientations in the deformation of bovine bone. Acta Biomater. 7, 2943–2951 (2011).

    Article  Google Scholar 

  71. Reznikov, N., Almany-Magal, R., Shahar, R. & Weiner, S. Three-dimensional imaging of collagen fibril organization in rat circumferential lamellar bone using a dual beam electron microscope reveals ordered and disordered sub-lamellar structures. Bone 52, 676–683 (2013).

    Article  CAS  Google Scholar 

  72. Reznikov, N., Shahar, R. & Weiner, S. Three-dimensional structure of human lamellar bone: the presence of two different materials and new insights into the hierarchical organization. Bone 59, 93–104 (2014).

    Article  CAS  Google Scholar 

  73. Utku, F. S., Klein, E., Saybasili, H., Yucesoy, C. A. & Weiner, S. Probing the role of water in lamellar bone by dehydration in the environmental scanning electron microscope. J. Struct. Biol. 162, 361–367 (2008).

    Article  Google Scholar 

  74. Johnson, R. C., Leopold, J. A. & Loscalzo, J. Vascular calcification. Pathobiological mechanisms and clinical implications. Circ. Res. 90, 1044–1059 (2006).

    Article  CAS  Google Scholar 

  75. Lee, D. Vascular calcification: Inducers and inhibitors. Mater. Sci. Eng. B 176, 1133–1141 (2011).

    Article  CAS  Google Scholar 

  76. Marulanda, J., Alqarni, S. & Murshed, M. Mechanisms of vascular calcification and associated diseases. Curr. Pharm. Design 20, 1–10 (2014).

    Article  CAS  Google Scholar 

  77. Ruiz, J. L., Hutcheson, J. D. & Aikawa, E. Cardiovascular calcification: current controversies and novel concepts. Cardiovasc. Pathol. 24, 207–212 (2015).

    Article  CAS  Google Scholar 

  78. Clarke, M. C. H. et al. Chronic apoptosis of vascular smooth muscle cells accelerates atherosclerosis and promotes calcification and medial degeneration. Circ. Res. 102, 1529–1538 (2008).

    Article  CAS  Google Scholar 

  79. Liaw, L., Lindner, V., Schwartz, S. M., Chambers, A. F. & Giachelli, C. M. Osteopontin and β3 integrin are coordinately expressed in regenerating endothelium in vivo and stimulate Arg–Gly–Asp-dependent endothelial migration in vitro . Circ. Res. 77, 665–672 (1995).

    Article  CAS  Google Scholar 

  80. Singleton, E. B. & Merten, D. F. An unusual syndrome of widened medullary cavities of the metacarpals and phalanges, aortic calcification and abnormal dentition. Pediatr. Radiol. 1, 2–7 (1973).

    Article  CAS  Google Scholar 

  81. Munroe, P. B. et al. Mutations in the gene encoding the human matrix Gla protein cause Keutel syndrome. Nat. Genet. 21, 142–144 (1999).

    Article  CAS  Google Scholar 

  82. Hofmann Bowman, M. A., & McNally, E. M. Genetic pathways of vascular calcification. Trends Cardiovasc. Med. 22, 93–98 (2012).

    Article  CAS  Google Scholar 

  83. Lanzer, P. et al. Medial vascular calcification revisited: review and perspectives. Eur. Heart J. 35, 1515–1525 (2014).

    Article  Google Scholar 

  84. Bertazzo, S. et al. Nano-analytical electron microscopy reveals fundamental insights into human cardiovascular tissue calcification. Nat. Mater. 12, 576–583 (2013). This work is an example of how traditional materials-oriented analytical electron microscopy techniques aid in resolving long-standing disputes of structural biology.

    Article  CAS  Google Scholar 

  85. Schlieper, G. et al. Ultrastructural analysis of vascular calcifications in uremia. J. Am. Soc. Nephrol. 21, 689–696 (2010).

    Article  CAS  Google Scholar 

  86. Murshed, M. & McKee, M. D. Molecular determinants of extracellular matrix mineralization in bone and blood vessels. Curr. Opin. Nephrol. Hypertens. 19, 359–365 (2010). This concise work underscores the common features between physiological and pathological mineralization and highlights the role of non-collagenous proteins in both.

    Article  CAS  Google Scholar 

  87. Demer, L. L., Watson, K. E. & Bostroem, K. Mechanism of calcification in atherosclerosis. Trends Cardiovasc. Med. 4, 45–49 (1994).

    Article  CAS  Google Scholar 

  88. Hutcheson, J. D. et al. Genesis and growth of extracellular-vesicle-derived microcalcification in atherosclerotic plaques. Nat. Mater. 15, 335–343 (2016).

    Article  CAS  Google Scholar 

  89. Engler, A. J., Sen, S., Sweeney, H. L. & Discher, D. E. Matrix elasticity directs stem cell lineage specification. Cell 126, 677–689 (2006).

    Article  CAS  Google Scholar 

  90. Breitbach, M. et al. Potential risks of bone marrow cell transplantation into infarcted hearts. Blood 110, 1362–1369 (2007).

    Article  CAS  Google Scholar 

  91. Schoen, F. J. & Levy, R. J. Calcification of tissue heart valve substitutes: progress toward understanding and prevention. Ann. Thorac. Surg. 79, 1072–1080 (2005).

    Article  Google Scholar 

  92. Park, J. C., Siegel, R. J. & Demer, L. L. Effect of calcification and formalin fixation on in vitro distensibility of human femoral arteries. Am. Heart J. 125, 344–349 (1993).

    Article  CAS  Google Scholar 

  93. Tam, H. et al. A novel crosslinking method for improved tear resistance and biocompatibility of tissue based biomaterials. Biomaterials 66, 83–91 (2015).

    Article  CAS  Google Scholar 

  94. Sundararaghavan, H. G. et al. Genipin-induced changes in collagen gels: correlation of mechanical properties to fluorescence. J. Biomed. Mater. Res. Part A 87, 308–320 (2008).

    Article  CAS  Google Scholar 

  95. Lim, H. G., Kim, S. H., Choi, S. Y. & Kim, Y. J. Anticalcification effects of decellularization, solvent, and detoxification treatment for genipin and glutaraldehyde fixation of bovine pericardium. Eur. J. Cardiothorac. Surg. 41, 383–390 (2012).

    Article  Google Scholar 

  96. Currey, J. D. The many adaptations of bone. J. Biomech. 36, 1487–1495 (2003).

    Article  CAS  Google Scholar 

  97. Levy, R. J., Schoen, F. J., Flowers, W. B. & Staelin, S. T. Initiation of mineralization in bioprosthetic heart valves: studies of alkaline phosphatase activity and its inhibition by AlCl3 or FeCl3 preincubations. J. Biomed. Mater. Res. 25, 905–935 (1991).

    Article  CAS  Google Scholar 

  98. Whyte, M. P. et al. Enzyme-replacement therapy in life-threatening hypophosphatasia. N. Engl. J. Med. 266, 904–913 (2012). This work is a striking illustration of a translational application of basic biomineralization research.

    Article  Google Scholar 

  99. Millán, J. L. et al. Enzyme replacement therapy for murine hypophosphatasia. J. Bone Miner. Res. 23, 777–787 (2008).

    Article  Google Scholar 

  100. Dash, M. et al. Enzymatically biomineralized chitosan scaffolds for tissue-engineering applications. J. Tissue Eng. Regen. Med. http://dx.doi.org/10.1002/term.2048 (2015).

  101. Suárez-González, D. et al. Controllable mineral coatings on PCL scaffolds as carriers for growth factor release. Biomaterials 33, 713–721 (2012).

    Article  CAS  Google Scholar 

  102. Liu, W. et al. Enhancing the stiffness of electrospun nanofiber scaffolds with a controlled surface coating and mineralization. Langmuir 27, 9088–9093 (2011).

    Article  CAS  Google Scholar 

  103. Gower, L. B. & Odum, D. J. Deposition of calcium carbonate films by a polymer-induced liquid-precursor (PILP) process. J. Cryst. Growth 210, 719–734 (2000).

    Article  CAS  Google Scholar 

  104. Thula, T. T. et al. In vitro mineralization of dense collagen substrates: a biomimetic approach toward the development of bone-graft materials. Acta Biomater. 7, 3158–3169 (2011).

    Article  CAS  Google Scholar 

  105. Smith, L. A., Liu, X., Hu, J., Wang, P. & Ma, P. X. Enhancing osteogenic differentiation of mouse embryonic stem cells by nanofibers. Tissue Eng. Part A 15, 1855–1864 (2009).

    Article  CAS  Google Scholar 

  106. Wei, G. & Ma, P. X. Partially noanofibrous architecture of 3D tissue engineering scaffolds. Biomaterials 30, 6426–6434 (2009).

    Article  CAS  Google Scholar 

  107. Dalby, M. J. et al. The control of human mesenchymal cell differentiation using nanoscale symmetry and disorder. Nat. Mater. 6, 997–1003 (2007).

    Article  CAS  Google Scholar 

  108. Faia-Torres, A. B. et al. Differential regulation of osteogenic differentiation of stem cells on surface roughness gradients. Biomaterials 35, 9023–9032 (2014).

    Article  CAS  Google Scholar 

  109. Wirth, C. et al. Nitinol surface roughness modulates in vitro cell response: a comparison between fibroblasts and osteoblasts. Mater. Sci. Eng. C 25, 51–60 (2005).

    Article  CAS  Google Scholar 

  110. Berner, A. K. et al. Protection against methylglyoxal-derived AGEs by regulation of glyoxalase 1 prevents retinal neuroglial and vasodegenerative pathology. Diabetologia 55, 845–854 (2012).

    Article  CAS  Google Scholar 

  111. Nerlich, A. G., Zink, A., Szeimies, U. & Hagedorn, H. G. Ancient Egyptian prosthesis of the big toe. Lancet 356, 2176–2179 (2000).

    Article  CAS  Google Scholar 

  112. Nudelman, F., de With, G. & Sommerdijk, N. A. J. M. Cryo-electron tomography: 3-dimensional imaging of soft matter. Soft Matter 7, 17–24 (2011).

    Article  CAS  Google Scholar 

  113. De Yoreo, J. J. & Sommerdijk, N. A. J. M. Investigating materials formation with liquid-phase and cryogenic TEM. Nat. Rev. Mater. 1, 16035 (2016).

    Article  CAS  Google Scholar 

  114. Verch, A., Morrison, I. E. G., van de Locht, R. & Kröger, R. In situ electron microscopy studies of calcium carbonate precipitation from aqueous solution with and without organic additives. J. Struct. Biol. 183, 270–277 (2013).

    Article  CAS  Google Scholar 

  115. Gentelman, E. et al. Comparative materials differences revealed in engineered bone as a function of cell-specific differentiation. Nat. Mater. 8, 763–770 (2009).

    Article  CAS  Google Scholar 

  116. Gordon, L. M. & Joester, D. Nanoscale chemical tomography of buried organic–inorganic interfaces in the chiton tooth. Nature 469, 194–197 (2011).

    Article  CAS  Google Scholar 

  117. Roschger, P., Paschalis, E. P., Fratzl, P. & Klaushofer, K. Bone mineralization density distribution in health and disease. Bone 42, 456–466 (2008).

    Article  CAS  Google Scholar 

  118. Achrai, B. & Wagner, H. D. Micro-structure and mechanical properties of the turtle carapace as a biological composite shield. Acta Biomater. 9, 5890–5902 (2013).

    Article  Google Scholar 

  119. Wagermaier, W. et al. Spiral twisting of fiber orientation inside bone lamellae. Biointerphases 1, 1–5 (2006).

    Article  CAS  Google Scholar 

  120. Stock, S. R., De Carlo, F. & Almer, J. D. High energy X-ray scattering tomography applied to bone. J. Struct. Biol. 161, 144–150 (2008).

    Article  CAS  Google Scholar 

  121. Rinnerthaler, S. et al. Scanning small angle X-ray scattering analysis of human bone sections. Calcif. Tissue Int. 64, 422–429 (1999).

    Article  CAS  Google Scholar 

  122. Liebi, M. et al. Nanostructure surveys of macroscopic specimens by small-angle scattering tensor tomography. Nature 527, 349–352 (2015).

    Article  CAS  Google Scholar 

  123. Li, C. et al. Strontium is incorporated into mineral crystals only in newly formed bone during strontium ranelate treatment. J. Bone Miner. Res. 25, 968–975 (2009).

    CAS  Google Scholar 

  124. Camacho, N. P. R. et al. Complementary information on bone ultrastructure from scanning small angle X-ray scattering and Fourier-transform infrared microspectroscopy. Bone 25, 287–293 (1999).

    Article  CAS  Google Scholar 

  125. Mueller, R. Hierarchical microimaging of bone structure and function. Nat. Rev. Rheumatol. 5, 373–381 (2009).

    Article  Google Scholar 

  126. Granke, M. et al. Microfibril orientation dominates the microelastic properties of human bone tissue at the lamellar length scale. PLoS ONE 8, e58046 (2013).

    Article  CAS  Google Scholar 

  127. Georgiadis, M. et al. 3D scanning SAXS: a novel method for the assessment of bone ultrastructure orientation. Bone 71, 42–52 (2015).

    Article  CAS  Google Scholar 

  128. Boskey, A. L. Bone composition: relationship to bone fragility and antiosteoporotic drug effects. Bonekey Rep. 2, 447 (2013).

    Article  CAS  Google Scholar 

  129. Kazanci, M. et al. Raman imaging of two orthogonal planes within cortical bone. Bone 41, 456–461 (2007).

    Article  CAS  Google Scholar 

  130. Weinkamer, R., Dunlop, J. W. C., Brechet, Y. & Fratzl, P. All but diamonds — biological materials are not forever. Acta Mater. 61, 880–889 (2013). Perfection is not necessarily a virtue: a broad understanding of biological materials structure underscores how ‘defects’ can be taken advantage of.

  131. King, J. D. & Bobechko, W. P. Osteogenesis Imperfecta. An orthopaedic description and surgical review. J. Bone Joint Surg. 53B, 72–89 (1984).

    Google Scholar 

  132. Harmey, D. et al. Concerted regulation of inorganic pyrophosphate and osteopontin by Akp2, Enpp1, and Ank: an integrated model of the pathogenesis of mineralization disorders. Am. J. Pathol. 164, 1199–1209 (2004).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank M. McKee (McGill University, Canada), S. Bertazzo (UCL, London), J-P St-Pierre and T. Whittaker (Imperial College London, London) for the critical reading of this manuscript and insightful comments.

Author information

Authors and Affiliations

  1. Department of Materials, Department of Bioengineering and Institute of Biomedical Engineering, Imperial College London, London, SW6 7PB, UK

    N. Reznikov & M. M. Stevens

  2. Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, SE 171 77, Sweden

    J. A. M. Steele & M. M. Stevens

  3. Department of Biomaterials, Max Planck Institute of Colloids and Interfaces, Potsdam-Golm, 14476, Germany

    P. Fratzl

Authors
  1. N. Reznikov
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. A. M. Steele
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. P. Fratzl
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. M. Stevens
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. M. Stevens.

Ethics declarations

Competing interests

The authors declare no competing interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Reznikov, N., Steele, J., Fratzl, P. et al. A materials science vision of extracellular matrix mineralization. Nat Rev Mater 1, 16041 (2016). https://doi.org/10.1038/natrevmats.2016.41

Download citation

  • Published:

  • DOI: https://doi.org/10.1038/natrevmats.2016.41

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing