Nanotechnology for Orthopedic Applications: From Manufacturing Processes to Clinical Applications

  • Dan Hickey
  • Thomas WebsterEmail author


This chapter covers the integration of artificial materials into natural tissues of the human body, particularly bone, and what can be achieved through a couple of key nano-manufacturing techniques (such as shot peening and electrophoretic deposition). To achieve proper mechanical anchorage and integration, orthopedic implanted materials should resemble the tissues they are replacing as much as possible. Thus, provided here is an overview of the structure and function of bone tissues, as well as a review of the concepts and methods used by other researchers attempting to regenerate orthopedic tissues, with a focus on nanotechnology.


Bone Spine Nanomedicine Growth Inflammation Infection Nanotextured Nano-topography Fibroblasts 


  1. 1.
    Magnusson SP, Langberg H, Kjaer M. The pathogenesis of tendinopathy: balancing the response to loading. Nat Rev Rheumatol. 2010;6(5):262–8.CrossRefPubMedGoogle Scholar
  2. 2.
    Sechler JL, Corbett SA, Wenk MB, Schwarzbauer JE. Modulation of cell-extracellular matrix interactions. Ann N Y Acad Sci. 1998;857:143–54.CrossRefPubMedGoogle Scholar
  3. 3.
    Sanes JR, Engvall E, Butkowski R, Hunter DD. Molecular heterogeneity of basal laminae: isoforms of laminin and collagen IV at the neuromuscular junction and elsewhere. J Cell Biol. 1990;111(4):1685–99.CrossRefPubMedGoogle Scholar
  4. 4.
    Barnes CP, Sell SA, Boland ED, Simpson DG, Bowlin GL. Nanofiber technology: designing the next generation of tissue engineering scaffolds. Adv Drug Deliv Rev. 2007;59:1413–33.CrossRefPubMedGoogle Scholar
  5. 5.
    Slavik GJ, Ragetly G, Ganesh N, Griffon DJ, Cunningham B. A replica molding technique for producing fibrous chitosan scaffolds for caritlage engineering. J Mater Chem. 2007;17:4095–101.CrossRefGoogle Scholar
  6. 6.
    Ma P. Biomimetic materials for tissue engineering. Adv Drug Deliv Rev. 2008;60(2):184–98.CrossRefPubMedGoogle Scholar
  7. 7.
    Flaumenhaft R, Rifkin DB. The extracellular regulation of growth factor action. Mol Biol Cell. 1992;3(10):1057–65.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Streuli CH, Schmidhauser C, Kobrin M, Bissell MJ, Derynck R. Extracellular matrix regulates expression of the TGF-beta 1 gene. J Cell Biol. 1993;120(1):253–60.CrossRefPubMedGoogle Scholar
  9. 9.
    Schuppan D, Schmid M, Somasundaram R, Ackermann R, Ruehl M, Nakamura T, Riecken E. Collagens in the liver extracellular matrix bind hepatocyte growth factor. Gastroenterology. 1998;114(1):139–52.CrossRefPubMedGoogle Scholar
  10. 10.
    Benoit DSW, Anseth KS. Nanostructured scaffolds for tissue engineering. In: Peppas NA, editor. Nanotechnology in therapeutics: current technology and applications. London: Taylor & Francis; 2007. p. 205–38.Google Scholar
  11. 11.
    Ravin T. Tensegrity to tendinosis. J Prolother. 2011;3(4):826–35.Google Scholar
  12. 12.
    Giancotti FG. Integrin signaling: specificity and control of cell survival and cell cycle progression. Curr Opin Cell Biol. 1997;9(5):691–700.CrossRefPubMedGoogle Scholar
  13. 13.
    Hemler ME. Integrin associated proteins. Curr Opin Cell Biol. 1998;10(5):578–85.CrossRefPubMedGoogle Scholar
  14. 14.
    Ruoslahti E, Yamaguchi Y, Hildebrand A, Border WA. Extracellular matrix/growth factor interactions. Cold Spring Harb Symp Quant Biol. 1992;57:309–15.CrossRefPubMedGoogle Scholar
  15. 15.
    Hynes RO. Integrins: a family of cell surface receptors. Cell. 1987;48(4):549–54.CrossRefPubMedGoogle Scholar
  16. 16.
    Hynes RO. Integrins: versatility, modulation, and signaling in cell adhesion. Cell. 1992;69(1):11–25.CrossRefPubMedGoogle Scholar
  17. 17.
    Rho JY, Juhn-Spearing L, Zioupos P. Mechanical properties and the hierarchical structure of bone. Med Eng Phys. 1998;20(2):92–102.CrossRefPubMedGoogle Scholar
  18. 18.
    Weiner S, Traub W. Bone structure: from angstroms to microns. FASEB J. 1992;6(3):879–85.CrossRefPubMedGoogle Scholar
  19. 19.
    Rho JY, Ashman RB, Turner CH. Young’s modulus of trabecular and cortical bone material: ultrasonic and microtensile measurements. J Biomech. 1993;26(2):111–9.CrossRefPubMedGoogle Scholar
  20. 20.
    Viola J, Lal B, Grad O. The emergence of tissue engineering as a research field. Arlington, VA: The National Science Foundation; 2003.Google Scholar
  21. 21.
    Berthiaume F, Maguire TJ, Yarmush ML. Tissue engineering and regenerative medicine: history, progress, and challenges. Annu Rev Chem Biomol Eng. 2011;2:403–30.CrossRefPubMedGoogle Scholar
  22. 22.
    Langer R, Vacanti JP. Tissue engineering. Science. 1993;260(5110):920–6.CrossRefGoogle Scholar
  23. 23.
    Nerem R. Regenerative medicine: the emergence of an industry. J R Soc Interface. 2010;7:S771–5.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    “Goldstein Research Group Homepage.” [Online].
  25. 25.
    Webster TJ. From nanotechnology to picotechnology: what is on the horizon? Nanotek-2013, OMICS International, Nanotek Expo, 2013.Google Scholar
  26. 26.
    Zhang L, Webster TJ. Nanotechnology and nanomaterials: promises for improved tissue regeneration. Nano Today. 2009;4(1):66–80.CrossRefGoogle Scholar
  27. 27.
    Woo KM, Chen VJ, Ma PX. Nano-fibrous scaffolding architecture selectively enhances protein adsorption contributing to cell attachment. J Biomed Mater Res A. 2003;67(2):531–7.CrossRefPubMedGoogle Scholar
  28. 28.
    Bettinger CJ, Langer R, Borenstein JT. Engineering substrate topography at the micro- and nanoscale to control cell function. Angew Chem Int Ed Engl. 2009;48(30):5406–15.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Teixeira AI, Abrams GA, Bertics PJ, Murphy CJ, Nealey PF. Epithelial contact guidance on well-defined micro- and nanostructured substrates. J Cell Sci. 2003;116:1881–92.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Wójciak-Stothard B, Curtis AS, Monaghan W, McGrath M, Sommer I, Wilkinson CD. Role of the cytoskeleton in the reaction of fibroblasts to multiple grooved substrata. Cell Motil Cytoskeleton. 1995;31(2):147–58.CrossRefPubMedGoogle Scholar
  31. 31.
    Dvir T, Timko BP, Kohane DS, Langer R. Nanotechnological strategies for engineering complex tissues. Nat Nanotechnol. 2011;6:13–22.CrossRefPubMedGoogle Scholar
  32. 32.
    Weiner S, Wagner HD. THE MATERIAL BONE: structure-mechanical function relations. Annu Rev Mater Sci. 1998;28(1):271–98.CrossRefGoogle Scholar
  33. 33.
    Song J, Malathong V, Bertozzi CR. Mineralization of synthetic polymer scaffolds: a bottom-up approach for the development of artificial bone. J Am Chem Soc. 2005;127(10):3366–72.CrossRefPubMedGoogle Scholar
  34. 34.
    Willmann G. Coating of implants with hydroxyapatite—material connections between bone and metal. Adv Eng Mater. 1999;1(2):95–105.CrossRefGoogle Scholar
  35. 35.
    Danie Kingsley J, Ranjan S, Dasgupta N, Saha P. Nanotechnology for tissue engineering: need, techniques and applications. J Pharm Res. 2013;7(2):200–4.Google Scholar
  36. 36.
    Navarro M, Michiardi A, Castano O, Planell JA. Biomaterials in orthopaedics. J R Soc Interface. 2008;5(27):1137–58.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Laurencin CT, Ambrosio AM, Borden MD, Cooper JA Jr. Tissue engineering: orthopedic applications. Annu Rev Biomed Eng. 1999;1:19–46.CrossRefPubMedGoogle Scholar
  38. 38.
    Brydone A, Meek D, Maclaine S. Bone grafting, orthopaedic biomaterials, and the clinical need for bone engineering. Proc Inst Mech Eng H. 2010;224(12):1329–43.CrossRefPubMedGoogle Scholar
  39. 39.
    Reid RL. Hernia through an iliac bone-graft donor site. A case report. J Bone Joint Surg Am. 1968;50(4):757–60.CrossRefPubMedGoogle Scholar
  40. 40.
    Dickson G, Buchanan F, Marsh D, Harkin-Jones E, Little U, McCaigue M. Orthopaedic tissue engineering and bone regeneration. Technol Health Care. 2007;15(1):57–67.PubMedGoogle Scholar
  41. 41.
    Ludwig SC, Kowalski JM, Boden SD. Osteoinductive bone graft substitutes. Eur Spine J. 2000;9(Suppl 1):S119–25.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Trampuz A, Zimmerli W. Diagnosis and treatment of infections associated with fracture-fixation devices. Injury. 2006;37(Suppl 2):S59–66.CrossRefPubMedGoogle Scholar
  43. 43.
    Spellberg B, Bartlett JG, Gilbert DN. The future of antibiotics and resistance. N Engl J Med. 2013;368(4):299–302.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Laxminarayan R, Duse A, Wattal C, Zaidi AKM, Wertheim HFL, Sumpradit N, Vlieghe E, Hara GL, Gould IM, Goossens H, Greko C, So AD, Bigdeli M, Tomson G, Woodhouse W, Ombaka E, Peralta AQ, Qamar FN, Mir F, Kariuki S, Bhutta ZA, Coates A, Bergstrom R, Wright GD, Brown ED, Cars O. Antibiotic resistance—the need for global solutions. Lancet Infect Dis. 2013;13(12):1057–98.CrossRefPubMedGoogle Scholar
  45. 45.
    Neu HC. The crisis in antibiotic resistance. Science. 1992;257(5073):1064–73.CrossRefPubMedGoogle Scholar
  46. 46.
    Laurencin C, Khan Y, El-Amin SF. Bone graft substitutes. Expert Rev Med Devices. 2006;3(1):49–57.CrossRefPubMedGoogle Scholar
  47. 47.
    Desai BM. Osteobiologics. Am J Orthop (Belle Mead NJ). 2007;36(4 Suppl):8–11.Google Scholar
  48. 48.
    De Long WG, Einhorn TA, Koval K, McKee M, Smith W, Sanders R, Watson T. Bone grafts and bone graft substitutes in orthopaedic trauma surgery. A critical analysis. J Bone Joint Surg Am. 2007;89(3):649–58.CrossRefPubMedGoogle Scholar
  49. 49.
    Toolan BC. Current concepts review: orthobiologics. Foot Ankle Int. 2006;27(7):561–6.CrossRefPubMedGoogle Scholar
  50. 50.
    Zhao G, Zinger O, Schwartz Z, Wieland M, Landolt D, Boyan BD. Osteoblast-like cells are sensitive to submicron-scale surface structure. Clin Oral Implants Res. 2006;17(3):258–64.CrossRefPubMedGoogle Scholar
  51. 51.
    McManus AJ, Doremus RH, Siegel RW, Bizios R. Evaluation of cytocompatibility and bending modulus of nanoceramic/polymer composites. J Biomed Mater Res A. 2005;72(1):98–106.CrossRefPubMedGoogle Scholar
  52. 52.
    Webster TJ, Ergun C, Doremus RH, Siegel RW, Bizios R. Specific proteins mediate enhanced osteoblast adhesion on nanophase ceramics. J Biomed Mater Res. 2000;51(3):475–83.CrossRefPubMedGoogle Scholar
  53. 53.
    Price RL, Gutwein LG, Kaledin L, Tepper F, Webster TJ. Osteoblast function on nanophase alumina materials: influence of chemistry, phase, and topography. J Biomed Mater Res A. 2003;67(4):1284–93.CrossRefPubMedGoogle Scholar
  54. 54.
    Shalabi MM, Gortemaker A, Van’t Hof MA, Jansen JA, Creugers NHJ. Implant surface roughness and bone healing: a systematic review. J Dent Res. 2006;85(6):496–500.CrossRefPubMedGoogle Scholar
  55. 55.
    Dolatshahi-Pirouz A, Nikkhah M, Kolind K, Dokmeci MR, Khademhosseini A. Micro- and nanoengineering approaches to control stem cell-biomaterial interactions. J Funct Biomater. 2011;2(4):88–106.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Dolatshahi-Pirouz A, Jensen T, Kraft DC, Foss M, Kingshott P, Hansen JL, Larsen AN, Chevallier J, Besenbacher F. Fibronectin adsorption, cell adhesion, and proliferation on nanostructured tantalum surfaces. ACS Nano. 2010;4(5):2874–82.CrossRefPubMedGoogle Scholar
  57. 57.
    Bagherifard S, Ghelichi R, Khademhosseini A, Guagliano M. Cell response to Nanocrystallized metallic substrates obtained through severe plastic deformation. ACS Appl Mater Interfaces. 2014;6(11):7963–85.CrossRefPubMedGoogle Scholar
  58. 58.
    Nikkhah M, Edalat F, Manoucheri S, Khademhosseini A. Engineering microscale topographies to control the cell-substrate interface. Biomaterials. 2012;33(21):5230–46.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Webster TJ, Ergun C, Doremus RH, Siegel RW, Bizios R. Enhanced functions of osteoblasts on nanophase ceramics. Biomaterials. 2000;21(17):1803–10.CrossRefPubMedGoogle Scholar
  60. 60.
    Guvendiren M, Burdick JA. Stiffening hydrogels to probe short- and long-term cellular responses to dynamic mechanics. Nat Commun. 2012;3:792.CrossRefPubMedGoogle Scholar
  61. 61.
    Hallab NJ, Bundy KJ, O’Connor K, Moses RL, Jacobs JJ. Evaluation of metallic and polymeric biomaterial surface energy and surface roughness characteristics for directed cell adhesion. Tissue Eng. 2001;7(1):55–71.CrossRefPubMedGoogle Scholar
  62. 62.
    Kieswetter K, Schwartz Z, Dean DD, Boyan BD. The role of implant surface characteristics in the healing of bone. Crit Rev Oral Biol Med. 1996;7(4):329–45.CrossRefPubMedGoogle Scholar
  63. 63.
    Zhao G, Raines AL, Wieland M, Schwartz Z, Boyan BD. Requirement for both micron- and submicron scale structure for synergistic responses of osteoblasts to substrate surface energy and topography. Biomaterials. 2007;28(18):2821–9.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Zhao G, Schwartz Z, Wieland M, Rupp F, Geis-Gerstorfer J, Cochran DL, Boyan BD. High surface energy enhances cell response to titanium substrate microstructure. J Biomed Mater Res Part A. 2005;74A(1):49–58.CrossRefGoogle Scholar
  65. 65.
    Ribeiro M, Monteiro FJ, Ferraz MP. Infection of orthopedic implants with emphasis on bacterial adhesion process and techniques used in studying bacterial-material interactions. Biomatter. 2012;2(4):176–94.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Donlan RM. Biofilms: microbial life on surfaces. Emerg Infect Dis. 2002;8(9):881–90.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Nazhat SN, Young AM, Pratten J. Sterility and infection. In: Biomedical materials. Boston, MA: Springer US; 2009. p. 239–60.CrossRefGoogle Scholar
  68. 68.
    Davies D. Understanding biofilm resistance to antibacterial agents. Nat Rev Drug Discov. 2003;2(2):114–22.Google Scholar
  69. 69.
    Gristina AG, Naylor P, Myrvik Q. Infections from biomaterials and implants: a race for the surface. Med Prog Technol. 14(3–4):205–24.Google Scholar
  70. 70.
    Puckett SD, Taylor E, Raimondo T, Webster TJ. The relationship between the nanostructure of titanium surfaces and bacterial attachment. Biomaterials. 2010;31(4):706–13.CrossRefPubMedGoogle Scholar
  71. 71.
    Epstein AK, Hochbaum AI, Kim P, Aizenberg J. Control of bacterial biofilm growth on surfaces by nanostructural mechanics and geometry. Nanotechnology. 2011;22(49):494007.CrossRefPubMedGoogle Scholar
  72. 72.
    Ivanova EP, Truong VK, Wang JY, Berndt CC, Jones RT, Yusuf II, Peake I, Schmidt HW, Fluke C, Barnes D, Crawford RJ. Impact of nanoscale roughness of titanium thin film surfaces on bacterial retention. Langmuir. 2010;26(3):1973–82.CrossRefPubMedGoogle Scholar
  73. 73.
    Kerr A, Cowling MJ. The effects of surface topography on the accumulation of biofouling. Philos Mag. 2003;83(24):2779–95.CrossRefGoogle Scholar
  74. 74.
    Whitehead KA, Verran J. The effect of surface topography on the retention of microorganisms. Food Bioprod Process. 2006;84(4):253–9.CrossRefGoogle Scholar
  75. 75.
    Graham M, Cady N. Nano and Microscale topographies for the prevention of bacterial surface fouling. Coatings. 2014;4(1):37–59.CrossRefGoogle Scholar
  76. 76.
    Helbig R, Günther D, Friedrichs J, Rößler F, Lasagni A, Werner C. The impact of structure dimensions on initial bacterial adhesion. Biomater Sci. 2016;4(7):1074–8.CrossRefPubMedGoogle Scholar
  77. 77.
    Bagherifard S, Guagliano M. Fatigue behavior of a low-alloy steel with nanostructured surface obtained by severe shot peening. Eng Fract Mech. 2012;81:56–68.CrossRefGoogle Scholar
  78. 78.
    Bagherifard S, Fernandez-Pariente I, Ghelichi R, Guagliano M. Fatigue behavior of notched steel specimens with nanocrystallized surface obtained by severe shot peening. Mater Des. 2013;45:497–503.CrossRefGoogle Scholar
  79. 79.
    Bagherifard S, Hickey DJ, de Luca AC, Malheiro VN, Markaki AE, Guagliano M, Webster TJ. The influence of nanostructured features on bacterial adhesion and bone cell functions on severely shot peened 316L stainless steel. Biomaterials. 2015;73:185–97.CrossRefPubMedGoogle Scholar
  80. 80.
    Besra L, Liu M. A review on fundamentals and applications of electrophoretic deposition (EPD). Prog Mater Sci. 2007;52(1):1–61.CrossRefGoogle Scholar
  81. 81.
    Mathew D, Bhardwaj G, Wang Q, Webster TJ. Decreased Staphylococcus aureus and increased osteoblast density on nanostructured electrophoretic-deposited hydroxyapatite on titanium without the use of pharmaceuticals. Int J Nanomed. 2014;9:1775–81.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Chemical EngineeringNortheastern UniversityBostonUSA

Personalised recommendations