Skip to main content

Nanoscale agents within 3D-printed constructs: intersection of nanotechnology and personalized bone tissue engineering

Abstract

Tissue engineering offers a solution to the worldwide shortage of bone substitutes for clinical implantation. Although the technique has been greatly improved since its first inception, one of the current problems it encounters is the lack of functionality, i.e., production of fully functional tissues and organs. This functionality could be achieved through the induction and control of cellular behavior within the tissue-engineered constructs to provide differentiation, mineralization, and vascularization. It is well documented that cellular activities in the body are strictly controlled and regulated by growth factors of several types. Therefore, controlled delivery strategies to mimic the bioavailability of the bioactive agents including growth factors became an important strategy in functional tissue engineering approaches. Moreover, the architecture of the scaffolds has absolute importance along with adaptability to the defect site so that cell behavior can be managed since the driving force of cellular activities and interconversions of the connective tissue cells (osteoblasts, chondrocytes, and fibroblasts) depend on their geometry and adhesion characteristics. 3D printing offers an important advancement along with this aim, which unites computer-aided design and computer-aided manufacturing approaches to obtain personalized structures. In this review, recent advancements in the incorporation of nanoscale agents to prepare nanocomposites as well as to produce controlled delivery platforms by using nanoparticles are described by special emphasis on 3D-printed bone tissue engineering applications.

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

Fig. 1
Fig. 2
Fig. 3

Adapted from Huang et al. (2019)

Fig. 4

References

  1. Marieb, Elaine Nicpon, Human anatomy & physiology / Elaine N. Marieb, Katja Hoehn.—9th ed.

  2. R.A.D. Carano, E.H. Filvaroff, Angiogenesis and bone repair. Drug Discovery Today 8, 980–989 (2003)

    CAS  Article  Google Scholar 

  3. A.C. Allori, A.M. Sailon, S.M. Warren, Biological basis of bone formation, remodeling, and repair- part I: biochemical signaling molecules. Tissue Eng Part B 14(3), 259–273 (2008)

    CAS  Article  Google Scholar 

  4. S.H. Lee, H. Shin, Matrices and scaffolds for delivery of bioactive molecules in bone and cartilage tissue engineering. Adv Drug Deliv Rev 59, 399–359 (2007)

    Article  CAS  Google Scholar 

  5. R. Fernandez-Urrusuno, E. Fattal, J.M. Rodrigues, J. Feger, P. Bedossa, P. Couvreur, Effect of polymeric nanoparticle administration on the clearance activity of the mononuclear phagocyte system in mice. J Biomed Mater Res 31(3), 401–408 (1996)

    CAS  Article  Google Scholar 

  6. C. Verdun, F. Brasseur, H. Vranckx, P. Couvreur, M. Roland, Tissue distribution of doxorubicin associated with polyisohexylcyanoacrylate nanoparticles. Cancer Chemother Pharmacol 26(1), 13–18 (1990)

    CAS  Article  Google Scholar 

  7. A. Rolland, B. Collet, R. Le Verge, L. Toujas, Blood clearance and organ distribution of intravenously administered polymethacrylic nanoparticles in mice. J Pharm Sci 78(6), 481–484 (1989)

    CAS  Article  Google Scholar 

  8. M.M. Patel, B.M. Patel, Crossing the blood–brain barrier: recent advances in drug delivery to the brain. CNS Drugs 31, 109–133 (2017). https://doi.org/10.1007/s40263-016-0405-9

    CAS  Article  Google Scholar 

  9. I.R. Khalil, A.T.H. Burns, I. Radecka, M. Kowalczuk, T. Khalaf, G. Adamus, B. Johnston, M.P. Khechara, Bacterial-derived polymer poly-y-glutamic acid (y-PGA)-based micro/nanoparticles as a delivery system for antimicrobials and other bio-medical applications. Int. J. Mol. Sci 18, 313 (2017). https://doi.org/10.3390/ijms18020313

    CAS  Article  Google Scholar 

  10. J.M Taboas; R.D Maddox; P.H Krebsbach; S.J Hollister (2003). Indirect solid free form fabrication of local and global porous, biomimetic and composite 3D polymer-ceramic scaffolds. , 24(1), 181–194. doi:https://doi.org/10.1016/s0142-9612(02)00276-4.

  11. J.M. Williams, A. Adewunmi, R.M. Schek, C.L. Flanagan, P.H. Krebsbach, S.E. Feinberg, S.J. Hollister, S. Das, Bone tissue engineering using polycaprolactone scaffolds fabricated via selective laser sintering. Biomaterials 26(23), 4817–4827 (2005). https://doi.org/10.1016/j.biomaterials.2004.11.057

    CAS  Article  Google Scholar 

  12. G. Rasperini, S.P. Pilipchuk, C.L. Flanagan, C.H. Park, G. Pagni, S.J. Hollister, W.V. Giannobile, 3D-printed bioresorbable scaffold for periodontal repair. J Dent Res 94(9 Suppl), 153S–7S (2015). https://doi.org/10.1177/0022034515588303

    CAS  Article  Google Scholar 

  13. N.Z. Laird, T.M. Acri, J.L. Chakka, J.C. Quarterman, W.I. Malkawi, S. Elangovan, A.K. Salem, Applications of nanotechnology in 3D printed tissue engineering scaffolds. Eur. J. Pharm. Biopharm. 161, 15–28 (2021). https://doi.org/10.1016/j.ejpb.2021.01.018

    CAS  Article  Google Scholar 

  14. Dos Santos, J., Oliveira, R. S., Oliveira, T. V., Velho, M. C., Konrad, M. V., da Silva, G. S., … Beck, R. C. R. (2021). 3D printing and nanotechnology: a multiscale alliance in personalized medicine. Advanced Functional Materials, 31(16), 2009691.https://doi.org/10.1002/adfm.202009691

  15. R. Trombetta, J.A. Inzana, E.M. Schwarz, S.L. Kates, H.A. Awad, 3D printing of calcium phosphate ceramics for bone tissue engineering and drug delivery. Ann. Biomed. Eng. 45, 23–44 (2017)

    Article  Google Scholar 

  16. J. Babilotte et al., 3D printed polymer–mineral composite biomaterials for bone tissue engineering: fabrication and characterization. J. Biomed. Mater. Res. B Appl. Biomater. 107, 2579–2595 (2019)

    CAS  Article  Google Scholar 

  17. C. Wang, Q. Zhao, M. Wang, Cryogenic 3D printing for producing hierarchical porous and rhBMP-2-loaded Ca-P/PLLA nanocomposite scaffolds for bone tissue engineering. Biofabrication 9, 025031 (2017)

    Article  CAS  Google Scholar 

  18. J. Yu, Y. Xu, S. Li, G.V. Seifert, M.L. Becker, Three-dimensional printing of nano hydroxyapatite/poly(ester urea) composite scaffolds with enhanced bioactivity. Biomacromol 18, 4171–4183 (2017)

    CAS  Article  Google Scholar 

  19. U.K. Roopavath, R. Soni, U. Mahanta, A.S. Deshpande, S.N. Rath, 3D printable SiO2 nanoparticle ink for patient specific bone regeneration. RSC Adv. 9, 23832–23842 (2019)

    CAS  Article  Google Scholar 

  20. X. Yang, et al., The stimulatory effect of silica nanoparticles on osteogenic differentiation of human mesenchymal stem cells, Biomed. Mater. 12 (2016), 015001.

  21. A.K. Jain, S. Thareja, Artif. Cells. Nanomed Biotechnol 47, 524 (2019)

    CAS  Google Scholar 

  22. Y. Zhang, F. Fang, L. Li, J. Zhang, A.C.S. Biomater, Sci. Eng. 6, 4816 (2020)

    CAS  Google Scholar 

  23. W. Yang, H. Veroniaina, X. Qi, P. Chen, F. Li, P.C. Ke, Adv. Ther. 3, 1900102 (2020)

    Article  Google Scholar 

  24. D.C. Luther, R. Huang, T. Jeon, X. Zhang, Y.W. Lee, H. Nagaraj, V.M. Rotello, Adv. Drug Delivery Rev. 156, 188 (2020)

    CAS  Article  Google Scholar 

  25. K. Khalid, X. Tan, H.F.M. Zaid, Y. Tao, C.L. Chew, D.T. Chu, M.K. Lam, Y.C. Ho, J.W. Lim, L.C. Wei, Bioengineered 11, 328 (2020)

    CAS  Article  Google Scholar 

  26. T.J. Webster, M.C. Waid, J.L. McKenzie, R.L. Price, J.U. Ejiofor, Nanobiotechnology: carbon nanofibers as improved neural and orthopedic implants. Nanotechnology 15, 48–54 (2004)

    CAS  Article  Google Scholar 

  27. G.D. Zhan, J.D. Kuntz, J. Wan, A.K. Mukherjee, Single-wall carbon nanotubes as attractive toughening agents in alumina-based nanocomposites. Nat Mater 2, 38–42 (2003)

    CAS  Article  Google Scholar 

  28. M. Jahanshahi, A.D. Kiadehi, Fabrication, purification and characterization of carbon nanotubes: arc-discharge in liquid media (ADLM). Synth. Appl. Carbon Nanotub. Their Compos. (2013). https://doi.org/10.5772/51116

    Article  Google Scholar 

  29. B. Huang et al., Fabrication and characterisation of 3D printed MWCNT composite porous scaffolds for bone regeneration. Mater. Sci. Eng. C 98, 266–278 (2019)

    CAS  Article  Google Scholar 

  30. Q. Cheng, K. Rutledge, E. Jabbarzadeh, Carbon nanotubepoly (lactide-co-glycolide) composite scaffolds for bone tissue engineering applications. Ann. Biomed. Eng. 41(904), 916 (2013)

    Google Scholar 

  31. D. Steven, L. David, M. Rakeshchandra, V. Shivaprasad, B. Brian, C. Chun-Tao, M. Kamal, Natural products for the treatment of autoimmune arthritis: Their mechanisms of action, targeted delivery, and interplay with the host microbiome. Int. J. Mol. Sci. 19(9), 2508 (2018)

    Article  CAS  Google Scholar 

  32. P.J. Yang, J.S. Temenoff, Engineering orthopedic tissue interfaces. Tissue Eng. Part B Rev. 15(2), 127–141 (2009)

    CAS  Article  Google Scholar 

  33. Y.T. Kim, J.M. Caldwell, R.V. Bellamkonda, Nanoparticle-mediated local delivery of methylprednisolone after spinal cord injury. Biomaterials 30(13), 2582–2590 (2009)

    CAS  Article  Google Scholar 

  34. C. Deng, C. Xu, Q. Zhou, Y. Cheng, Advances of nanotechnology in osteochondral regeneration. WIREs Nanomed Nanobiotechnol. 11(6), e1576 (2019). https://doi.org/10.1002/wnan.1576

    Article  Google Scholar 

  35. A. Tautzenberger, A. Kovtun, A. Ignatius, Nanoparticles and their potential for application in bone. Int J Nanomedicine 7, 4545–4557 (2012)

    CAS  Article  Google Scholar 

  36. J. Zhuang, C.H. Kuo, L.Y. Chou, D.Y. Liu, E. Weerapana, C.K. Tsung, Optimized metal-organic-framework nanospheres for drug delivery: evaluation of small-molecule encapsulation. ACS Nano 8(3), 2812–2819 (2014)

    CAS  Article  Google Scholar 

  37. B.G. Trewyn, I.I. Slowing, S. Giri, H.T. Chen, V.S. Lin, Synthesis and functionalization of a mesoporous silica nanoparticle based on the sol–gel process and applications in controlled release. Acc Chem Res 40(9), 846–853 (2007)

    CAS  Article  Google Scholar 

  38. A. Mahapatro, D.K. Singh, Biodegradable nanoparticles are excellent vehicle for site directed in-vivo delivery of drugs and vaccines. J Nanobiotechnol 9, 1–11 (2011)

    Article  CAS  Google Scholar 

  39. J.M. Orban, K.G. Marra, J.O. Hollinger, Composition options for tissue engineered bone. Tissue Eng 8(4), 529–539 (2002)

    CAS  Article  Google Scholar 

  40. G.G. Walmsley et al., Nanotechnology in bone tissue engineering. Nanomedicine 11, 1253–1263 (2015). https://doi.org/10.1016/j.nano.2015.02.013

    CAS  Article  Google Scholar 

  41. A.S. Wahajuddin, Superparamagnetic iron oxide nanoparticles: magnetic nanoplatforms as drug carriers. Int J Nanomedicine 7, 3445–3471 (2012)

    CAS  Article  Google Scholar 

  42. A. Skouras, S. Mourtas, E. Markoutsa, M.C. De Goltstein, C. Wallon, S. Catoen et al., Magnetoliposomes with high USPIO entrapping efficiency, stability and magnetic properties. Nanomedicine 7(5), 572–579 (2011)

    CAS  Article  Google Scholar 

  43. M.L. Hans, A. Lowman, Biodegradable nanoparticles for drug delivery and targeting. Curr Opinion Solid State Mater Sci 6(4), 319–327 (2002)

    CAS  Article  Google Scholar 

  44. M.D. Kofron, L. Xudong, C.T. Laurencin, Protein- and gene-based tissue engineering in bone repair. Curr. Opin. Biotechnol. 15(5), 399–405 (2004)

    CAS  Article  Google Scholar 

  45. K.H. Park, H. Kim, S. Moon, K. Na, Bone morphogenic protein-2 (BMP-2) loaded nanoparticles mixed with human mesenchymal stem cell in fibrin hydrogel for bone tissue engineering. J Biosci Bioeng 108(6), 530–537 (2009)

    CAS  Article  Google Scholar 

  46. C. Qiao, K. Zhang, H. Jin, L. Miao, C. Shi, X. Liu et al., Using poly(lactic co-glycolic acid) microspheres to encapsulate plasmid of bone morphogenetic protein 2/polyethylenimine nanoparticles to promote bone formation in vitro and in vivo. Int J Nanomedicine 8, 2985–2995 (2013)

    Google Scholar 

  47. M. Rodriguez-Evora, A. Delgado, R. Reyes, A. Hernandez-Daranas, I. Soriano, J. San Roman et al., Osteogenic effect of local, long versus short term BMP-2 delivery from a novel SPU PLGA-betaTCP concentric system in a critical size defect in rats. Eur J Pharm Sci 49(5), 873–884 (2013)

    CAS  Article  Google Scholar 

  48. T.A. Holland, E.W.H. Bodde, V.M.J.I. Cuijpers, L.S. Baggett, Y. Tabata, A.G. Mikos, J.A. Jansen, Degradable hydrogel scaffolds for in vivo delivery of single and dual growth factors in cartilage repair. Osteoarthritis Cartilage 15(2), 187–197 (2007)

    CAS  Article  Google Scholar 

  49. M.S. Lim, S. Heang, H.H.G. LeeYuk, Dual growth factor-releasing nanoparticle/hydrogel system for cartilage tissue engineering. J. Mater. Sci. - Mater. Med. 21(9), 2593 (2010)

    CAS  Article  Google Scholar 

  50. N.J. Castro, J. O’Brien, L.G. Zhang, Integrating biologically inspired nanomaterials and table-top stereolithography for 3D printed biomimetic osteochondral scaffolds. Nanoscale 7(33), 14010–14022 (2015)

    CAS  Article  Google Scholar 

  51. Y. Wan, W. Wei, D. Zeve, J.M. Suh, X. Wang, Y. Du, J.M. Graff, Biphasic and dosage-dependent regulation of osteoclastogenesis by beta-catenin. Mol. Cell. Biol. 48(23), S160–S160 (2011)

    Google Scholar 

  52. K. Kim, J.P. Fisher, Nanoparticle technology in bone tissue engineering. J Drug Target 15(4), 241–252 (2007)

    CAS  Article  Google Scholar 

  53. Andersen, M. O., Nygaard, J. V., Burns, J. S., Raarup, M. K., Nyengaard, J. R., Bunger, C., … Kjems, J. (2010). siRNA nanoparticle functionalization of nanostructured scaffolds enables controlled multilineage differentiation of stem cells. Molecular Therapy the Journal of the American Society of Gene Therapy, 18(11), 2018–2027

  54. J. Chun-Ping, C. Yu-Hung, F. Chun-Sheng, Y. Chen-Sheng, L. Yu-Cheng, S. Dar-Bin, C. Chen-Hsi, A nonviral transfection approach in vitro: the design of a gold nanoparticle vector joint with microelectromechanical systems. Langmuir the ACS Journal of Surfaces & Colloids 20(4), 1369 (2004)

    Article  CAS  Google Scholar 

  55. G. Zhang, B. Guo, H. Wu, T. Tang, B.T. Zhang, L. Zheng, H. Chow, A delivery system targeting bone formation surfaces to facilitate RNAi-based anabolic therapy. Nat. Med. 18(2), 307–314 (2012)

    Article  CAS  Google Scholar 

  56. P. Hairong, W. Vonda, U. Arvydas, G. Brian, S. Hsain-Chung, C. James, H. Johnny, Synergistic enhancement of bone formation and healing by stem cell-expressed VEGF and bone morphogenetic protein-4. J. Clin. Investig. 355(6), 751–759 (2002)

    Google Scholar 

  57. M.D. Krebs, E. Salter, E. Chen, K.A. Sutter, E. Alsberg, Calcium phosphate DNA nanoparticle gene delivery from alginate hydrogels induces in vivo osteogenesis. J. Biomed. Mater. Res., Part A 92A(3), 1131–1138 (2010)

    CAS  Google Scholar 

  58. S. Odabas, G.A. Feichtinger, P. Korkusuz, I. Inci, E. Bilgic, A.S. Yar, E. Piskin, Auricular cartilage repair using cryogel scaffolds loaded with BMP-7-expressing primary chondrocytes. J. Tissue Eng. Regen. Med. 7(10), 831–840 (2013)

    CAS  Google Scholar 

  59. F. Shahabipour, N. Ashammakhi, R.K. Oskuee, S. Bonakdar, T. Hoffman, M.A. Shokrgozar, A. Khademhosseini, Key components of engineering vascularized 3-dimensional bioprinted bone constructs. Transl. Res. 216, 57–76 (2020). https://doi.org/10.1016/j.trsl.2019.08.010

    CAS  Article  Google Scholar 

  60. E.Y. Heo, N.R. Ko, M.S. Bae, S.J. Lee, B.J. Choi, J.H. Kim, H.K. Kim, S.A. Park, I.K. Kwon, Novel 3D printed alginate–BFP1 hybrid scaffolds for enhanced bone regeneration. J. Ind. Eng. Chem. 45, 61–67 (2017). https://doi.org/10.1016/j.jiec.2016.09.003

    CAS  Article  Google Scholar 

  61. G. Turnbull, J. Clarke, F. Picard, P. Riches, L. Jia, F. Han, B. Li, W. Shu, 3D bioactive composite scaffolds for bone tissue engineering. Bioact. Mater. 3, 278–314 (2018). https://doi.org/10.1016/j.bioactmat.2017.10.001

    Article  Google Scholar 

  62. Z. Wan, P. Zhang, Y. Liu, L. Lv, Y. Zhou, Four-dimensional bioprinting: current developments and applications in bone tissue engineering. Acta Biomater. 101, 26–42 (2020)

    CAS  Article  Google Scholar 

  63. N. Beheshtizadeh, N. Lotfibakhshaiesh, Z. Pazhouhnia, M. Hoseinpour, M. Nafari, A review of 3D bio-printing for bone and skin tissue engineering: a commercial approach. J. Mater. Sci. 55, 3729–3749 (2020)

    CAS  Article  Google Scholar 

  64. M.N. Sithole, P. Kumar, L.C. du Toit, T. Marimuthu, Y.E. Choonara, V. Pillay, A 3D bioprinted in situ conjugated-co-fabricated scaffold for potential bone tissue engineering applications. J. Biomed. Mater. Res. A 106, 1311–1321 (2018)

    CAS  Article  Google Scholar 

  65. H.-J. Jeong, H. Nam, J. Jang, S.-J. Lee, 3D bioprinting strategies for the regeneration of functional tubular tissues and organs. Bioengineering 7, 32 (2020)

    CAS  Article  Google Scholar 

  66. Y. Luo, Y. Li, X. Qin, Q. Wa, 3D printing of concentrated alginate/gelatin scaffolds with homogeneous nano apatite coating for bone tissue engineering. Mater. Des. 146, 12–19 (2018)

    CAS  Article  Google Scholar 

  67. H. Lee, G.H. Yang, M. Kim, J. Lee, J. Huh, G. Kim, Fabrication of micro/ nanoporous collagen/dECM/silk-fibroin biocomposite scaffolds using a low temperature 3D printing process for bone tissue regeneration. Mater. Sci. Eng. C 84, 140–147 (2018)

    CAS  Article  Google Scholar 

  68. I. Noh, N. Kim, H.N. Tran, J. Lee, C. Lee, 3D printable hyaluronic acid-based hydrogel for its potential application as a bioink in tissue engineering. Biomater. Res. 23, 3 (2019)

    Article  Google Scholar 

  69. A. Haleem, M. Javaid, R.H. Khan, R. Suman, 3D printing applications in bone tissue engineering. J. Clin. Orthopaedics Trauma 11, S118–S124 (2020)

    Article  Google Scholar 

  70. M. Neufurth, X. Wang, S. Wang, R. Steffen, M. Ackermann, N.D.H.C. HaepSchr¨oder, W.E.G. Müller, 3D printing of hybrid biomaterials for bone tissue engineering: calcium-polyphosphate microparticles encapsulated by polycaprolactone. Acta Biomater 64, 377–388 (2017)

    CAS  Article  Google Scholar 

  71. D. Zhao, T. Zhu, J. Li, L. Cui, Z. Zhang, X. Zhuang, J. Ding, Poly(lactic-co-glycolic acid)-based composite bone-substitute materials. Bioactive Mater. 6, 346–360 (2021)

    CAS  Article  Google Scholar 

  72. C.M.B. Ho et al., 3D printed polycaprolactone carbon nanotube composite scaffolds for cardiac tissue engineering. Macromol. Biosci. 17, 1600250 (2017)

    Article  CAS  Google Scholar 

  73. M. Izadifar, D. Chapman, P. Babyn, X. Chen, M.E. Kelly, UV-assisted 3D bioprinting of nanoreinforced hybrid cardiac patch for myocardial tissue engineering, Tissue Eng. Part C. Methods 24, 74–88 (2018)

    CAS  Google Scholar 

  74. 3D printed medical parts with different materials using additive manufacturing. Clinical Epidemiology and Global Health, 8(1), 215–223.

  75. Current status and applications of additive manufacturing in dentistry: a literature-based review. Journal of oral biology and craniofacial research, 9(3), 179–185.

  76. Additive manufacturing applications in medical cases: a literature based review. Alexandria Journal of Medicine, 54(4), 411–422.

  77. Polyether ether ketone (PEEK) and its 3D printed implants applications in medical field: an overview. Clinical Epidemiology and Global Health, 7(4), 571–577.

  78. Polyether ether ketone (PEEK) and its manufacturing of customised 3D printed dentistry parts using additive manufacturing. Clinical Epidemiology and Global Health, 7(4), 654–660.

  79. 3D printing for development of medical equipment amidst coronavirus (COVID-19) pandemic—review and advancements. Research on Biomedical Engineering, 1–11.

  80. Exploring the significant applications of Internet of Things (IoT) with 3D printing using advanced materials in medical field. Materials Today: Proceedings.

  81. 3D printed tissue and organ using additive manufacturing: an overview. Clinical Epidemiology and Global Health, 8(2), 586–594.'

  82. Automation and manufacturing of smart materials in additive manufacturing technologies using Internet of Things towards the adoption of Industry 4.0. Materials Today: Proceedings.

  83. Additive manufacturing applications in orthopaedics: a review. Journal of clinical orthopaedics and trauma, 9(3), 202–206.

Download references

Acknowledgements

The authors would like to thank the Scientific and Technological Research Council of Turkey (TUBITAK) grant no. 119S131 for providing financial support.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Pinar Yilgor Huri.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Hindy, O.A., Goker, M. & Yilgor Huri, P. Nanoscale agents within 3D-printed constructs: intersection of nanotechnology and personalized bone tissue engineering. emergent mater. 5, 195–205 (2022). https://doi.org/10.1007/s42247-022-00366-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s42247-022-00366-y

Keywords

  • Nanotechnology
  • Nanoparticles
  • Controlled release
  • Bone tissue engineering
  • Scaffold
  • 3D printing
  • Bioprinting