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:

Materials design for bone-tissue engineering

Nature Reviews Materials volume 5, pages 584–603 (2020)Cite this article

Subjects

Abstract

Successful materials design for bone-tissue engineering requires an understanding of the composition and structure of native bone tissue, as well as appropriate selection of biomimetic natural or tunable synthetic materials (biomaterials), such as polymers, bioceramics, metals and composites. Scalable fabrication technologies that enable control over construct architecture at multiple length scales, including three-dimensional printing and electric-field-assisted techniques, can then be employed to process these biomaterials into suitable forms for bone-tissue engineering. In this Review, we provide an overview of materials-design considerations for bone-tissue-engineering applications in both disease modelling and treatment of injuries and disease in humans. We outline the materials-design pathway from implementation strategy through selection of materials and fabrication methods to evaluation. Finally, we discuss unmet needs and current challenges in the development of ideal materials for bone-tissue regeneration and highlight emerging strategies in the field.

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

Fig. 1: Timeline of major milestones in biomaterials design for bone-tissue engineering.
Fig. 2: Bone physiology for biomimicry of candidate biomaterials for bone-tissue engineering.
Fig. 3: Important fabrication techniques for bone-tissue-engineering materials.

Similar content being viewed by others

References

  1. Annamalai, R. T. et al. Injectable osteogenic microtissues containing mesenchymal stromal cells conformally fill and repair critical-size defects. Biomaterials 208, 32–44 (2019).

    CAS  Google Scholar 

  2. Zhang, X. J., Li, Y., Chen, Y. E., Chen, J. H. & Ma, P. X. Cell-free 3D scaffold with two-stage delivery of miRNA-26a to regenerate critical-sized bone defects. Nat. Commun. 7, 10376 (2016).

    CAS  Google Scholar 

  3. Schemitsch, E. H. Size matters: defining critical in bone defect size! J. Orthop. Trauma 31, S20–S22 (2017).

    Google Scholar 

  4. Atala, A., Kasper, F. K. & Mikos, A. G. Engineering complex tissues. Sci. Transl. Med. 4, 160rv12 (2012).

    Google Scholar 

  5. McDermott, A. M. et al. Recapitulating bone development through engineered mesenchymal condensations and mechanical cues for tissue regeneration. Sci. Transl. Med. 11, eaav7756 (2019).

    CAS  Google Scholar 

  6. Lee, J. W. et al. Long-term clinical study and multiscale analysis of in vivo biodegradation mechanism of Mg alloy. Proc. Natl Acad. Sci. USA 113, 716–721 (2016). These researchers studied the bone-forming mechanism of biodegradable magnesium alloy implants and conducted a clinical study that confirmed total implant degradation and bone-defect regeneration within 1 year.

    CAS  Google Scholar 

  7. Bhumiratana, S. et al. Tissue-engineered autologous grafts for facial bone reconstruction. Sci. Transl. Med. 8, 343ra83 (2016).

    Google Scholar 

  8. Bez, M. et al. In situ bone tissue engineering via ultrasound-mediated gene delivery to endogenous progenitor cells in mini-pigs. Sci. Transl. Med. 9, eaal3128 (2017).

    Google Scholar 

  9. Norris, C. J., Meadway, G. J., O’Sullivan, M. J., Bond, I. P. & Trask, R. S. Self-healing fibre reinforced composites via a bioinspired vasculature. Adv. Funct. Mater. 21, 3624–3633 (2011).

    CAS  Google Scholar 

  10. Dorozhkin, S. V. A detailed history of calcium orthophosphates from 1770s till 1950. Mater. Sci. Eng. C 33, 3085–3110 (2013).

    CAS  Google Scholar 

  11. Woodruff, M. A. et al. Bone tissue engineering: from bench to bedside. Mater. Today 15, 430–435 (2012).

    CAS  Google Scholar 

  12. Martino, M. M. et al. Growth factors engineered for super-affinity to the extracellular matrix enhance tissue healing. Science 343, 885–888 (2014).

    CAS  Google Scholar 

  13. Liu, Y., Luo, D. & Wang, T. Hierarchical structures of bone and bioinspired bone tissue engineering. Small 12, 4611–4632 (2016).

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  15. Bohner, M. & Miron, R. J. A proposed mechanism for material-induced heterotopic ossification. Mater. Today 22, 132–141 (2019).

    CAS  Google Scholar 

  16. Gautieri, A., Vesentini, S., Redaelli, A. & Buehler, M. J. Hierarchical structure and nanomechanics of collagen microfibrils from the atomistic scale up. Nano Lett. 11, 757–766 (2011).

    CAS  Google Scholar 

  17. Liu, Y. et al. Hierarchical intrafibrillar nanocarbonated apatite assembly improves the nanomechanics and cytocompatibility of mineralized collagen. Adv. Funct. Mater. 23, 1404–1411 (2013).

    CAS  Google Scholar 

  18. Feng, C. et al. 3D printing of lotus root-like biomimetic materials for cell delivery and tissue regeneration. Adv. Sci. 4, 1700401 (2017).

    Google Scholar 

  19. Zhou, T. et al. A mussel-inspired persistent ROS-scavenging, electroactive, and osteoinductive scaffold based on electrochemical-driven in situ nanoassembly. Small 15, e1805440 (2019).

    Google Scholar 

  20. Ryu, J., Ku, S. H., Lee, H. & Park, C. B. Mussel-inspired polydopamine coating as a universal route to hydroxyapatite crystallization. Adv. Funct. Mater. 20, 2132–2139 (2010).

    CAS  Google Scholar 

  21. Hu, X. X. et al. A difunctional regeneration scaffold for knee repair based on aptamer-directed cell recruitment. Adv. Mater. 29, 1605235 (2017).

    Google Scholar 

  22. Yu, L. et al. BMP9 stimulates joint regeneration at digit amputation wounds in mice. Nat. Commun. 10, 424 (2019).

    CAS  Google Scholar 

  23. Hunter, N. L. & Sherman, R. E. Combination products: modernizing the regulatory paradigm. Nat. Rev. Drug Discov. 16, 513–514 (2017).

    CAS  Google Scholar 

  24. Burdick, J. A., Mauck, R. L., Gorman, J. H. 3rd & Gorman, R. C. Acellular biomaterials: an evolving alternative to cell-based therapies. Sci. Transl. Med. 5, 176ps4 (2013).

    Google Scholar 

  25. Wang, S. et al. Mineralized collagen-based composite bone materials for cranial bone regeneration in developing sheep. ACS Biomater. Sci. Eng. 3, 1092–1099 (2017).

    CAS  Google Scholar 

  26. Wang, S. et al. A high-strength mineralized collagen bone scaffold for large-sized cranial bone defect repair in sheep. Regen. Biomater. 5, 283–292 (2018).

    CAS  Google Scholar 

  27. Kim, Y. S., Smoak, M. M., Melchiorri, A. J. & Mikos, A. G. An overview of the tissue engineering market in the United States from 2011 to 2018. Tissue Eng. A 25, 1–8 (2019).

    CAS  Google Scholar 

  28. Kretlow, J. D., Young, S., Klouda, L., Wong, M. & Mikos, A. G. Injectable biomaterials for regenerating complex craniofacial tissues. Adv. Mater. 21, 3368–3393 (2009).

    CAS  Google Scholar 

  29. Reichert, J. C. et al. A tissue engineering solution for segmental defect regeneration in load-bearing long bones. Sci. Transl. Med. 4, 141ra93 (2012).

    Google Scholar 

  30. Du, Y., Guo, J. L., Wang, J., Mikos, A. G. & Zhang, S. Hierarchically designed bone scaffolds: from internal cues to external stimuli. Biomaterials 218, 119334 (2019).

    CAS  Google Scholar 

  31. Jin, S. S. et al. A biomimetic hierarchical nanointerface orchestrates macrophage polarization and mesenchymal stem cell recruitment to promote endogenous bone regeneration. ACS Nano 13, 6581–6595 (2019).

    CAS  Google Scholar 

  32. Stuckensen, K. et al. Tissue mimicry in morphology and composition promotes hierarchical matrix remodeling of invading stem cells in osteochondral and meniscus scaffolds. Adv. Mater. 30, 1706754 (2018).

    Google Scholar 

  33. Jakus, A. E. et al. Hyperelastic “bone”: a highly versatile, growth factor-free, osteoregenerative, scalable, and surgically friendly biomaterial. Sci. Transl. Med. 8, 358ra127 (2016).

    Google Scholar 

  34. Roohani-Esfahani, S. I., Newman, P. & Zreiqat, H. Design and fabrication of 3D printed scaffolds with a mechanical strength comparable to cortical bone to repair large bone defects. Sci. Rep. 6, 19468 (2016).

    CAS  Google Scholar 

  35. Nasajpour, A. et al. A multifunctional polymeric periodontal membrane with osteogenic and antibacterial characteristics. Adv. Funct. Mater. 28, 1703437 (2018).

    Google Scholar 

  36. Holloway, J. L. One step solution for fighting bacteria and growing bone. Sci. Transl. Med. 11, eaaw5326 (2019).

    Google Scholar 

  37. Lai, Y. X. et al. Porous composite scaffold incorporating osteogenic phytomolecule icariin for promoting skeletal regeneration in challenging osteonecrotic bone in rabbits. Biomaterials 153, 1–13 (2018).

    CAS  Google Scholar 

  38. Li, C. Y. et al. Engineered multifunctional nanomedicine for simultaneous stereotactic chemotherapy and inhibited osteolysis in an orthotopic model of bone metastasis. Adv. Mater. 29, 1605754 (2017).

    Google Scholar 

  39. Mora-Raimundo, P., Lozano, D., Manzano, M. & Vallet-Regi, M. Nanoparticles to knockdown osteoporosis-related gene and promote osteogenic marker expression for osteoporosis treatment. ACS Nano 13, 5451–5464 (2019).

    CAS  Google Scholar 

  40. Liu, M., Nakasaki, M., Shih, Y. V. & Varghese, S. Effect of age on biomaterial-mediated in situ bone tissue regeneration. Acta Biomater. 78, 329–340 (2018).

    CAS  Google Scholar 

  41. Josephson, A. M. et al. Age-related inflammation triggers skeletal stem/progenitor cell dysfunction. Proc. Natl Acad. Sci. USA 116, 6995–7004 (2019).

    CAS  Google Scholar 

  42. Feins, E. N. et al. A growth-accommodating implant for paediatric applications. Nat. Biomed. Eng. 1, 818–825 (2017).

    CAS  Google Scholar 

  43. Hollister, S. J. Paediatric devices that grow up. Nat. Biomed. Eng. 1, 777–778 (2017).

    Google Scholar 

  44. Gabel, L., Macdonald, H. M. & McKay, H. A. Sex differences and growth-related adaptations in bone microarchitecture, geometry, density, and strength from childhood to early adulthood: a mixed longitudinal HR-pQCT study. J. Bone Miner. Res. 32, 250–263 (2017).

    Google Scholar 

  45. Fong, E. L. S., Watson, B. M., Kasper, F. K. & Mikos, A. G. Building bridges: leveraging interdisciplinary collaborations in the development of biomaterials to meet clinical needs. Adv. Mater. 24, 4995–5013 (2012).

    CAS  Google Scholar 

  46. Thrivikraman, G. et al. Rapid fabrication of vascularized and innervated cell-laden bone models with biomimetic intrafibrillar collagen mineralization. Nat. Commun. 10, 3520 (2019).

    Google Scholar 

  47. Shih, Y. V. & Varghese, S. Tissue engineered bone mimetics to study bone disorders ex vivo: role of bioinspired materials. Biomaterials 198, 107–121 (2019).

    CAS  Google Scholar 

  48. Fong, E. L. S. et al. Modeling Ewing sarcoma tumors in vitro with 3D scaffolds. Proc. Natl Acad. Sci. USA 110, 6500–6505 (2013).

    CAS  Google Scholar 

  49. Martine, L. C. et al. Engineering a humanized bone organ model in mice to study bone metastases. Nat. Protoc. 12, 639–663 (2017).

    CAS  Google Scholar 

  50. He, F. et al. Multiscale characterization of the mineral phase at skeletal sites of breast cancer metastasis. Proc. Natl Acad. Sci. USA 114, 10542–10547 (2017).

    CAS  Google Scholar 

  51. Talukdar, S. & Kundu, S. C. Engineered 3D silk-based metastasis models: interactions between human breast adenocarcinoma, mesenchymal stem cells and osteoblast-like cells. Adv. Funct. Mater. 23, 5249–5260 (2013).

    CAS  Google Scholar 

  52. Dondossola, E. et al. Intravital microscopy of osteolytic progression and therapy response of cancer lesions in the bone. Sci. Transl. Med. 10, eaao5726 (2018).

    Google Scholar 

  53. Williams, D. F. The Williams Dictionary of Biomaterials (Liverpool Univ. Press, 1999).

  54. Pajarinen, J. et al. Mesenchymal stem cell-macrophage crosstalk and bone healing. Biomaterials 196, 80–89 (2019).

    CAS  Google Scholar 

  55. Kohane, D. S. & Langer, R. Biocompatibility and drug delivery systems. Chem. Sci. 1, 441–446 (2010).

    CAS  Google Scholar 

  56. Lei, M. et al. Programmable electrofabrication of porous Janus films with tunable Janus balance for anisotropic cell guidance and tissue regeneration. Adv. Funct. Mater. 29, 1900065 (2019).

    Google Scholar 

  57. Lu, J. Y. et al. Multilayered graphene hydrogel membranes for guided bone regeneration. Adv. Mater. 28, 4025–4031 (2016).

    CAS  Google Scholar 

  58. Deng, C. J. et al. Micro/nanometer-structured scaffolds for regeneration of both cartilage and subchondral bone. Adv. Funct. Mater. 29, 1806068 (2019).

    Google Scholar 

  59. Petersen, A. et al. A biomaterial with a channel-like pore architecture induces endochondral healing of bone defects. Nat. Commun. 9, 4430 (2018). In this study, pore channels within collagen scaffolds directed cell alignment and ECM fibre orientation, resulting in fibrocartilage, which is progressively mineralized into bone.

    CAS  Google Scholar 

  60. Guo, J. L. et al. Modular, tissue-specific, and biodegradable hydrogel cross-linkers for tissue engineering. Sci. Adv. 5, eaaw7396 (2019).

    CAS  Google Scholar 

  61. Blokhuis, T. J. & Arts, J. J. C. Bioactive and osteoinductive bone graft substitutes: definitions, facts and myths. Injury 42 (Suppl. 2), S26–S29 (2011).

    Google Scholar 

  62. Gaharwar, A. K. et al. Bioactive silicate nanoplatelets for osteogenic differentiation of human mesenchymal stem cells. Adv. Mater. 25, 3329–3336 (2013).

    CAS  Google Scholar 

  63. Hoppe, A., Güldal, N. S. & Boccaccini, A. R. A review of the biological response to ionic dissolution products from bioactive glasses and glass-ceramics. Biomaterials 32, 2757–2774 (2011).

    CAS  Google Scholar 

  64. Tatara, A. M. et al. Biomaterials-aided mandibular reconstruction using in vivo bioreactors. Proc. Natl Acad. Sci. USA 116, 6954–6963 (2019). This report describes bioreactor chambers filled with bioceramics and implanted against the ribs in a large-animal model. The generated bone was used to reconstruct a craniofacial defect.

    CAS  Google Scholar 

  65. Ma, Q.-L. et al. Improved implant osseointegration of a nanostructured titanium surface via mediation of macrophage polarization. Biomaterials 35, 9853–9867 (2014).

    CAS  Google Scholar 

  66. Zhu, Y. et al. Bone regeneration with micro/nano hybrid-structured biphasic calcium phosphate bioceramics at segmental bone defect and the induced immunoregulation of MSCs. Biomaterials 147, 133–144 (2017).

    CAS  Google Scholar 

  67. Nonoyama, T. et al. Double-network hydrogels strongly bondable to bones by spontaneous osteogenesis penetration. Adv. Mater. 28, 6740–6745 (2016).

    CAS  Google Scholar 

  68. Wang, S. F. et al. Molecularly engineered biodegradable polymer networks with a wide range of stiffness for bone and peripheral nerve regeneration. Adv. Funct. Mater. 25, 2715–2724 (2015). In this study, varying the compositional ratio in copolymers of PCL and poly(propylene fumarate) enabled tuning of scaffold mechanical properties, thermal behaviour and tissue-specific regenerative capacity.

    CAS  Google Scholar 

  69. Du, Y. Z. et al. Development of a multifunctional platform based on strong, intrinsically photoluminescent and antimicrobial silica-poly(citrates)-based hybrid biodegradable elastomers for bone regeneration. Adv. Funct. Mater. 25, 5016–5029 (2015).

    CAS  Google Scholar 

  70. Takizawa, T. et al. Titanium fiber plates for bone tissue repair. Adv. Mater. 30, 1703608 (2018).

    Google Scholar 

  71. Pobloth, A.-M. et al. Mechanobiologically optimized 3D titanium-mesh scaffolds enhance bone regeneration in critical segmental defects in sheep. Sci. Transl. Med. 10, eaam8828 (2018).

    Google Scholar 

  72. Zhang, B., Filion, T. M., Kutikov, A. B. & Song, J. Facile stem cell delivery to bone grafts enabled by smart shape recovery and stiffening of degradable synthetic periosteal membranes. Adv. Funct. Mater. 27, 1604784 (2017).

    Google Scholar 

  73. Feng, P. et al. A multimaterial scaffold with tunable properties: toward bone tissue repair. Adv. Sci. 5, 1700817 (2018).

    Google Scholar 

  74. Mahony, O. et al. Silica-gelatin hybrids with tailorable degradation and mechanical properties for tissue regeneration. Adv. Funct. Mater. 20, 3835–3845 (2010).

    CAS  Google Scholar 

  75. Wei, D. X., Dao, J. W. & Chen, G. Q. A micro-ark for cells: highly open porous polyhydroxyalkanoate microspheres as injectable scaffolds for tissue regeneration. Adv. Mater. 30, 1802273 (2018).

    Google Scholar 

  76. Lin, Z. J. et al. Precisely controlled delivery of magnesium ions thru sponge-like monodisperse PLGA/nano-MgO-alginate core-shell microsphere device to enable in-situ bone regeneration. Biomaterials 174, 1–16 (2018).

    CAS  Google Scholar 

  77. Cui, H. T., Zhu, W., Holmes, B. & Zhang, L. G. Biologically inspired smart release system based on 3D bioprinted perfused scaffold for vascularized tissue regeneration. Adv. Sci. 3, 1600058 (2016).

    Google Scholar 

  78. Luo, Z. Y. et al. Injectable 3D porous micro-scaffolds with a bio-engine for cell transplantation and tissue regeneration. Adv. Funct. Mater. 28, 1804335 (2018).

    Google Scholar 

  79. Wang, M. O. et al. Evaluating 3D-printed biomaterials as scaffolds for vascularized bone tissue engineering. Adv. Mater. 27, 138–144 (2015).

    CAS  Google Scholar 

  80. Karageorgiou, V. & Kaplan, D. Porosity of 3D biomaterial scaffolds and osteogenesis. Biomaterials 26, 5474–5491 (2005).

    CAS  Google Scholar 

  81. Zhu, C. L., Pongkitwitoon, S., Qiu, J. C., Thomopoulos, S. & Xia, Y. N. Design and fabrication of a hierarchically structured scaffold for tendon-to-bone repair. Adv. Mater. 30, 1707306 (2018).

    Google Scholar 

  82. Brazill, J. M., Beeve, A. T., Craft, C. S., Ivanusic, J. J. & Scheller, E. L. Nerves in bone: evolving concepts in pain and anabolism. J. Bone Miner. Res. 34, 1393–1406 (2019).

    Google Scholar 

  83. Sayilekshmy, M. et al. Innervation is higher above bone remodeling surfaces and in cortical pores in human bone: lessons from patients with primary hyperparathyroidism. Sci. Rep. 9, 5361 (2019).

    Google Scholar 

  84. Jones, R. E. et al. Skeletal stem cell–Schwann cell circuitry in mandibular repair. Cell Rep. 28, 2757–2766 (2019).

    CAS  Google Scholar 

  85. Diba, M. et al. Composite colloidal gels made of bisphosphonate-functionalized gelatin and bioactive glass particles for regeneration of osteoporotic bone defects. Adv. Funct. Mater. 27, 1703438 (2017). These researchers demonstrated that injectable and self-healing composite gels assembled from pharmaceutical-functionalized gelatin and bioactive glass particles could regenerate bone defects and increase bone density in osteoporotic animals.

    Google Scholar 

  86. Zhang, K. Y. et al. Adaptable hydrogels mediate cofactor-assisted activation of biomarker-responsive drug delivery via positive feedback for enhanced tissue regeneration. Adv. Sci. 5, 1800875 (2018).

    Google Scholar 

  87. Rosales, A. M. & Anseth, K. S. The design of reversible hydrogels to capture extracellular matrix dynamics. Nat. Rev. Mater. 1, 15012 (2016).

    CAS  Google Scholar 

  88. Feng, Q. et al. Mechanically resilient, injectable, and bioadhesive supramolecular gelatin hydrogels crosslinked by weak host-guest interactions assist cell infiltration and in situ tissue regeneration. Biomaterials 101, 217–228 (2016).

    CAS  Google Scholar 

  89. Diba, M. et al. Self-healing biomaterials: from molecular concepts to clinical applications. Adv. Mater. Interfaces 5, 1800118 (2018).

    Google Scholar 

  90. Tan, J. L. et al. Sustained release of two bioactive factors from supramolecular hydrogel promotes periodontal bone regeneration. ACS Nano 13, 5616–5622 (2019).

    CAS  Google Scholar 

  91. Xu, B. et al. A mineralized high strength and tough hydrogel for skull bone regeneration. Adv. Funct. Mater. 27, 1604327 (2017).

    Google Scholar 

  92. Bittner, S. M., Guo, J. L., Melchiorri, A. & Mikos, A. G. Three-dimensional printing of multilayered tissue engineering scaffolds. Mater. Today 21, 861–874 (2018).

    CAS  Google Scholar 

  93. Sant, S. et al. Self-assembled hydrogel fiber bundles from oppositely charged polyelectrolytes mimic micro-/nanoscale hierarchy of collagen. Adv. Funct. Mater. 27, 1606273 (2017).

    Google Scholar 

  94. Loessner, D. et al. Functionalization, preparation and use of cell-laden gelatin methacryloyl-based hydrogels as modular tissue culture platforms. Nat. Protoc. 11, 727–746 (2016).

    CAS  Google Scholar 

  95. Ying, G. L. et al. Aqueous two-phase emulsion bioink-enabled 3D bioprinting of porous hydrogels. Adv. Mater. 30, 1805460 (2018).

    Google Scholar 

  96. Ren, X. Y. et al. Osteoprotegerin reduces osteoclast resorption activity without affecting osteogenesis on nanoparticulate mineralized collagen scaffolds. Sci. Adv. 5, eaaw4991 (2019).

    CAS  Google Scholar 

  97. Lausch, A. J., Chong, L. C., Uludag, H. & Sone, E. D. Multiphasic collagen scaffolds for engineered tissue interfaces. Adv. Funct. Mater. 28, 1804730 (2018).

    Google Scholar 

  98. Liu, Y. et al. Hierarchically staggered nanostructure of mineralized collagen as a bone-grafting scaffold. Adv. Mater. 28, 8740–8748 (2016).

    CAS  Google Scholar 

  99. Neffe, A. T. et al. One step creation of multifunctional 3D architectured hydrogels inducing bone regeneration. Adv. Mater. 27, 1738–1744 (2015).

    CAS  Google Scholar 

  100. Sarker, B. et al. Oxidized alginate-gelatin hydrogel: a favorable matrix for growth and osteogenic differentiation of adipose-derived stem cells in 3D. ACS Biomater. Sci. Eng. 3, 1730–1737 (2017).

    CAS  Google Scholar 

  101. Chang, S. W. & Buehler, M. J. Molecular biomechanics of collagen molecules. Mater. Today 17, 70–76 (2014).

    CAS  Google Scholar 

  102. Zhao, X. et al. Injectable stem cell-laden photocrosslinkable microspheres fabricated using microfluidics for rapid generation of osteogenic tissue constructs. Adv. Funct. Mater. 26, 2809–2819 (2016).

    CAS  Google Scholar 

  103. Luo, Z. Y. et al. Time-responsive osteogenic niche of stem cells: a sequentially triggered, dual-peptide loaded, alginate hybrid system for promoting cell activity and osteo-differentiation. Biomaterials 163, 25–42 (2018).

    CAS  Google Scholar 

  104. Darnell, M. et al. Material microenvironmental properties couple to induce distinct transcriptional programs in mammalian stem cells. Proc. Natl Acad. Sci. USA 115, E8368–E8377 (2018).

    CAS  Google Scholar 

  105. Jeon, O., Lee, K. & Alsberg, E. Spatial micropatterning of growth factors in 3D hydrogels for location-specific regulation of cellular behaviors. Small 14, e1800579 (2018).

    Google Scholar 

  106. Lueckgen, A. et al. Enzymatically-degradable alginate hydrogels promote cell spreading and in vivo tissue infiltration. Biomaterials 217, 119294 (2019).

    CAS  Google Scholar 

  107. Shi, L. Y. et al. Self-healing silk fibroin-based hydrogel for bone regeneration: dynamic metal-ligand self-assembly approach. Adv. Funct. Mater. 27, 1700591 (2017).

    Google Scholar 

  108. Liu, H. et al. Composite scaffolds of nano-hydroxyapatite and silk fibroin enhance mesenchymal stem cell-based bone regeneration via the interleukin 1α autocrine/paracrine signaling loop. Biomaterials 49, 103–112 (2015).

    CAS  Google Scholar 

  109. Partlow, B. P. et al. Highly tunable elastomeric silk biomaterials. Adv. Funct. Mater. 24, 4615–4624 (2014).

    CAS  Google Scholar 

  110. Marelli, B. et al. Silk fibroin derived polypeptide-induced biomineralization of collagen. Biomaterials 33, 102–108 (2012).

    CAS  Google Scholar 

  111. Rai, R., Keshavarz, T., Roether, J. A., Boccaccini, A. R. & Roy, I. Medium chain length polyhydroxyalkanoates, promising new biomedical materials for the future. Mater. Sci. Eng. R Rep. 72, 29–47 (2011).

    Google Scholar 

  112. Ruan, J. et al. Enhanced physiochemical and mechanical performance of chitosan-grafted graphene oxide for superior osteoinductivity. Adv. Funct. Mater. 26, 1085–1097 (2016).

    CAS  Google Scholar 

  113. Muller, W. E. G. et al. Transformation of amorphous polyphosphate nanoparticles into coacervate complexes: an approach for the encapsulation of mesenchymal stem cells. Small 14, e1801170 (2018).

    Google Scholar 

  114. Papageorgiou, P. et al. Expanded skeletal stem and progenitor cells promote and participate in induced bone regeneration at subcritical BMP-2 dose. Biomaterials 217, 119278 (2019).

    CAS  Google Scholar 

  115. Li, L. et al. 3D molecularly functionalized cell-free biomimetic scaffolds for osteochondral regeneration. Adv. Funct. Mater. 29, 1807356 (2019).

    Google Scholar 

  116. Hasani-Sadrabadi, M. M. et al. Hierarchically patterned polydopamine-containing membranes for periodontal tissue engineering. ACS Nano 13, 3830–3838 (2019).

    CAS  Google Scholar 

  117. Yan, Y. F. et al. Vascularized 3D printed scaffolds for promoting bone regeneration. Biomaterials 190–191, 97–110 (2019).

    Google Scholar 

  118. Kasper, F. K., Tanahashi, K., Fisher, J. P. & Mikos, A. G. Synthesis of poly(propylene fumarate). Nat. Protoc. 4, 518–525 (2009).

    CAS  Google Scholar 

  119. Wilson, J. A. et al. Magnesium catalyzed polymerization of end functionalized poly(propylene maleate) and poly(propylene fumarate) for 3D printing of bioactive scaffolds. J. Am. Chem. Soc. 140, 277–284 (2018).

    CAS  Google Scholar 

  120. Zhang, S. et al. Polylactic acid nanopillar array-driven osteogenic differentiation of human adipose-derived stem cells determined by pillar diameter. Nano Lett. 18, 2243–2253 (2018).

    CAS  Google Scholar 

  121. Yao, Q. Q. et al. Three dimensional electrospun PCL/PLA blend nanofibrous scaffolds with significantly improved stem cells osteogenic differentiation and cranial bone formation. Biomaterials 115, 115–127 (2017).

    CAS  Google Scholar 

  122. Washington, M. A. et al. The impact of monomer sequence and stereochemistry on the swelling and erosion of biodegradable poly(lactic-co-glycolic acid) matrices. Biomaterials 117, 66–76 (2017).

    CAS  Google Scholar 

  123. Kirillova, A., Kelly, C., von Windheim, N. & Gall, K. Bioinspired mineral–organic bioresorbable bone adhesive. Adv. Healthc. Mater. 7, e1800467 (2018).

    Google Scholar 

  124. Shi, X. T. et al. Periosteum-mimetic structures made from freestanding microgrooved nanosheets. Adv. Mater. 26, 3290–3296 (2014).

    CAS  Google Scholar 

  125. Johnson, C. T. et al. Hydrogel delivery of lysostaphin eliminates orthopedic implant infection by Staphylococcus aureus and supports fracture healing. Proc. Natl Acad. Sci. USA 115, E4960–E4969 (2018).

    CAS  Google Scholar 

  126. Vo, T. N. et al. Injectable dual-gelling cell-laden composite hydrogels for bone tissue engineering. Biomaterials 83, 1–11 (2016).

    CAS  Google Scholar 

  127. Lin, P., Ma, S., Wang, X. & Zhou, F. Molecularly engineered dual-crosslinked hydrogel with ultrahigh mechanical strength, toughness, and good self-recovery. Adv. Mater. 27, 2054–2059 (2015).

    CAS  Google Scholar 

  128. Rodell, C. B. et al. Shear-thinning supramolecular hydrogels with secondary autonomous covalent crosslinking to modulate viscoelastic properties in vivo. Adv. Funct. Mater. 25, 636–644 (2015).

    CAS  Google Scholar 

  129. Gong, J. P., Katsuyama, Y., Kurokawa, T. & Osada, Y. Double-network hydrogels with extremely high mechanical strength. Adv. Mater. 15, 1155–1158 (2003).

    CAS  Google Scholar 

  130. Zhao, Y. et al. Proteoglycans and glycosaminoglycans improve toughness of biocompatible double network hydrogels. Adv. Mater. 26, 436–442 (2014).

    Google Scholar 

  131. Mredha, M. T. I. et al. Anisotropic tough double network hydrogel from fish collagen and its spontaneous in vivo bonding to bone. Biomaterials 132, 85–95 (2017).

    CAS  Google Scholar 

  132. Vallet-Regí, M. & Ruiz-Hernández, E. Bioceramics: from bone regeneration to cancer nanomedicine. Adv. Mater. 23, 5177–5218 (2011).

    Google Scholar 

  133. Zhou, Y. L., Wu, C. T. & Chang, J. Bioceramics to regulate stem cells and their microenvironment for tissue regeneration. Mater. Today 24, 41–56 (2019).

    CAS  Google Scholar 

  134. Chen, L. et al. 3D printing of a lithium-calcium-silicate crystal bioscaffold with dual bioactivities for osteochondral interface reconstruction. Biomaterials 196, 138–150 (2019).

    CAS  Google Scholar 

  135. Félix Lanao, R. P., Leeuwenburgh, S. C. G., Wolke, J. G. C. & Jansen, J. A. Bone response to fast-degrading, injectable calcium phosphate cements containing PLGA microparticles. Biomaterials 32, 8839–8847 (2011).

    Google Scholar 

  136. Tang, Z., Li, X., Tan, Y., Fan, H. & Zhang, X. The material and biological characteristics of osteoinductive calcium phosphate ceramics. Regen. Biomater. 5, 43–59 (2018).

    CAS  Google Scholar 

  137. Bohner, M. et al. Characterization and distribution of mechanically competent mineralized tissue in micropores of β-tricalcium phosphate bone substitutes. Mater. Today 20, 106–115 (2017).

    CAS  Google Scholar 

  138. Groen, N. et al. Linking the transcriptional landscape of bone induction to biomaterial design parameters. Adv. Mater. 29, 1603259 (2017).

    Google Scholar 

  139. Kim, J. A. et al. Magnesium phosphate ceramics incorporating a novel indene compound promote osteoblast differentiation in vitro and bone regeneration in vivo. Biomaterials 157, 51–61 (2018).

    CAS  Google Scholar 

  140. Bunpetch, V. et al. Silicate-based bioceramic scaffolds for dual-lineage regeneration of osteochondral defect. Biomaterials 192, 323–333 (2019).

    CAS  Google Scholar 

  141. Fujishiro, Y., Hench, L. L. & Oonishi, H. Quantitative rates of in vivo bone generation for Bioglass® and hydroxyapatite particles as bone graft substitute. J. Mater. Sci. Mater. Med. 8, 649–652 (1997).

    CAS  Google Scholar 

  142. Jones, J. R. Review of bioactive glass: from Hench to hybrids. Acta Biomater. 9, 4457–4486 (2013).

    CAS  Google Scholar 

  143. Hench, L. L., Splinter, R. J., Allen, W. C. & Greenlee, T. K. Bonding mechanisms at the interface of ceramic prosthetic materials. J. Biomed. Mater. Res. 5, 117–141 (1971).

    Google Scholar 

  144. Hench, L. L. & Polak, J. M. Third-generation biomedical materials. Science 295, 1014–1017 (2002).

    CAS  Google Scholar 

  145. Zhao, F. J. et al. Promoting in vivo early angiogenesis with sub-micrometer strontium-contained bioactive microspheres through modulating macrophage phenotypes. Biomaterials 178, 36–47 (2018).

    CAS  Google Scholar 

  146. Lin, D. et al. Rapid initiation of guided bone regeneration driven by spatiotemporal delivery of IL-8 and BMP-2 from hierarchical MBG-based scaffold. Biomaterials 196, 122–137 (2019).

    CAS  Google Scholar 

  147. Rouquerol, J. et al. Recommendations for the characterization of porous solids. Pure Appl. Chem. 66, 1739–1758 (1994).

    CAS  Google Scholar 

  148. Li, J. H. et al. Valence state manipulation of cerium oxide nanoparticles on a titanium surface for modulating cell fate and bone formation. Adv. Sci. 5, 1700678 (2018).

    Google Scholar 

  149. Yu, H. J. et al. Ductile biodegradable Mg-based metallic glasses with excellent biocompatibility. Adv. Funct. Mater. 23, 4793–4800 (2013).

    CAS  Google Scholar 

  150. Jo, Y. K., Choi, B. H., Kim, C. S. & Cha, H. J. Diatom-inspired silica nanostructure coatings with controllable microroughness using an engineered mussel protein glue to accelerate bone growth on titanium-based implants. Adv. Mater. 29, 1704906 (2017).

    Google Scholar 

  151. Zhao, W. T. et al. Rapid evaluation of bioactive Ti-based surfaces using an in vitro titration method. Nat. Commun. 10, 2062 (2019).

    Google Scholar 

  152. Kohno, Y. et al. Treating titanium particle-induced inflammation with genetically modified NF-κB sensing IL-4 secreting or preconditioned mesenchymal stem cells in vitro. ACS Biomater. Sci. Eng. 5, 3032–3038 (2019).

    CAS  Google Scholar 

  153. Virtanen, S. Biodegradable Mg and Mg alloys: corrosion and biocompatibility. Mater. Sci. Eng. B 176, 1600–1608 (2011).

    CAS  Google Scholar 

  154. Cheng, P. F. et al. High-purity magnesium interference screws promote fibrocartilaginous entheses regeneration in the anterior cruciate ligament reconstruction rabbit model via accumulation of BMP-2 and VEGF. Biomaterials 81, 14–26 (2016).

    CAS  Google Scholar 

  155. Wang, Q. W. et al. Response of MAPK pathway to iron oxide nanoparticles in vitro treatment promotes osteogenic differentiation of hBMSCS. Biomaterials 86, 11–20 (2016).

    CAS  Google Scholar 

  156. Lee, J. S. & Murphy, W. L. Functionalizing calcium phosphate biomaterials with antibacterial silver particles. Adv. Mater. 25, 1173–1179 (2013).

    CAS  Google Scholar 

  157. Shimizu, M. et al. Carbon nanotubes induce bone calcification by bidirectional interaction with osteoblasts. Adv. Mater. 24, 2176–2185 (2012).

    CAS  Google Scholar 

  158. Nardecchia, S. et al. Osteoconductive performance of carbon nanotube scaffolds homogeneously mineralized by flow-through electrodeposition. Adv. Funct. Mater. 22, 4411–4420 (2012).

    CAS  Google Scholar 

  159. Nayak, T. R. et al. Graphene for controlled and accelerated osteogenic differentiation of human mesenchymal stem cells. ACS Nano 5, 4670–4678 (2011).

    CAS  Google Scholar 

  160. Lee, W. C. et al. Origin of enhanced stem cell growth and differentiation on graphene and graphene oxide. ACS Nano 5, 7334–7341 (2011).

    CAS  Google Scholar 

  161. Li, K. H. et al. Biomimetic ultralight, highly porous, shape-adjustable, and biocompatible 3D graphene minerals via incorporation of self-assembled peptide nanosheets. Adv. Funct. Mater. 28, 1801056 (2018).

  162. Ma, H. S. et al. A bifunctional biomaterial with photothermal effect for tumor therapy and bone regeneration. Adv. Funct. Mater. 26, 1197–1208 (2016).

    CAS  Google Scholar 

  163. Arnold, A. M., Holt, B. D., Daneshmandi, L., Laurencin, C. T. & Sydlik, S. A. Phosphate graphene as an intrinsically osteoinductive scaffold for stem cell-driven bone regeneration. Proc. Natl Acad. Sci. USA 116, 4855–4860 (2019). These researchers generated graphene oxide nanosheets functionalized with polyphosphates, which resulted in graphene-based materials capable of releasing osteoinductive phosphate and calcium ions, and, thereby, promoting the in vivo formation of mineralized matrix.

    CAS  Google Scholar 

  164. Wang, Y. Q. et al. Bioinspired extracellular vesicles embedded with black phosphorus for molecular recognition-guided biomineralization. Nat. Commun. 10, 2829 (2019).

    Google Scholar 

  165. Yang, B. W. et al. 2D-black-phosphorus-reinforced 3D-printed scaffolds: a stepwise countermeasure for osteosarcoma. Adv. Mater. 30, 1705611 (2018).

    Google Scholar 

  166. Wang, X. Z. et al. Near-infrared light-triggered drug delivery system based on black phosphorus for in vivo bone regeneration. Biomaterials 179, 164–174 (2018).

    CAS  Google Scholar 

  167. Laurenti, M. et al. Two-dimensional magnesium phosphate nanosheets form highly thixotropic gels that up-regulate bone formation. Nano Lett. 16, 4779–4787 (2016).

    CAS  Google Scholar 

  168. Yoo, S. C., Park, Y. K., Park, C., Ryu, H. & Hong, S. H. Biomimetic artificial nacre: boron nitride nanosheets/gelatin nanocomposites for biomedical applications. Adv. Funct. Mater. 28, 1805948 (2018).

    Google Scholar 

  169. Tiwari, J. N. et al. Accelerated bone regeneration by two-photon photoactivated carbon nitride nanosheets. ACS Nano 11, 742–751 (2017).

    CAS  Google Scholar 

  170. Ma, C. Y. et al. Citrate-based materials fuel human stem cells by metabonegenic regulation. Proc. Natl Acad. Sci. USA 115, E11741–E11750 (2018).

    CAS  Google Scholar 

  171. Du, Y. Y. et al. Selective laser sintering scaffold with hierarchical architecture and gradient composition for osteochondral repair in rabbits. Biomaterials 137, 37–48 (2017).

    CAS  Google Scholar 

  172. Moreau, D., Chauvet, C., Etienne, F., Rannou, F. P. & Corte, L. Hydrogel films and coatings by swelling-induced gelation. Proc. Natl Acad. Sci. USA 113, 13295–13300 (2016).

    CAS  Google Scholar 

  173. Lai, Y. X. et al. Osteogenic magnesium incorporated into PLGA/TCP porous scaffold by 3D printing for repairing challenging bone defect. Biomaterials 197, 207–219 (2019).

    CAS  Google Scholar 

  174. Zhai, X. Y. et al. 3D-bioprinted osteoblast-laden nanocomposite hydrogel constructs with induced microenvironments promote cell viability, differentiation, and osteogenesis both in vitro and in vivo. Adv. Sci. 5, 1700550 (2018).

    Google Scholar 

  175. Basu, S. et al. Harnessing the noncovalent interactions of DNA backbone with 2D silicate nanodisks to fabricate injectable therapeutic hydrogels. ACS Nano 12, 9866–9880 (2018).

    CAS  Google Scholar 

  176. Yun, H. M. et al. Magnetic nanocomposite scaffolds combined with static magnetic field in the stimulation of osteoblastic differentiation and bone formation. Biomaterials 85, 88–98 (2016).

    CAS  Google Scholar 

  177. Liu, Y. et al. Thermodynamically controlled self-assembly of hierarchically staggered architecture as an osteoinductive alternative to bone autografts. Adv. Funct. Mater. 29, 1806445 (2019).

    Google Scholar 

  178. Sun, J. L. et al. Intrafibrillar silicified collagen scaffold modulates monocyte to promote cell homing, angiogenesis and bone regeneration. Biomaterials 113, 203–216 (2017).

    CAS  Google Scholar 

  179. Zhang, J. et al. Ionic colloidal molding as a biomimetic scaffolding strategy for uniform bone tissue regeneration. Adv. Mater. 29, 1605546 (2017).

    Google Scholar 

  180. Canadas, R. F. et al. Biochemical gradients to generate 3D heterotypic-like tissues with isotropic and anisotropic architectures. Adv. Funct. Mater. 28, 1804148 (2018).

    Google Scholar 

  181. Goldberg, O., Greenfeld, I. & Wagner, H. D. Composite reinforcement by magnetic control of fiber density and orientation. ACS Appl. Mater. Interfaces 10, 16802–16811 (2018).

    CAS  Google Scholar 

  182. Fu, Q., Saiz, E., Rahaman, M. N. & Tomsia, A. P. Toward strong and tough glass and ceramic scaffolds for bone repair. Adv. Funct. Mater. 23, 5461–5476 (2013).

    CAS  Google Scholar 

  183. Zhu, Y. et al. Protein corona of magnetic hydroxyapatite scaffold improves cell proliferation via activation of mitogen-activated protein kinase signaling pathway. ACS Nano 11, 3690–3704 (2017).

    CAS  Google Scholar 

  184. Martin-Moldes, Z. et al. Intracellular pathways involved in bone regeneration triggered by recombinant silk-silica chimeras. Adv. Funct. Mater. 28, 1702570 (2018).

    Google Scholar 

  185. Tolba, E. et al. In situ polyphosphate nanoparticle formation in hybrid poly(vinyl alcohol)/karaya gum hydrogels: a porous scaffold inducing infiltration of mesenchymal stem cells. Adv. Sci. 6, 1801452 (2019).

    Google Scholar 

  186. Zinger, A. et al. Proteolytic nanoparticles replace a surgical blade by controllably remodeling the oral connective tissue. ACS Nano 12, 1482–1490 (2018).

    CAS  Google Scholar 

  187. Kang, M. S. et al. Nanocements produced from mesoporous bioactive glass nanoparticles. Biomaterials 162, 183–199 (2018).

    CAS  Google Scholar 

  188. Wang, Y. C. et al. Fracture-targeted delivery of β-catenin agonists via peptide-functionalized nanoparticles augments fracture healing. ACS Nano 11, 9445–9458 (2017).

    CAS  Google Scholar 

  189. Geuli, O., Metoki, N., Eliaz, N. & Mandler, D. Electrochemically driven hydroxyapatite nanoparticles coating of medical implants. Adv. Funct. Mater. 26, 8003–8010 (2016).

    CAS  Google Scholar 

  190. Zheng, C. P. et al. Functional selenium nanoparticles enhanced stem cell osteoblastic differentiation through BMP signaling pathways. Adv. Funct. Mater. 24, 6872–6883 (2014).

    CAS  Google Scholar 

  191. Yu, X. H., Khalil, A., Dang, P. N., Alsberg, E. & Murphy, W. L. Multilayered inorganic microparticles for tunable dual growth factor delivery. Adv. Funct. Mater. 24, 3082–3093 (2014).

    CAS  Google Scholar 

  192. Cheng, G. et al. Controlled co-delivery of growth factors through layer-by-layer assembly of core-shell nanofibers for improving bone regeneration. ACS Nano 13, 6372–6382 (2019).

    CAS  Google Scholar 

  193. Naskar, D. et al. Dual growth factor loaded nonmulberry silk fibroin/carbon nanofiber composite 3D scaffolds for in vitro and in vivo bone regeneration. Biomaterials 136, 67–85 (2017).

    CAS  Google Scholar 

  194. Newcomb, C. J. et al. Supramolecular nanofibers enhance growth factor signaling by increasing lipid raft mobility. Nano Lett. 16, 3042–3050 (2016).

    CAS  Google Scholar 

  195. Gazquez, G. C. et al. Flexible yttrium-stabilized zirconia nanofibers offer bioactive cues for osteogenic differentiation of human mesenchymal stromal cells. ACS Nano 10, 5789–5799 (2016).

    Google Scholar 

  196. Xue, J. J. et al. Electrospun microfiber membranes embedded with drug-loaded clay nanotubes for sustained antimicrobial protection. ACS Nano 9, 1600–1612 (2015).

    CAS  Google Scholar 

  197. Li, L. et al. Controlled dual delivery of BMP-2 and dexamethasone by nanoparticle-embedded electrospun nanofibers for the efficient repair of critical-sized rat calvarial defect. Biomaterials 37, 218–229 (2015).

    CAS  Google Scholar 

  198. Cheng, Z. A. et al. Nanoscale coatings for ultralow dose BMP-2-driven regeneration of critical-sized bone defects. Adv. Sci. 6, 1800361 (2019).

    Google Scholar 

  199. Min, J. H. et al. Designer dual therapy nanolayered implant coatings eradicate biofilms and accelerate bone tissue repair. ACS Nano 10, 4441–4450 (2016).

    CAS  Google Scholar 

  200. Machillot, P. et al. Automated buildup of biomimetic films in cell culture microplates for high-throughput screening of cellular behaviors. Adv. Mater. 30, 1801097 (2018).

    Google Scholar 

  201. Ha, Y. et al. Phase-transited lysozyme as a universal route to bioactive hydroxyapatite crystalline film. Adv. Funct. Mater. 28, 1704476 (2018).

    Google Scholar 

  202. Jordahl, J. H. et al. 3D jet writing: functional microtissues based on tessellated scaffold architectures. Adv. Mater. 30, 1707196 (2018).

    Google Scholar 

  203. Gao, F. et al. Direct 3D printing of high strength biohybrid gradient hydrogel scaffolds for efficient repair of osteochondral defect. Adv. Funct. Mater. 28, 1706644 (2018).

    Google Scholar 

  204. Chisca, S., Musteata, V.-E., Sougrat, R., Behzad, A. R. & Nunes, S. P. Artificial 3D hierarchical and isotropic porous polymeric materials. Sci. Adv. 4, eaat0713 (2018).

    Google Scholar 

  205. Zhang, W. J. et al. 3D-printed scaffolds with synergistic effect of hollow-pipe structure and bioactive ions for vascularized bone regeneration. Biomaterials 135, 85–95 (2017).

    CAS  Google Scholar 

  206. Deng, C. J. et al. 3D printing of bilineage constructive biomaterials for bone and cartilage regeneration. Adv. Funct. Mater. 27, 1703117 (2017).

    Google Scholar 

  207. Pati, F. et al. Ornamenting 3D printed scaffolds with cell-laid extracellular matrix for bone tissue regeneration. Biomaterials 37, 230–241 (2015).

    CAS  Google Scholar 

  208. Bose, S., Vahabzadeh, S. & Bandyopadhyay, A. Bone tissue engineering using 3D printing. Mater. Today 16, 496–504 (2013).

    CAS  Google Scholar 

  209. Chen, Y. et al. A biocompatible thermoset polymer binder for direct ink writing of porous titanium scaffolds for bone tissue engineering. Mater. Sci. Eng. C 95, 160–165 (2019).

    CAS  Google Scholar 

  210. Kolken, H. M. A. et al. Rationally designed meta-implants: a combination of auxetic and conventional meta-biomaterials. Mater. Horiz. 5, 28–35 (2018).

    CAS  Google Scholar 

  211. Farahani, R. D., Dube, M. & Therriault, D. Three-dimensional printing of multifunctional nanocomposites: manufacturing techniques and applications. Adv. Mater. 28, 5794–5821 (2016).

    CAS  Google Scholar 

  212. Gremare, A. et al. Characterization of printed PLA scaffolds for bone tissue engineering. J. Biomed. Mater. Res. A 106, 887–894 (2018).

    CAS  Google Scholar 

  213. Guvendiren, M., Molde, J., Soares, R. M. & Kohn, J. Designing biomaterials for 3D printing. ACS Biomater. Sci. Eng. 2, 1679–1693 (2016).

    CAS  Google Scholar 

  214. Korpela, J. et al. Biodegradable and bioactive porous scaffold structures prepared using fused deposition modeling. J. Biomed. Mater. Res. B Appl. Biomater. 101, 610–619 (2013).

    Google Scholar 

  215. Franco, J., Hunger, P., Launey, M. E., Tomsia, A. P. & Saiz, E. Direct write assembly of calcium phosphate scaffolds using a water-based hydrogel. Acta Biomater. 6, 218–228 (2010).

    CAS  Google Scholar 

  216. Peng, E., Zhang, D. & Ding, J. Ceramic robocasting: recent achievements, potential, and future developments. Adv. Mater. 30, e1802404 (2018).

    Google Scholar 

  217. Placone, J. K. & Engler, A. J. Recent advances in extrusion-based 3D printing for biomedical applications. Adv. Healthc. Mater. 7, e1701161 (2018).

    Google Scholar 

  218. Hinton, T. J. et al. Three-dimensional printing of complex biological structures by freeform reversible embedding of suspended hydrogels. Sci. Adv. 1, e1500758 (2015).

    Google Scholar 

  219. Surjadi, J. U. et al. Mechanical metamaterials and their engineering applications. Adv. Eng. Mater. 21, 1800864 (2019).

    CAS  Google Scholar 

  220. Rajasekharan, A. K., Bordes, R., Sandstrom, C., Ekh, M. & Andersson, M. Hierarchical and heterogeneous bioinspired composites — merging molecular self-assembly with additive manufacturing. Small 13, 1700550 (2017).

    Google Scholar 

  221. Liu, W. et al. Rapid continuous multimaterial extrusion bioprinting. Adv. Mater. 29, 1604630 (2017).

    Google Scholar 

  222. Diaz-Gomez, L. et al. Multimaterial segmented fiber printing for gradient tissue engineering. Tissue Eng. C 25, 12–24 (2019).

    CAS  Google Scholar 

  223. Diaz-Gomez, L., Kontoyiannis, P. D., Melchiorri, A. J. & Mikos, A. G. Three-dimensional printing of tissue engineering scaffolds with horizontal pore and composition gradients. Tissue Eng. C 25, 411–420 (2019).

    CAS  Google Scholar 

  224. Costantini, M. et al. 3D-printing of functionally graded porous materials using on-demand reconfigurable microfluidics. Angew. Chem. Int. Ed. 58, 7620–7625 (2019).

    CAS  Google Scholar 

  225. Raman, R. et al. High-resolution projection microstereolithography for patterning of neovasculature. Adv. Healthc. Mater. 5, 610–619 (2016).

    CAS  Google Scholar 

  226. Grigoryan, B. et al. Multivascular networks and functional intravascular topologies within biocompatible hydrogels. Science 364, 458–464 (2019).

    CAS  Google Scholar 

  227. Bernal, P. N. et al. Volumetric bioprinting of complex living-tissue constructs within seconds. Adv. Mater. 31, e1904209 (2019).

    Google Scholar 

  228. Yavari, S. A. et al. Bone regeneration performance of surface-treated porous titanium. Biomaterials 35, 6172–6181 (2014).

    Google Scholar 

  229. Kamboj, N., Aghayan, M., Rodrigo-Vazquez, C. S., Rodríguez, M. A. & Hussainova, I. Novel silicon-wollastonite based scaffolds for bone tissue engineering produced by selective laser melting. Ceram. Int. 45, 24691–24701 (2019).

    CAS  Google Scholar 

  230. Brunello, G. et al. Powder-based 3D printing for bone tissue engineering. Biotechnol. Adv. 34, 740–753 (2016).

    CAS  Google Scholar 

  231. Duan, B. & Wang, M. Selective laser sintering and its application in biomedical engineering. MRS Bull. 36, 998–1005 (2011).

    CAS  Google Scholar 

  232. Marino, A. et al. The osteoprint: a bioinspired two-photon polymerized 3-D structure for the enhancement of bone-like cell differentiation. Acta Biomater. 10, 4304–4313 (2014).

    CAS  Google Scholar 

  233. Cui, H. et al. Hierarchical fabrication of engineered vascularized bone biphasic constructs via dual 3D bioprinting: integrating regional bioactive factors into architectural design. Adv. Healthc. Mater. 5, 2174–2181 (2016).

    CAS  Google Scholar 

  234. Li, T. et al. 3D printing of hot dog-like biomaterials with hierarchical architecture and distinct bioactivity. Adv. Sci. 6, 1901146 (2019).

    CAS  Google Scholar 

  235. Lui, Y. S. et al. 4D printing and stimuli-responsive materials in biomedical aspects. Acta Biomater. 92, 19–36 (2019).

    CAS  Google Scholar 

  236. Kirillova, A., Maxson, R., Stoychev, G., Gomillion, C. T. & Ionov, L. 4D biofabrication using shape-morphing hydrogels. Adv. Mater. 29, 1703443 (2017).

    Google Scholar 

  237. Jiang, T., Carbone, E. J., Lo, K. W. H. & Laurencin, C. T. Electrospinning of polymer nanofibers for tissue regeneration. Prog. Polym. Sci. 46, 1–24 (2015).

    Google Scholar 

  238. Keller, L. et al. Preclinical safety study of a combined therapeutic bone wound dressing for osteoarticular regeneration. Nat. Commun. 10, 2156 (2019).

    Google Scholar 

  239. Xue, J. J. et al. Drug loaded homogeneous electrospun PCL/gelatin hybrid nanofiber structures for anti-infective tissue regeneration membranes. Biomaterials 35, 9395–9405 (2014).

    CAS  Google Scholar 

  240. Kishan, A. P. et al. Fabrication of macromolecular gradients in aligned fiber scaffolds using a combination of in-line blending and air-gap electrospinning. Acta Biomater. 56, 118–128 (2017).

    CAS  Google Scholar 

  241. Xie, M. J. et al. Electro-assisted bioprinting of low-concentration GelMA microdroplets. Small 15, 1804216 (2019).

    Google Scholar 

  242. Brown, T. D., Dalton, P. D. & Hutmacher, D. W. Melt electrospinning today: an opportune time for an emerging polymer process. Prog. Polym. Sci. 56, 116–166 (2016).

    CAS  Google Scholar 

  243. Brown, T. D., Dalton, P. D. & Hutmacher, D. W. Direct writing by way of melt electrospinning. Adv. Mater. 23, 5651–5657 (2011).

    CAS  Google Scholar 

  244. Wunner, F. M. et al. Melt electrospinning writing of highly ordered large volume scaffold architectures. Adv. Mater. 30, 1706570 (2018).

    Google Scholar 

  245. Workman, V. L., Tezera, L. B., Elkington, P. T. & Jayasinghe, S. N. Controlled generation of microspheres incorporating extracellular matrix fibrils for three-dimensional cell culture. Adv. Funct. Mater. 24, 2648–2657 (2014).

    CAS  Google Scholar 

  246. de Jonge, L. T., Leeuwenburgh, S. C. G., van den Beucken, J. J. J. P., Wolke, J. G. C. & Jansen, J. A. Electrosprayed enzyme coatings as bioinspired alternatives to bioceramic coatings for orthopedic and oral implants. Adv. Funct. Mater. 19, 755–762 (2009).

    Google Scholar 

  247. Song, J. et al. Electrophoretic deposition of chitosan coatings modified with gelatin nanospheres to tune the release of antibiotics. ACS Appl. Mater. Interfaces 8, 13785–13792 (2016).

    CAS  Google Scholar 

  248. Avcu, E. et al. Electrophoretic deposition of chitosan-based composite coatings for biomedical applications: a review. Prog. Mater. Sci. 103, 69–108 (2019).

    CAS  Google Scholar 

  249. Qassemyar, Q., Assouly, N., Madar, Y., Temam, S. & Kolb, F. Total nasal reconstruction with 3D custom made porous titanium prosthesis and free thoracodorsal artery perforator flap: a case report. Microsurgery 38, 567–571 (2018).

    Google Scholar 

  250. Kieser, D. C. et al. The use of an Ossis custom 3D-printed tri-flanged acetabular implant for major bone loss: minimum 2-year follow-up. HIP Int. 28, 668–674 (2018).

    Google Scholar 

  251. Li, J., Hsu, Y., Luo, E., Khadka, A. & Hu, J. Computer-aided design and manufacturing and rapid prototyped nanoscale hydroxyapatite/polyamide (n-HA/PA) construction for condylar defect caused by mandibular angle ostectomy. Aesthetic Plast. Surg. 35, 636–640 (2011).

    CAS  Google Scholar 

  252. Ahn, G., Lee, J. S., Yun, W. S., Shim, J. H. & Lee, U. L. Cleft alveolus reconstruction using a three-dimensional printed bioresorbable scaffold with human bone marrow cells. J. Craniofac. Surg. 29, 1880–1883 (2018).

    Google Scholar 

  253. Walsh, W. R. et al. Does implantation site influence bone ingrowth into 3D-printed porous implants? Spine J. 19, 1885–1898 (2019).

    Google Scholar 

  254. Jacome-Galarza, C. E. et al. Developmental origin, functional maintenance and genetic rescue of osteoclasts. Nature 568, 541–545 (2019).

    CAS  Google Scholar 

  255. Diesendruck, C. E. et al. Mechanically triggered heterolytic unzipping of a low-ceiling-temperature polymer. Nat. Chem. 6, 623–628 (2014).

    CAS  Google Scholar 

  256. Lin, K. L. et al. Enhanced osteoporotic bone regeneration by strontium-substituted calcium silicate bioactive ceramics. Biomaterials 34, 10028–10042 (2013).

    CAS  Google Scholar 

  257. Hayder, M. et al. A phosphorus-based dendrimer targets inflammation and osteoclastogenesis in experimental arthritis. Sci. Transl. Med. 3, 81ra35 (2011).

    Google Scholar 

  258. Jin, X. et al. Self-adaptive antibacterial porous implants with sustainable responses for infected bone defect therapy. Adv. Funct. Mater. 29, 1807915 (2019).

    Google Scholar 

  259. Li, J. et al. Balancing bacteria–osteoblast competition through selective physical puncture and biofunctionalization of ZnO/polydopamine/arginine-glycine-aspartic acid-cysteine nanorods. ACS Nano 11, 11250–11263 (2017).

    CAS  Google Scholar 

  260. Zhao, H. et al. Antitumor effect by hydroxyapatite nanospheres: activation of mitochondria dependent apoptosis and negative regulation of phosphatidylinositol-3-kinase/protein kinase B pathway. ACS Nano 12, 7838–7854 (2018).

    CAS  Google Scholar 

  261. James, A. W. et al. A review of the clinical side effects of bone morphogenetic protein-2. Tissue Eng. B 22, 284–297 (2016).

    CAS  Google Scholar 

  262. Chaudhuri, O. et al. Hydrogels with tunable stress relaxation regulate stem cell fate and activity. Nat. Mater. 15, 326–334 (2016). These researchers developed alginate hydrogels with differing stress-relaxation properties but similar elasticity. They showed that hydrogel stress-relaxation behaviour regulates osteogenic differentiation of encapsulated MSCs.

    CAS  Google Scholar 

  263. Watson, B. M., Kasper, F. K., Engel, P. S. & Mikos, A. G. Synthesis and characterization of injectable, biodegradable, phosphate-containing, chemically cross-linkable, thermoresponsive macromers for bone tissue engineering. Biomacromolecules 15, 1788–1796 (2014).

    CAS  Google Scholar 

  264. Watson, B. M. et al. Biodegradable, phosphate-containing, dual-gelling macromers for cellular delivery in bone tissue engineering. Biomaterials 67, 286–296 (2015).

    CAS  Google Scholar 

  265. Badeau, B. A., Comerford, M. P., Arakawa, C. K., Shadish, J. A. & DeForest, C. A. Engineered modular biomaterial logic gates for environmentally triggered therapeutic delivery. Nat. Chem. 10, 251–258 (2018).

    CAS  Google Scholar 

  266. Liu, W. et al. Zinc-modified sulfonated polyetheretherketone surface with immunomodulatory function for guiding cell fate and bone regeneration. Adv. Sci. 5, 1800749 (2018).

    Google Scholar 

  267. Kim, C. S. et al. A specific groove pattern can effectively induce osteoblast differentiation. Adv. Funct. Mater. 27, 1703569 (2017).

    Google Scholar 

  268. Chrzanowski, W. et al. Nano-bio-chemical braille for cells: the regulation of stem cell responses using bi-functional surfaces. Adv. Funct. Mater. 25, 193–205 (2015).

    CAS  Google Scholar 

  269. Alakpa, E. V. et al. Nacre topography produces higher crystallinity in bone than chemically induced osteogenesis. ACS Nano 11, 6717–6727 (2017).

    CAS  Google Scholar 

  270. Bencherif, S. A. et al. Injectable preformed scaffolds with shape-memory properties. Proc. Natl Acad. Sci. USA 109, 19590–19595 (2012).

    CAS  Google Scholar 

  271. Gorgin Karaji, Z. et al. Additively manufactured and surface biofunctionalized porous nitinol. ACS Appl. Mater. Interfaces 9, 1293–1304 (2017).

    CAS  Google Scholar 

  272. Zadpoor, A. A. Meta-biomaterials. Biomater. Sci. 8, 18–38 (2019).

    Google Scholar 

  273. Han, H. Y. et al. Silk biomaterials with vascularization capacity. Adv. Funct. Mater. 26, 421–432 (2016).

    CAS  Google Scholar 

  274. Cai, L., Chen, J. H., Rondinone, A. J. & Wang, S. F. Injectable and biodegradable nanohybrid polymers with simultaneously enhanced stiffness and toughness for bone repair. Adv. Funct. Mater. 22, 3181–3190 (2012).

    CAS  Google Scholar 

  275. Shen, X. F. et al. Sequential and sustained release of SDF-1 and BMP-2 from silk fibroin-nanohydroxyapatite scaffold for the enhancement of bone regeneration. Biomaterials 106, 205–216 (2016).

    CAS  Google Scholar 

  276. Quinlan, E. et al. Hypoxia-mimicking bioactive glass/collagen glycosaminoglycan composite scaffolds to enhance angiogenesis and bone repair. Biomaterials 52, 358–366 (2015).

    CAS  Google Scholar 

  277. Yang, Y. et al. Influence of cell spreading area on the osteogenic commitment and phenotype maintenance of mesenchymal stem cells. Sci. Rep. 9, 6891 (2019).

    Google Scholar 

  278. Seo, B. B., Koh, J. T. & Song, S. C. Tuning physical properties and BMP-2 release rates of injectable hydrogel systems for an optimal bone regeneration effect. Biomaterials 122, 91–104 (2017).

    CAS  Google Scholar 

  279. Dashnyam, K. et al. Promoting angiogenesis with mesoporous microcarriers through a synergistic action of delivered silicon ion and VEGF. Biomaterials 116, 145–157 (2017).

    CAS  Google Scholar 

  280. Spiller, K. L. et al. Sequential delivery of immunomodulatory cytokines to facilitate the M1-to-M2 transition of macrophages and enhance vascularization of bone scaffolds. Biomaterials 37, 194–207 (2015).

    CAS  Google Scholar 

  281. Hao, J. et al. Multigrowth factor delivery via immobilization of gene therapy vectors. Adv. Mater. 28, 3145–3151 (2016).

    CAS  Google Scholar 

  282. Cui, Z. K. et al. Design and characterization of a therapeutic non-phospholipid liposomal nanocarrier with osteoinductive characteristics to promote bone formation. ACS Nano 11, 8055–8063 (2017).

    CAS  Google Scholar 

  283. Zeng, H. C. et al. MicroRNA miR-23a cluster promotes osteocyte differentiation by regulating TGF-β signalling in osteoblasts. Nat. Commun. 8, 15000 (2017).

    CAS  Google Scholar 

  284. Yang, L., Tsang, K. Y., Tang, H. C., Chan, D. & Cheah, K. S. Hypertrophic chondrocytes can become osteoblasts and osteocytes in endochondral bone formation. Proc. Natl Acad. Sci. USA 111, 12097–12102 (2014).

    CAS  Google Scholar 

  285. Wolff, J. The Law of Bone Remodelling (Springer, 1986).

  286. Ruff, C., Holt, B. & Trinkaus, E. Who’s afraid of the big bad Wolff?: “Wolff’s law” and bone functional adaptation. Am. J. Phys. Anthropol. 129, 484–498 (2006).

    Google Scholar 

  287. Shi, M. C. et al. Europium-doped mesoporous silica nanosphere as an immune-modulating osteogenesis/angiogenesis agent. Biomaterials 144, 176–187 (2017).

    CAS  Google Scholar 

  288. Dhand, C. et al. Bio-inspired in situ crosslinking and mineralization of electrospun collagen scaffolds for bone tissue engineering. Biomaterials 104, 323–338 (2016).

    CAS  Google Scholar 

  289. Damaraju, S. M. et al. Three-dimensional piezoelectric fibrous scaffolds selectively promote mesenchymal stem cell differentiation. Biomaterials 149, 51–62 (2017).

    CAS  Google Scholar 

  290. Daly, A. C., Pitacco, P., Nulty, J., Cunniffe, G. M. & Kelly, D. J. 3D printed microchannel networks to direct vascularisation during endochondral bone repair. Biomaterials 162, 34–46 (2018).

    CAS  Google Scholar 

  291. Vergroesen, P. P., Kroeze, R. J., Helder, M. N. & Smit, T. H. The use of poly(l-lactide-co-caprolactone) as a scaffold for adipose stem cells in bone tissue engineering: application in a spinal fusion model. Macromol. Biosci. 11, 722–730 (2011).

    CAS  Google Scholar 

  292. Boden, S. D. Overview of the biology of lumbar spine fusion and principles for selecting a bone graft substitute. Spine 27, S26–S31 (2002).

    Google Scholar 

  293. Johnson, E. O., Troupis, T. & Soucacos, P. N. Tissue-engineered vascularized bone grafts: basic science and clinical relevance to trauma and reconstructive microsurgery. Microsurgery 31, 176–182 (2011).

    Google Scholar 

  294. Frick, S. L. in Green’s Skeletal Trauma in Children (eds Mencio, G. A. & Swiontkowski, M. F.) 1–15 (Elsevier Saunders, 2015).

  295. Thapa, M. & Pruthi, S. in Pediatric Radiology (eds Reid, J., Lee, E., Paladin, A., Carrico, C. & Davros, W.) 273–277 (Oxford Univ. Press, 2014).

  296. Conith, A. J., Lam, D. T. & Albertson, R. C. Muscle-induced loading as an important source of variation in craniofacial skeletal shape. Genesis 57, e23263 (2019).

    Google Scholar 

  297. Kneser, U., Schaefer, D. J., Polykandriotis, E. & Horch, R. E. Tissue engineering of bone: the reconstructive surgeon’s point of view. J. Cell. Mol. Med. 10, 7–19 (2006).

    CAS  Google Scholar 

  298. Nyberg, E. L. et al. 3D-printing technologies for craniofacial rehabilitation, reconstruction, and regeneration. Ann. Biomed. Eng. 45, 45–57 (2017).

    Google Scholar 

  299. Hollister, S. J. et al. Design control for clinical translation of 3D printed modular scaffolds. Ann. Biomed. Eng. 43, 774–786 (2015).

    Google Scholar 

  300. O’Donnell, B. T., Ives, C. J., Mohiuddin, O. A. & Bunnell, B. A. Beyond the present constraints that prevent a wide spread of tissue engineering and regenerative medicine approaches. Front. Bioeng. Biotechnol. 7, 95 (2019).

    Google Scholar 

  301. Webber, M. J., Khan, O. F., Sydlik, S. A., Tang, B. C. & Langer, R. A perspective on the clinical translation of scaffolds for tissue engineering. Ann. Biomed. Eng. 43, 641–656 (2015).

    Google Scholar 

  302. Morrison, R. J. et al. Regulatory considerations in the design and manufacturing of implantable 3D-printed medical devices. Clin. Transl. Sci. 8, 594–600 (2015).

    Google Scholar 

  303. Lee, M. H. et al. Considerations for tissue-engineered and regenerative medicine product development prior to clinical trials in the United States. Tissue Eng. B 16, 41–54 (2010).

    CAS  Google Scholar 

  304. Kang, H. M. et al. Remote control of intracellular calcium using upconversion nanotransducers regulates stem cell differentiation in vivo. Adv. Funct. Mater. 28, 1802642 (2018).

    Google Scholar 

  305. Kallai, I. et al. Microcomputed tomography-based structural analysis of various bone tissue regeneration models. Nat. Protoc. 6, 105–110 (2011).

    CAS  Google Scholar 

  306. Shah, S. R. et al. A composite critical-size rabbit mandibular defect for evaluation of craniofacial tissue regeneration. Nat. Protoc. 11, 1989–2009 (2016).

    CAS  Google Scholar 

  307. Seeherman, H. J. et al. A BMP/activin A chimera is superior to native BMPs and induces bone repair in nonhuman primates when delivered in a composite matrix. Sci. Transl. Med. 11, eaar4953 (2019).

    Google Scholar 

  308. Bourgine, P. E. et al. Engineered extracellular matrices as biomaterials of tunable composition and function. Adv. Funct. Mater. 27, 1605486 (2017).

    Google Scholar 

Download references

Acknowledgements

The authors’ work towards the development of materials for bone-tissue-engineering applications has been supported by the US National Institutes of Health grants P41 EB023833, R01 AR068073 and R01 CA180279 (to A.G.M.). G.L.K. is supported by the Robert and Janice McNair Foundation MD/PhD Student Scholar Program. M.D. is supported by a Rubicon postdoctoral fellowship from the Netherlands Organisation for Scientific Research (project no. 019.182EN.004).

Author information

Author notes

  1. These authors contributed equally: Gerry L. Koons, Mani Diba.

Authors and Affiliations

  1. Department of Bioengineering, Rice University, Houston, TX, USA

    Gerry L. Koons, Mani Diba & Antonios G. Mikos

Authors
  1. Gerry L. Koons
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mani Diba
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Antonios G. Mikos
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

G.L.K. and M.D. researched the literature and wrote the article. G.L.K., M.D. and A.G.M. discussed, reviewed and edited the manuscript.

Corresponding author

Correspondence to Antonios G. Mikos.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Koons, G.L., Diba, M. & Mikos, A.G. Materials design for bone-tissue engineering. Nat Rev Mater 5, 584–603 (2020). https://doi.org/10.1038/s41578-020-0204-2

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41578-020-0204-2

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