Abstract
Nanotechnology has revolutionized the field of bone regeneration, offering innovative solutions to address the challenges associated with conventional therapies. This comprehensive review explores the diverse landscape of nanomaterials – including nanoparticles, nanocomposites and nanofibers – tailored for bone tissue engineering. We delve into the intricate design principles, structural mimicry of native bone and the crucial role of biomaterial selection, encompassing bioceramics, polymers, metals and their hybrids. Furthermore, we analyze the interface between cells and nanostructured materials and their pivotal role in engineering and regenerating bone tissue. In the concluding outlook, we highlight emerging frontiers and potential research directions in harnessing nanomaterials for bone regeneration.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1. . Injectable osteogenic microtissues containing mesenchymal stromal cells conformally fill and repair critical size defects. Biomaterials 208, 32–44 (2019). • Explores the development of injectable microtissues containing mesenchymal stromal cells, focusing on their ability to repair critical-size bone defects efficiently.
- 2. . Roles of stem cell exosomes and their microRNA carrier in bone and cartilage regeneration. Curr. Stem Cell Res. Ther. 18(7), 917–925 (2023). •• Provides insights into the mechanisms by which stem cell exosomes contribute to tissue repair, offering valuable information for researchers and clinicians interested in regenerative medicine.
- 3. Recapitulating bone development through engineered mesenchymal condensations and mechanical cues for tissue regeneration. Sci. Transl. Med. 11(495), eaav7756 (2019). • Presents a novel approach to recapitulate bone development by engineering mesenchymal condensations and applying mechanical cues, and explores how these engineered processes can be leveraged for tissue regeneration, particularly in the context of bone.
- 4. Long-term clinical study and multiscale analysis of in vivo biodegradation mechanism of Mg alloy. Proc. Natl Acad. Sci. USA 113(3), 716–721 (2016). • Long-term clinical study and multiscale analysis of the in vivo biodegradation mechanism of magnesium alloy, contributing to our understanding of magnesium alloy implants’ long-term performance and safety.
- 5. . Improving biocompatibility for next generation of metallic implants. Prog. Mater. Sci. 133, 101053 (2022). •• Provides insights into innovative materials and surface modification techniques aimed at reducing adverse reactions and promoting better tissue integration, thus advancing the field of implantology.
- 6. . A literature review of autograft and allograft anterior cruciate ligament reconstruction. Knee Surg. Sports Traumatol. Arthrosc. 15, 690–704 (2007). • Comprehensive overview of autograft and allograft options for anterior cruciate ligament reconstruction. Discusses the advantages and disadvantages of each approach, helping clinicians make informed decisions regarding graft selection.
- 7. . Silk-based bioinspired structural and functional materials. iScience 25(3), 103940 (2022). •• Explores the development of bioinspired materials based on silk; discusses the structural and functional properties of silk and how these properties can inspire the design of innovative biomaterials for various applications, including tissue engineering and regenerative medicine.
- 8. . Nanomaterials and bone regeneration. Bone Res. 3(1), 1–7 (2015). • Provides insights into the role of nanomaterials in bone regeneration; discusses various nanomaterials, their properties and how they can enhance bone tissue engineering and regeneration.
- 9. . Bench-to-bedside: feasibility of nano-engineered and drug-delivery biomaterials for bone-anchored implants and periodontal applications. Mater. Today Bio 18, 100540 (2022).
- 10. . Growth factor delivery using extracellular matrix-mimicking substrates for musculoskeletal tissue engineering and repair. Bioact. Mater. 6(7), 1945–1956 (2021).
- 11. . Mineralized collagen fibrils: an essential component in determining the mechanical behavior of cortical bone. ACS Biomater. Sci. Eng. 9(5), 2203–2219 (2023).
- 12. Hierarchical intrafibrillar nanocarbonated apatite assembly improves the nanomechanics and cytocompatibility of mineralized collagen. Adv. Funct. Mater. 23(11), 1404–1411 (2013).
- 13. . Hierarchical structures of bone and bioinspired bone tissue engineering. Small 12(34), 4611–4632 (2016).
- 14. 3D printing of lotus root-like biomimetic materials for cell delivery and tissue regeneration. Adv. Sci. 4(12), 1700401 (2017).
- 15. A mussel-inspired persistent ROS-scavenging, electroactive, and osteoinductive scaffold based on electrochemical-driven in situ nanoassembly. Small 15(25), 1805440 (2019).
- 16. A review of 3D polymeric scaffolds for bone tissue engineering: principles, fabrication techniques, immunomodulatory roles, and challenges. Bioengineering 10(2), 204 (2023).
- 17. . Long non-coding RNAs: novel regulators of cellular physiology and function. Pflugers Arch. 474(2), 191–204 (2021).
- 18. . MIR503HG: a potential diagnostic and therapeutic target in human diseases. Biomed. Pharmacother. 160, 114314 (2023).
- 19. Distinct processing of lncRNAs contributes to non-conserved functions in stem cells. Cell 181(3), 621–636 (2020).
- 20. . Gene regulation by long non-coding RNAs and its biological functions. Nat. Rev. Mol. Cell Biol. 22(2), 96–118 (2021).
- 21. . A novel N6-methyladenosine (m6A)-dependent fate decision for the lncRNA THOR. Cell Death Dis. 11(8), 613 (2020).
- 22. . The regulatory activities of MALAT1 in the development of bone and cartilage diseases. Front. Endocrinol. 13, 1054827 (2022).
- 23. . Therapeutic nanoparticles and their targeted delivery applications. Mole 25(9), 2193 (2020).
- 24. . Chitosan-based nanoparticles as drug delivery systems: a review on two decades of research. J. Drug Target. 27(4), 379–393 (2019).
- 25. . Biomaterials for bone tissue engineering scaffolds: a review. RSC Adv. 9(45), 26252–26262 (2019).
- 26. . Processing of biomaterials for bone tissue engineering: state of the art. Mater. Today Proc. 50, 2206–2217 (2022).
- 27. . Cell sheet technology as an engineering-based approach to bone regeneration. Int. J. Nanomed. 17, 6491–6511 (2022).
- 28. Nanomaterial-assisted theranosis of bone diseases. Bioact. Mater. 24, 263–312 (2023).
- 29. . Development of nanomaterials for bone repair and regeneration. J. Biomed. Mater. Res. B Appl. Biomater. 101(2), 387–397 (2013).
- 30. The advances in nanomedicine for bone and cartilage repair. J. Nanobiotechnol. 20(1), 141 (2022).
- 31. . An overview of the tissue engineering market in the United States from 2011 to 2018. Tissue Eng. A 25(1–2), 1–8 (2019).
- 32. A biomimetic hierarchical nanointerface orchestrates macrophage polarization and mesenchymal stem cell recruitment to promote endogenous bone regeneration. ACS Nano 13(6), 6581–6595 (2019).
- 33. Tissue mimicry in morphology and composition promotes hierarchical matrix remodeling of invading stem cells in osteochondral and meniscus scaffolds. Adv. Mater. 30(28), 1706754 (2018).
- 34. Clinical translation of a patient-specific scaffold-guided bone regeneration concept in four cases with large long bone defects. J. Orthop. Translat. 34, 73–84 (2022).
- 35. . Personalized 3D printed bone scaffolds: a review. Acta Biomater. 156, 110–124 (2023).
- 36. . Biodegradable interbody cages for lumbar spine fusion: current concepts and future directions. Biomaterials 288, 121699 (2022).
- 37. . A systematic review and meta-analysis of fusion rate enhancements and bone graft options for spine surgery. Sci. Rep. 12(1), 7546 (2022).
- 38. 3D bioprinting of in situ vascularized tissue-engineered bone for repairing large segmental bone defects. Mater. Today Bio 16, 100382 (2022).
- 39. . Nerves in bone: evolving concepts in pain and anabolism. J. Bone Miner. Res. 34(8), 1393–1406 (2019).
- 40. . Close-to-native bone repair via tissue engineered endochondral ossification approaches. iScience 25(11), 105370 (2022).
- 41. Tissue-engineered autologous grafts for facial bone reconstruction. Sci. Transl. Med. 8(343), 343ra383–343ra383 (2016).
- 42. . Muscle-induced loading as an important source of variation in craniofacial skeletal shape. Genesis 57(1), e23263 (2019).
- 43. Biomedical applications of three-dimensional bioprinted craniofacial tissue engineering. Bioeng. Transl. Med. 8(1), e10333 (2023).
- 44. . Strategies of prevascularization in tissue engineering and regeneration of craniofacial tissues. Tissue Eng. B Rev. 28(2), 464–475 (2022).
- 45. Towards resorbable 3D-printed scaffolds for craniofacial bone regeneration. Orthod. Craniofac. Res.
doi: 10.1111/ocr.12645 (2023) (Epub ahead of print). - 46. . Effect of age on biomaterial-mediated in situ bone tissue regeneration. Acta Biomater. 78, 329–340 (2018).
- 47. . Pediatric pulmonary valve replacements: clinical challenges and emerging technologies. Bioeng. Transl. Med. 8(4), e10501 (2023).
- 48. . 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(2), 250–263 (2017).
- 49. . Biobridge: an outlook on translational bioinks for 3D bioprinting. Adv. Sci. 9(3), 2103469 (2022).
- 50. Rapid fabrication of vascularized and innervated cell-laden bone models with biomimetic intrafibrillar collagen mineralization. Nat. Commun. 10(1), 3520 (2019).
- 51. Engineering a humanized bone organ model in mice to study bone metastases. Nat. Protoc. 12(4), 639–663 (2017).
- 52. From breast cancer cell homing to the onset of early bone metastasis: dynamic bone (re) modeling as a driver of metastasis. bioRxiv 2023.2001.2024.525352
https://doi.org/10.1101/2023.01.24.525352 (2023). - 53. . Biomaterials science: an interdisciplinary endeavor. In: Biomaterials Science: an Introduction to Materials in Medicine. Elsevier, USA, 1–8 (1996).
- 54. Dual-targeted nanodiscs revealing the cross-talk between osteogenic differentiation of mesenchymal stem cells and macrophages. ACS Nano 17(3), 3153–3167 (2023).
- 55. Modular, tissue-specific, and biodegradable hydrogel cross-linkers for tissue engineering. Sci. Adv. 5(6), eaaw7396 (2019).
- 56. Micro/nanometer-structured scaffolds for regeneration of both cartilage and subchondral bone. Adv. Funct. Mater. 29(4), 1806068 (2019).
- 57. Recent progress in 3D printing degradable polylactic acid-based bone repair scaffold for the application of cancellous bone defect. MedComm Biomater. Appl. 1(1), e14 (2022).
- 58. . A proposed mechanism for material-induced heterotopic ossification. Mater. Today 22, 132–141 (2019).
- 59. PLA/hydroxyapatite scaffolds exhibit in vitro immunological inertness and promote robust osteogenic differentiation of human mesenchymal stem cells without osteogenic stimuli. Sci. Rep. 12(1), 2333 (2022).
- 60. . Tailoring the osteogenic properties of bioactive glasses by incorporation of therapeutic ions for orthopedic applications. In: Bioactive Glasses and Glass-Ceramics: Fundamentals and Applications. Wiley, Hoboken, NJ, USA, 203–226 (2022).
- 61. Biopolymer-based composites for tissue engineering applications: a basis for future opportunities. Compos. B Eng. 258, 110701 (2023).
- 62. 3D-printed LEGO®-inspired titanium scaffolds for patient-specific regenerative medicine. bioRxiv 2023.2003.2030.534953
https://doi.org/10.1101/2023.03.30.534953 (2023). - 63. . Smart hydrogels for bone reconstruction via modulating the microenvironment. Research (Wash. DC) 6, 89 (2023).
- 64. . A micro-ark for cells: highly open porous polyhydroxyalkanoate microspheres as injectable scaffolds for tissue regeneration. Adv. Mater. 30(31), 1802273 (2018).
- 65. 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).
- 66. Sustained release of two bioactive factors from supramolecular hydrogel promotes periodontal bone regeneration. ACS Nano 13(5), 5616–5622 (2019).
- 67. Biomineralized dipeptide self-assembled hydrogel with ultrahigh mechanical strength and osteoinductivity for bone regeneration. Colloids Surf. A Physicochem. Eng. Asp. 657, 130622 (2023).
- 68. . Sculpting tissues by phase transitions. Nat. Commun. 13(1), 664 (2022).
- 69. . Current trends in bone grafts – a review. J. Pharm. Negat. Results 13(7), 474–481 (2022).
- 70. Design and testing of nanobiomaterials for orthopedic implants. In: Engineered Nanostructures for Therapeutics and Biomedical Applications. Kaushik AKKumar SChaudhary GR (Eds). Elsevier, Amsterdam, 227–271 (2023).
- 71. Type I collagen decorated nanoporous network on titanium implant surface promotes osseointegration through mediating immunomodulation, angiogenesis, and osteogenesis. Biomaterials 288, 121684 (2022).
- 72. . The influence of nanotopography on cell behaviour through interactions with the extracellular matrix – a review. Bioact. Mater. 15, 145–159 (2022).
- 73. . Overview of scaffold reinforcement for tissue repair. In: Tissue Repair: Reinforced Scaffolds. Li X (Ed.). Springer, NY, USA, 1–23 (2017).
- 74. . Carbon nanofiber/polycaprolactone/mineralized hydroxyapatite nanofibrous scaffolds for potential orthopedic applications. ACS Appl. Mater. Interfaces 9(7), 6342–6355 (2017).
- 75. . Understanding the impact of grain structure in austenitic stainless steel from a nanograined regime to a coarse-grained regime on osteoblast functions using a novel metal deformation–annealing sequence. Acta Biomater. 9(4), 6245–6258 (2013).
- 76. . Nano-biotechnology: carbon nanofibres as improved neural and orthopaedic implants. Nanotechnology 15(1), 9 (2004).
- 77. . Porous tantalum and tantalum oxide nanoparticles for regenerative medicine. Acta Neurobiologiae Experimentalis 74(2), 188–196 (2014).
- 78. . Osteogenic and osteoclastogenic differentiation of co-cultured cells in polylactic acid–nanohydroxyapatite fiber scaffolds. J. Biotechnol. 204, 53–62 (2015).
- 79. . Enhanced functions of osteoblasts on nanophase ceramics. Biomaterials 21(17), 1803–1810 (2000).
- 80. . Covalently linked biocompatible graphene/polycaprolactone composites for tissue engineering. Carbon 52, 296–304 (2013).
- 81. Biocompatibility and bone tissue compatibility of alumina ceramics reinforced with carbon nanotubes. Nanomedicine 7(7), 981–993 (2012).
- 82. . Antibacterial properties of novel poly (methyl methacrylate) nanofiber containing silver nanoparticles. Langmuir 24(5), 2051–2056 (2008).
- 83. . Effect of TiO2 nanoparticle loading on poly(L-lactic acid) porous scaffolds fabricated by TIPS. Composites B Eng. 81, 189–195 (2015).
- 84. . Biomedical applications of chitin and chitosan based nanomaterials – a short review. Carbohydr. Polym. 82(2), 227–232 (2010).
- 85. . Growth of mesenchymal stem cells on electrospun type I collagen nanofibers. Stem Cells 24(11), 2391–2397 (2006).
- 86. . Nanoarchitectured Co–Cr–Mo orthopedic implant alloys: nitrogen-enhanced nanostructural evolution and its effect on phase stability. Acta Biomater. 9(4), 6259–6267 (2013).
- 87. Bioactive glass in tissue engineering. Acta Biomater. 7(6), 2355–2373 (2011).
- 88. . Synthesis and characterization of bioactive forsterite nanopowder. Ceram. Int. 35(6), 2449–2454 (2009).
- 89. . Calcium phosphate nanoparticles in biomineralization and biomaterials. J. Mater. Chem. 18(32), 3775–3787 (2008).
- 90. . One-and three-dimensional growth of hydroxyapatite nanowires during sol–gel–hydrothermal synthesis. (2012).
- 91. . Self-assembly of synthetic hydroxyapatite nanorods into an enamel prism-like structure. J. Colloid Interface Sci. 288(1), 97–103 (2005).
- 92. . Nanoscale hydroxyapatite particles for bone tissue engineering. Acta Biomater. 7(7), 2769–2781 (2011).
- 93. . Increased osteoblast adhesion on nanophase metals: Ti, Ti6Al4V, and CoCrMo. Biomaterials 25(19), 4731–4739 (2004).
- 94. Promoted osteogenic differentiation of human induced pluripotent stem cells using composited polycaprolactone/polyvinyl alcohol/carbopol nanofibrous scaffold. J. Drug Deliv. Sci. Technol. 71, 103318 (2022).
- 95. . Scaffold production and bone tissue healing using electrospinning: trends and gap of knowledge. Regen. Eng. Transl. Med. 8(4), 506–522 (2022).
- 96. Three dimensional electrospun PCL/PLA blend nanofibrous scaffolds with significantly improved stem cells osteogenic differentiation and cranial bone formation. Biomaterials 115, 115–127 (2017).
- 97. Bio-inspired in situ cross-linking and mineralization of electrospun collagen scaffolds for bone tissue engineering. Biomaterials 104, 323–338 (2016).
- 98. . Direct synthesis of highly stretchable ceramic nanofibrous aerogels via 3D reaction electrospinning. Nat. Commun. 13(1), 2637 (2022).
- 99. NSC-derived extracellular matrix-modified GelMA hydrogel fibrous scaffolds for spinal cord injury repair. NPG Asia Mater. 14(1), 20 (2022).
- 100. . Electrospun layered double hydroxide/poly (ϵ-caprolactone) nanocomposite scaffolds for adipogenic differentiation of adipose-derived mesenchymal stem cells. Appl. Clay Sci. 127, 52–63 (2016).
- 101. . Bone tissue engineering electrospun scaffolds based on layered double hydroxides with the ability to release vitamin D3: fabrication, characterization and in vitro study. Appl. Clay Sci. 185, 105434 (2020).
- 102. . Effects of polyacrylonitrile/MoS2 composite nanofibers on the growth behavior of bone marrow mesenchymal stem cells. ACS Appl. Nano Mater. 1(1), 337–343 (2017).
- 103. Electrospun PCL/MoS2 nanofiber membranes combined with NIR-triggered photothermal therapy to accelerate bone regeneration. Small 17(51), 2104747 (2021).
- 104. Electrospun fibers coated with nanostructured biomimetic hydroxyapatite: a new platform for regeneration at the bone interfaces. Biomater. Adv. 144, 213231 (2023).
- 105. . Synthetic biopolymer nanocomposites for tissue engineering scaffolds. Prog. Polym. Sci. 38(10–11), 1487–1503 (2013).
- 106. Nanomaterial-based scaffolds for bone tissue engineering and regeneration. Nanomedicine 15(20), 1995–2017 (2020).
- 107. Antioxidant, and enhanced flexible nano porous scaffolds for bone tissue engineering applications. Nano Select 2(7), 1356–1367 (2021).
- 108. A scaffold with zinc–whitlockite nanoparticles accelerates bone reconstruction by promoting bone differentiation and angiogenesis. Nano Res. 16(1), 757–770 (2023).
- 109. . Nanocomposites drug delivery systems for the healing of bone fractures. Int. J. Pharm. 585, 119477 (2020).
- 110. . Nanomaterials and bone regeneration. Bone Res. 3, 15029 (2015).
- 111. Porous titanium scaffolds with self-assembled micro/nano-hierarchical structure for dual functions of bone regeneration and anti-infection. J. Biomed. Mater. Res. A 105(12), 3482–3492 (2017).
- 112. . A renewable resource based carbon dot decorated hydroxyapatite nanohybrid and its fabrication with waterborne hyperbranched polyurethane for bone tissue engineering. RSC Adv. 6(31), 26066–26076 (2016).
- 113. Zero-dimensional carbon dots enhance bone regeneration, osteosarcoma ablation, and clinical bacterial eradication. Bioconjug. Chem. 29(9), 2982–2993 (2018).
- 114. . Electrospun captopril-loaded PCL–carbon quantum dots nanocomposite scaffold: fabrication, characterization, and in vitro studies. Polym. Adv. Technol. 31(12), 3302–3315 (2020).
- 115. . Construction of bioactive and reinforced bioresorbable nanocomposites by reduced nano-graphene oxide carbon dots. Biomacromolecules 19(3), 1074–1081 (2018).
- 116. Designing nanotopographical density of extracellular matrix for controlled morphology and function of human mesenchymal stem cells. Sci. Rep. 3(1), 3552 (2013).
- 117. Multiscale patterned transplantable stem cell patches for bone tissue regeneration. Biomaterials 35(33), 9058–9067 (2014).
- 118. . Effects of nanopillars and surface coating on dynamic traction force. Microsystems Nanoengineer. 9, 6 (2023).
- 119. Chitosan/hydroxyapatite nanocomposite scaffolds to modulate osteogenic and inflammatory response. J. Biomed. Mater Res. A 110(2), 266–272 (2022).
- 120. Biomineralization-inspired 3D printed bioactive glass nanocomposite scaffolds orchestrate diabetic bone regeneration by remodeling micromilieu. Bioact. Mater. 25, 239–255 (2023).
- 121. Carbon based nanomaterials for tissue engineering of bone: building new bone on small black scaffolds: a review. J. Adv. Res. 18, 185–201 (2019).
- 122. . Radially patterned transplantable biodegradable scaffolds as topographically defined contact guidance platforms for accelerating bone regeneration. J. Biol. Eng. 15(1), 12 (2021).
- 123. . Engineered barriers regulate osteoblast cell migration in vertical direction. Sci. Rep. 12(1), 4459 (2022).
- 124. Nanotechnology in bone tissue engineering. Nanomedicine 11(5), 1253–1263 (2015).
- 125. . Electrospinning and electrospun nanofibers: methods, materials, and applications. Chem. Rev. 119(8), 5298–5415 (2019).
- 126. . Nanotechnology-based biomaterials for orthopaedic applications: recent advances and future prospects. Mater. Sci. Eng. C 106, 110154 (2020).
- 127. . Nanoparticles‐induced potential toxicity on human health: applications, toxicity mechanisms, and evaluation models. MedComm. 4(4), e327 (2023).