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Mesoporous silica rods with cone shaped pores modulate inflammation and deliver BMP-2 for bone regeneration

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Abstract

Biomaterials with suitable osteoimmunomodulation properties and ability to deliver osteoinductive biomolecules, such as bone morphogenetic proteins, are desired for bone regeneration. Herein, we report the development of mesoporous silica rods with large cone-shaped pores (MSR-CP) to load and deliver large protein drugs. It is noted that those cone-shaped pores on the surface modulated the immune response and reduced the pro-inflammatory reaction of stimulated macrophage. Furthermore, bone morphogenetic proteins 2 (BMP-2) loaded MSR-CP facilitated osteogenic differentiation and promoted osteogenesis of bone marrow stromal cells. In vivo tests confirmed BMP-2 loaded MSR-CP improved the bone regeneration performance. This study provides a potential strategy for the design of drug delivery systems for bone regeneration.

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References

  1. Stevens, M. M. Biomaterials for bone tissue engineering. Mater. Today2008, 11, 18–25.

    CAS  Google Scholar 

  2. Marrella, A.; Lee, T. Y.; Lee, D. H.; Karuthedom, S.; Syla, D.; Chawla, A.; Khademhosseini, A.; Jang, H. L. Engineering vascularized and innervated bone biomaterials for improved skeletal tissue regeneration. Mater. Today2018, 21, 362–376.

    CAS  Google Scholar 

  3. Krishnakumar, G. S.; Sampath, S.; Muthusamy, S.; John, M. A. Importance of crosslinking strategies in designing smart biomaterials for bone tissue engineering: A systematic review. Mat. Sci. Eng. C2019, 96, 941–954.

    CAS  Google Scholar 

  4. Roi, A.; Ardelean, L. C.; Roi, C. I.; Boia, E. R.; Boia, S.; Rusu, L. C. Oral bone tissue engineering: Advanced biomaterials for cell adhesion, proliferation and differentiation. Materials2019, 12, 2296.

    CAS  Google Scholar 

  5. Qu, H. W.; Fu, H. Y.; Han, Z. Y.; Sun, Y. Biomaterials for bone tissue engineering scaffolds: A review. RSC Adv.2019, 9, 26252–26262.

    CAS  Google Scholar 

  6. Byambaa, B.; Annabi, N.; Yue, K.; Trujillo-de Santiago, G.; Alvarez, M. M.; Jia, W. T.; Kazemzadeh-Narbat, M.; Shin, S. R.; Tamayol, A.; Khademhosseini, A. Bioprinted osteogenic and vasculogenic patterns for engineering 3D bone tissue. Adv. Healthc. Mater.2017, 6, DOI: https://doi.org/10.1002/adhm.201700015.

  7. Termaat, M. F.; Den Boer, F. C.; Bakker, F. C.; Patka, P.; Haarman, H. J. T. M. Bone morphogenetic proteins. Development and clinical efficacy in the treatment of fractures and bone defects. J. Bone Joint Surg. Am.2005, 87, 1367–1378.

    CAS  Google Scholar 

  8. Haidar, Z. S.; Hamdy, R. C.; Tabrizian, M. Delivery of recombinant bone morphogenetic proteins for bone regeneration and repair. Part A: Current challenges in BMP delivery. Biotechnol. Lett.2009, 31, 1817–1824.

    CAS  Google Scholar 

  9. Chen, D.; Zhao, M.; Mundy, G. R. Bone morphogenetic proteins. Growth Factors2004, 22, 233–241.

    CAS  Google Scholar 

  10. Park, S. B.; Park, S. H.; Kim, N. H.; Chung, C. K. BMP-2 induced early bone formation in spine fusion using rat ovariectomy osteoporosis model. Spine J.2013, 13, 1273–1280.

    Google Scholar 

  11. Zhang, S. F.; Kucharski, C.; Doschak, M. R.; Sebald, W.; Uludağ, H. Polyethylenimine-PEG coated albumin nanoparticles for BMP-2 delivery. Biomaterials2010, 31, 952–963.

    Google Scholar 

  12. Engstrand, T.; Veltheim, R.; Arnander, C.; Docherty-Skogh, A. C.; Westermark, A.; Ohlsson, C.; Adolfsson, L.; Larm, O. A novel biodegradable delivery system for bone morphogenetic protein-2. Plast. Reconstr. Surg.2008, 121, 1920–1928.

    CAS  Google Scholar 

  13. Mont, M. A.; Ragland, P. S.; Biggins, B.; Friedlaender, G.; Patel, T.; Cook, S.; Etienne, G.; Shimmin, A.; Kildey, R.; Rueger, D. C. et al. Use of bone morphogenetic proteins for musculoskeletal applications. An overview. J. Bone Joint Surg. Am.2004, 86, 41–55.

    Google Scholar 

  14. Wu, C. T.; Zhou, Y. H.; Xu, M. C.; Han, P. P.; Chen, L.; Chang, J.; Xiao, Y. Copper-containing mesoporous bioactive glass scaffolds with multifunctional properties of angiogenesis capacity, osteostimulation and antibacterial activity. Biomaterials2013, 34, 422–433.

    CAS  Google Scholar 

  15. Cheng, H.; Chewla, A.; Yang, Y. F.; Li, Y. X.; Zhang, J.; Jang, H. L.; Khademhosseini, A. Development of nanomaterials for bone-targeted drug delivery. Drug Discov. Today2017, 22, 1336–1350.

    CAS  Google Scholar 

  16. Porter, J. R.; Ruckh, T. T.; Popat, K. C. Bone tissue engineering: A review in bone biomimetics and drug delivery strategies. Biotechnol. Prog.2009, 25, 1539–1560.

    CAS  Google Scholar 

  17. Xu, C.; Niu, Y. T.; Popat, A.; Jambhrunkar, S.; Karmakar, S.; Yu, C. Z. Rod-like mesoporous silica nanoparticles with rough surfaces for enhanced cellular delivery. J. Mater. Chem. B2014, 2, 253–256.

    CAS  Google Scholar 

  18. Niu, Y. T.; Yu, M. H.; Zhang, J.; Yang, Y. N.; Xu, C.; Yeh, M.; Taran, E.; Hou, J. J. C.; Gray, P. P.; Yu, C. Z. Synthesis of silica nanoparticles with controllable surface roughness for therapeutic protein delivery. J. Mater. Chem. B2015, 3, 8477–8485.

    CAS  Google Scholar 

  19. Xu, C.; Yu, M. H.; Noonan, O.; Zhang, J.; Song, H.; Zhang, H. W.; Lei, C.; Niu, Y. T.; Huang, X. D.; Yang, Y. N. et al. Core-cone structured monodispersed mesoporous silica nanoparticles with ultra-large cavity for protein delivery. Small2015, 11, 5949–5955.

    CAS  Google Scholar 

  20. Xu, C.; Lei, C.; Huang, L. L.; Zhang, J.; Zhang, H. W.; Song, H.; Yu, M. H.; Wu, Y. D.; Chen, C.; Yu, C. Z. Glucose-responsive nanosystem mimicking the physiological insulin secretion via an enzyme-polymer layer-by-layer coating strategy. Chem. Mater.2017, 29, 7725–7732.

    CAS  Google Scholar 

  21. Xu, C.; He, Y.; Li, Z. H.; Nor, Y. A.; Ye, Q. S. Nanoengineered hollow mesoporous silica nanoparticles for the delivery of antimicrobial proteins into biofilms. J. Mater. Chem. B2018, 6, 1899–1902.

    CAS  Google Scholar 

  22. Xu, C.; Lei, C.; Yu, C. Z. Mesoporous silica nanoparticles for protein protection and delivery. Fron. Chem.2019, 7, 290.

    CAS  Google Scholar 

  23. Xia, W.; Chang, J. Well-ordered mesoporous bioactive glasses (MBG): A promising bioactive drug delivery system. J. Control. Release2006, 110, 522–530.

    CAS  Google Scholar 

  24. Zhu, G. J.; Zhang, F. Z.; Li, X. M.; Luo, W.; Li, L.; Zhang, H.; Wang, L. J.; Wang, Y. X.; Jiang, W.; Liu, H. K. et al. Engineering the distribution of carbon in silicon oxide nanospheres at the atomic level for highly stable anodes. Angew. Chem., Int. Ed.2019, 58, 6669–6673.

    CAS  Google Scholar 

  25. Yang, J. P.; Zhang, F.; Li, W.; Gu, D.; Shen, D. K.; Fan, J. W.; Zhang, W. X.; Zhao, D. Y. Large pore mesostructured cellular silica foam coated magnetic oxide composites with multilamellar vesicle shells for adsorption. Chem. Commun.2014, 50, 713–715.

    CAS  Google Scholar 

  26. Qu, F. Y.; Lin, H. M.; Wu, X.; Li, X. F.; Qiu, S. L.; Zhu, G. S. Bio-templated synthesis of highly ordered macro-mesoporous silica material for sustained drug delivery. Solid State Sci.2010, 12, 851–856.

    CAS  Google Scholar 

  27. Manzano, M.; Vallet-Regí, M. New developments in ordered mesoporous materials for drug delivery. J. Mater. Chem.2010, 20, 5593–5604.

    CAS  Google Scholar 

  28. Yang, J. P.; Shen, D. K.; Zhou, L.; Li, W.; Li, X. M.; Yao, C.; Wang, R.; El-Toni, A. M.; Zhang, F.; Zhao, D. Y. Spatially confined fabrication of core-shell gold nanocages@mesoporous silica for near-infrared controlled photothermal drug release. Chem. Mater.2013, 25, 3030–3037.

    CAS  Google Scholar 

  29. Shi, M. C.; Zhou, Y. H.; Shao, J.; Chen, Z. T.; Song, B. T.; Chang, J.; Wu, C. T.; Xiao, Y. Stimulation of osteogenesis and angiogenesis of hBMSCs by delivering Si ions and functional drug from mesoporous silica nanospheres. Acta Biomater.2015, 21, 178–189.

    CAS  Google Scholar 

  30. Gaharwar, A. K.; Mihaila, S. M.; Swami, A.; Patel, A.; Sant, S.; Reis, R. L.; Marques, A. P.; Gomes, M. E.; Khademhosseini, A. Bioactive silicate nanoplatelets for osteogenic differentiation of human mesenchymal stem cells. Adv. Mater.2013, 25, 3329–3336.

    CAS  Google Scholar 

  31. Meka, A. K.; Abbaraju, P. L.; Song, H.; Xu, C.; Zhang, J.; Zhang, H. W.; Yu, M. H.; Yu, C. Z. A vesicle supra-assembly approach to synthesize amine-functionalized hollow dendritic mesoporous silica nanospheres for protein delivery. Small2016, 12, 5169–5177.

    CAS  Google Scholar 

  32. Li, H. M.; Guo, H. L.; Lei, C.; Liu, L.; Xu, L. Q.; Feng, Y. P.; Ke, J.; Fang, W.; Song, H.; Xu, C. et al. Nanotherapy in joints: Increasing endogenous hyaluronan production by delivering hyaluronan synthase 2. Adv. Mater.2019, 31, 1904535.

    CAS  Google Scholar 

  33. Shen, D. K.; Yang, J. P.; Li, X. M.; Zhou, L.; Zhang, R. Y.; Li, W.; Chen, L.; Wang, R.; Zhang, F.; Zhao, D. Y. Biphase stratification approach to three-dimensional dendritic biodegradable mesoporous silica nanospheres. Nano Lett.2014, 14, 923–932.

    CAS  Google Scholar 

  34. Chen, Z. T.; Bachhuka, A.; Han, S. W.; Wei, F.; Lu, S.; Visalakshan, R. M.; Vasilev, K.; Xiao, Y. Tuning chemistry and topography of nanoengineered surfaces to manipulate immune response for bone regeneration applications. ACS Nano2017, 11, 4494–4506.

    CAS  Google Scholar 

  35. Chen, Z. T.; Klein, T.; Murray, R. Z.; Crawford, R.; Chang, J.; Wu, C. T.; Xiao, Y. Osteoimmunomodulation for the development of advanced bone biomaterials. Mater. Today2016, 19, 304–321.

    CAS  Google Scholar 

  36. Chen, Z. T.; Yuen, J.; Crawford, R.; Chang, J.; Wu, C. T.; Xiao, Y. The effect of osteoimmunomodulation on the osteogenic effects of cobalt incorporated β-tricalcium phosphate. Biomaterials2015, 61, 126–138.

    CAS  Google Scholar 

  37. Yamamura, M.; Mukai, T.; Otsuka, F.; Yamashita, M.; Takasugi, K.; Makino, H. Inhibition of bone morphogenetic protein-induced osteoblast differentiation by tumor necrosis factor-a. Ann. Rheum Dis.2007, 66, 155–155.

    Google Scholar 

  38. Yamashita, M.; Otsuka, F.; Mukai, T.; Otani, H.; Inagaki, K.; Miyoshi, T.; Goto, J.; Yamamura, M.; Makino, H. Simvastatin antagonizes tumor necrosis factor-α inhibition of bone morphogenetic proteins-2-induced osteoblast differentiation by regulating Smad signaling and Ras/Rhomitogen-activated protein kinase pathway. J. Endocrinol.2008, 196, 601–613.

    CAS  Google Scholar 

  39. Caetano-Lopes, J.; Canhão, H.; Fonseca, J. E. Osteoimmunology-The hidden immune regulation of bone. Autoimmun. Rev.2009, 8, 250–255.

    CAS  Google Scholar 

  40. Lü, W. L.; Wang, N.; Gao, P.; Li, C. Y.; Zhao, H. S.; Zhang, Z. T. Effects of anodic titanium dioxide nanotubes of different diameters on macrophage secretion and expression of cytokines and chemokines. Cell Proliferat.2015, 48, 95–104.

    Google Scholar 

  41. Jakobsen, S. S.; Larsen, A.; Stoltenberg, M.; Bruun, J. M.; Soballe, K. Effects of as-cast and wrought cobalt-chrome-molybdenum and titanium-aluminium-vanadium alloys on cytokine gene expression and protein secretion in J774A.1 macrophages. Eur. Cell. Mater.2007, 14, 45–54.

    CAS  Google Scholar 

  42. Neacsu, P.; Mazare, A.; Cimpean, A.; Park, J.; Costache, M.; Schmuki, P.; Demetrescu, I. Reduced inflammatory activity of RAW 264.7 macrophages on titania nanotube modified Ti surface. Int. J. Biochem. Cell Biol.2014, 55, 187–195.

    CAS  Google Scholar 

  43. Tan, J.; Zhao, C. J.; Wang, Y.; Li, Y. T.; Duan, K.; Wang, J. X.; Weng, J.; Feng, B. Nano-topographic titanium modulates macrophage response in vitro and in an implant-associated rat infection model. RSC Adv.2016, 6, 111919–111927.

    CAS  Google Scholar 

  44. Ariganello, M. B.; Guadarrama Bello, D.; Rodriguez-Contreras, A.; Sadeghi, S.; Isola, G.; Variola, F.; Nanci, A. Surface nanocavitation of titanium modulates macrophage activity. Int. J. Nanomedicine2018, 13, 8297–8308.

    CAS  Google Scholar 

  45. Farley, J. R.; Wergedal, J. E.; Baylink, D. J. Fluoride directly stimulates proliferation and alkaline phosphatase activity of bone-forming cells. Science1983, 222, 330–332.

    CAS  Google Scholar 

  46. Xu, C.; Xu, J.; Xiao, L.; Li, Z. H.; Xiao, Y.; Dargusch, M.; Lei, C.; He, Y.; Ye, Q. S. Double-layered microsphere based dual growth factor delivery system for guided bone regeneration. RSC Adv.2018, 8, 16503–16512.

    CAS  Google Scholar 

  47. Kim, K. S.; Lee, J. Y.; Kang, Y. M.; Kim, E. S.; Kim, G. H.; Dal Rhee, S.; Cheon, H. G.; Kim, J. H.; Min, B. H.; Lee, H. B. et al. Small intestine submucosa sponge for in vivo support of tissue-engineered bone formation in the presence of rat bone marrow stem cells. Biomaterials2010, 31, 1104–1113.

    CAS  Google Scholar 

  48. Zhao, D. Y.; Feng, J. L.; Huo, Q. S.; Melosh, N.; Fredrickson, G. H.; Chmelka, B. F.; Stucky, G. D. Triblock copolymer syntheses of mesoporous silica with periodic 50 to 300 angstrom pores. Science1998, 279, 548–552.

    CAS  Google Scholar 

  49. Spicer, P. P.; Kretlow, J. D.; Young, S.; Jansen, J. A.; Kasper, F. K.; Mikos, A. G. Evaluation of bone regeneration using the rat critical size calvarial defect. Nat. Protoc.2012, 7, 1918–1929.

    CAS  Google Scholar 

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Acknowledgements

The authors acknowledge the support from UQ Early Career Researcher Grant (1717673) and the National Natural Science Foundation of China (Nos. 81871503 and 81701032). C. X. acknowledges the support of National Health & Medical Research Council of Australia (NHMRC) Early Career Fellowship. Y. H., L. X. and C. L. extended their appreciations to the support of Advanced Queensland. The authors acknowledge the support from the Australian Microscopy and Microanalysis Research Facility at the Centre for Microscopy and Microanalysis, the University of Queensland.

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  1. Qingsong Ye

    Present address: Present address: Center of Regenerative Medicine, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, 430060, China

Authors and Affiliations

  1. School of Dentistry, The University of Queensland, Herston, QLD, 4006, Australia

    Chun Xu, Yuxue Cao & Yan He

  2. Center for Minimally Invasive Therapeutics (C-MIT), University of California, Los Angeles (UCLA), Los Angeles, CA, 90095, USA

    Chun Xu, Wujin Sun, Samad Ahadian & Ali Khademhosseini

  3. Department of Bioengineering, University of California, Los Angeles (UCLA), Los Angeles, CA, 90095, USA

    Chun Xu, Wujin Sun, Samad Ahadian & Ali Khademhosseini

  4. Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove Campus, Brisbane, 4006, Australia

    Lan Xiao & Yin Xiao

  5. School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, 325035, China

    Yan He & Qingsong Ye

  6. Department of Oral and Maxillofacial Surgery, Massachusetts General Hospital and Harvard School of Dental Medicine, Boston, MA, 02114, USA

    Yan He & Qingsong Ye

  7. Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, 4072, Australia

    Chang Lei

  8. Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA, 90095, USA

    Xueting Zhou

  9. Department of Chemical and Biomolecular Engineering, University of California, Los Angeles (UCLA), Los Angeles, CA, 90095, USA

    Ali Khademhosseini

  10. Department of Radiological Sciences, University of California, Los Angeles (UCLA), Los Angeles, CA, 90095, USA

    Ali Khademhosseini

  11. Terasaki Institute for Biomedical Innovation, Los Angeles, CA, 90095, USA

    Ali Khademhosseini

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  1. Chun Xu
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  2. Lan Xiao
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  3. Yuxue Cao
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  4. Yan He
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  10. Ali Khademhosseini
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Correspondence to Ali Khademhosseini or Qingsong Ye.

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Xu, C., Xiao, L., Cao, Y. et al. Mesoporous silica rods with cone shaped pores modulate inflammation and deliver BMP-2 for bone regeneration. Nano Res. 13, 2323–2331 (2020). https://doi.org/10.1007/s12274-020-2783-z

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  • DOI: https://doi.org/10.1007/s12274-020-2783-z

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