AI Chat Paper
Note: Please note that the following content is generated by AMiner AI. SciOpen does not take any responsibility related to this content.
{{lang === 'zh_CN' ? '文章概述' : 'Summary'}}
{{lang === 'en_US' ? '中' : 'Eng'}}
Chat more with AI
Powered by AMiner. Clicking this button will take you away from SciOpen.
Home Nano Research Article
Article Link
Cite
EndNote(RIS) BibTeX
Collect
Submit Manuscript
Show Outline
Outline
Show full outline
Hide outline
Outline
Show full outline
Hide outline
Research Article

A scaffold with zinc-whitlockite nanoparticles accelerates bone reconstruction by promoting bone differentiation and angiogenesis

Mingming Wang1,§, Jiaxin Yao2,§, Shihong Shen1, Chunning Heng1, Yanyi Zhang3, Tao Yang4( ), Xiaoyan Zheng1,2( )
Shaanxi Key Laboratory of Degradable Biomedical Materials, Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Xi’an 710069, China
Biotech. & Biomed. Research Institute, Northwest University, Xi’an 710069, China
Xi’an Giant Biogene Technology Co., Ltd., Xi’an 710069, China
Shaanxi Key Laboratory for Theoretical Physics Frontiers, Institute of Modern Physics, Northwest University, Xi’an 710127, China

§ Mingming Wang and Jiaxin Yao contributed equally to this work.

Show Author Information

Graphical Abstract

This diagram showed the construction mechanism of the nanocomposite scaffold and its application in the treatment of bone defects.

Abstract

The therapy of bone defects based on advanced biological scaffolds offers the most promising therapeutic strategy for bone reconstruction. It is still challenging to develop scaffolds with the mechanical, osteogenic, angiogenic, and antibacterial properties required for bone defect reconstruction. Here, a novel organic/inorganic composite scaffold (zinc-whitlockite (ZnWH)/G/H) was synthesized using gellan gum (GG), human-like collagen (HLC), and ZnWH nanoparticles. The scaffold had excellent mechanical properties, adjustable swelling ratio, and interconnected pore structure. In addition to its excellent biocompatibility, it could promote osteogenic differentiation by releasing ZnWH nanoparticles to stimulate human bone marrow mesenchymal stem cells (hBMSCs) to upregulate the levels of alkaline phosphatase (ALP), osteocalcin (OCN), and osteopontin (OPN). In addition, this study showed that ZnWH nanoparticles could also promote angiogenesis by upregulating the paracrine secretion of vascular endothelial growth factor (VEGF) in hBMSCs. At the same time, the scaffold could inhibit the proliferation of bacteria. After 12 weeks of treatment in the rabbit femoral defect model, the ZnWH/G/H scaffold significantly accelerated the process of bone reconstruction. Therefore, these results demonstrate that the prepared novel nanocomposite scaffold, ZnWH/G/H, offers a promising candidate for bone regeneration.

Keywords

bone repairnanocomposite scaffoldzinc-whitlockiteosteogenesisangiogenesis

Electronic Supplementary Material

Download File(s)
12274_2022_4644_MOESM1_ESM.pdf (1.7 MB)

References

[1]

Wang, M. Q.; Li, H. J.; Yang, Y. Q.; Yuan, K.; Zhou, F.; Liu, H. B.; Zhou, Q. H.; Yang, S. B.; Tang, T. T. A 3D-bioprinted scaffold with doxycycline-controlled BMP2-expressing cells for inducing bone regeneration and inhibiting bacterial infection. Bioact. Mater. 2021, 6, 1318–1329.
Crossref Google Scholar
[2]

Zhang, X. T.; He, Y. Y.; Huang, P. Z.; Jiang, G. W.; Zhang, M. D.; Yu, F.; Zhang, W. T.; Fu, G.; Wang, Y.; Li, W. Q. et al. A novel mineralized high strength hydrogel for enhancing cell adhesion and promoting skull bone regeneration in situ. Compos. B. Eng. 2020, 197, 108183.
Crossref Google Scholar
[3]

Xiang, H. J.; Yang, Q. H.; Gao, Y. S.; Zhu, D. Y.; Pan, S. S.; Xu, T. M.; Chen, Y. Cocrystal strategy toward multifunctional 3D-printing scaffolds enables NIR-activated photonic osteosarcoma hyperthermia and enhanced bone defect regeneration. Adv. Funct. Mater. 2020, 30, 1909938.
Crossref Google Scholar
[4]

Yi, H.; Ur Rehman, F.; Zhao, C. Q.; Liu, B.; He, N. Y. Recent advances in nano scaffolds for bone repair. Bone Res. 2016, 4, 16050.
Crossref Google Scholar
[5]

Nonoyama, T.; Wada, S.; Kiyama, R.; Kitamura, N.; Mredha, M. T. I.; Zhang, X.; Kurokawa, T.; Nakajima, T.; Takagi, Y.; Yasuda, K. et al. Double-network hydrogels strongly bondable to bones by spontaneous osteogenesis penetration. Adv. Mater. 2016, 28, 6740–6745.
Crossref Google Scholar
[6]

Liu, W. W.; Li, X. K.; Jiao, Y. L.; Wu, C.; Guo, S.; Xiao, X.; Wei, X. H.; Wu, J.; Gao, P.; Wang, N. et al. Biological effects of a three-dimensionally printed Ti6Al4V scaffold coated with piezoelectric BaTiO3 nanoparticles on bone formation. ACS Appl. Mater. Interfaces 2020, 12, 51885–51903.
Crossref Google Scholar
[7]

Zhou, K.; Yu, P.; Shi, X. J.; Ling, T. X.; Zeng, W. N.; Chen, A. J.; Yang, W.; Zhou, Z. K. Hierarchically porous hydroxyapatite hybrid scaffold incorporated with reduced graphene oxide for rapid bone ingrowth and repair. ACS Nano 2019, 13, 9595–9606.
Crossref Google Scholar
[8]

Lei, C.; Cao, Y. X.; Hosseinpour, S.; Gao, F.; Liu, J. Y.; Fu, J. Y.; Staples, R.; Ivanovski, S.; Xu, C. Hierarchical dual-porous hydroxyapatite doped dendritic mesoporous silica nanoparticles based scaffolds promote osteogenesis in vitro and in vivo. Nano Res. 2021, 14, 770–777.
Crossref Google Scholar
[9]

Dong, W. Y.; Ma, W. D.; Zhao, S. S.; Wang, Y. L.; Yao, J. H.; Liu, Z. W.; Chen, Z.; Sun, D. H.; Jiang, Z. H.; Zhang, M. The surface modification of long carbon fiber reinforced polyether ether ketone with bioactive composite hydrogel for effective osteogenicity. Mater. Sci. Eng. C 2021, 130, 112451.
Crossref Google Scholar
[10]

Shen, X. F.; Zhang, Y. X.; Gu, Y.; Xu, Y.; Liu, Y.; Li, B.; Chen, L. Sequential and sustained release of SDF-1 and BMP-2 from silk fibroin-nanohydroxyapatite scaffold for the enhancement of bone regeneration. Biomaterials 2016, 106, 205–216.
Crossref Google Scholar
[11]

Xu, C.; Xiao, L.; Cao, Y. X.; He, Y.; Lei, C.; Xiao, Y.; Sun, W. J.; Ahadian, S.; Zhou, X. T.; Khademhosseini, A. et al. Mesoporous silica rods with cone shaped pores modulate inflammation and deliver BMP-2 for bone regeneration. Nano Res. 2020, 13, 2323–2331.
Crossref Google Scholar
[12]
Ding, R. Y.; Liu, Y. J.; Cheng, D. W.; Yang, G.; Wu, W. J.; Du, H. R.; Jin, X.; Chen, Y. H.; Wang, Y. Y.; Heng, B. C. et al. A novel gene-activated matrix composed of PEI/plasmid-BMP2 complexes and hydroxyapatite/chitosan-microspheres promotes bone regeneration. Nano Res., in press, https://doi.org/10.1007/s12274-022-4292-8.
[13]

Wang, Y.; Kankala, R. K.; Ou, C. W.; Chen, A. Z.; Yang, Z. L. Advances in hydrogel-based vascularized tissues for tissue repair and drug screening. Bioact. Mater. 2022, 9, 198–220.
Crossref Google Scholar
[14]

Fu, J. N.; Zhu, W. D.; Liu, X. M.; Liang, C. Y.; Zheng, Y. F.; Li, Z. Y.; Liang, Y. Q.; Zheng, D.; Zhu, S. L.; Cui, Z. D. et al. Self-activating anti-infection implant. Nat. Commun. 2021, 12, 6907.
Crossref Google Scholar
[15]

Masters, E. A.; Trombetta, R. P.; De Mesy Bentley, K. L.; Boyce, B. F.; Gill, A. L.; Gill, S. R.; Nishitani, K.; Ishikawa, M.; Morita, Y.; Ito, H. et al. Evolving concepts in bone infection: Redefining “biofilm”, “acute vs. chronic osteomyelitis”, “the immune proteome” and “local antibiotic therapy”. Bone Res. 2019, 7, 20.
Crossref Google Scholar
[16]

Chen, H. M.; Huang, H. Y.; Xue, Y.; Li, K.; Ding, T. X.; Cai, X. J.; Chen, J.; Zhang, L. Immobilization of pegylated AMP on hydroxyapatite nanorods for antibiosis. Rare Met. 2022, 41, 713–722.
Crossref Google Scholar
[17]

Lee, N. H.; Kang, M. S.; Kim, T. H.; Yoon, D. S.; Mandakhbayar, N.; Jo, S. B.; Kim, H. S.; Knowles, J. C.; Lee, J. H.; Kim, H. W. Dual actions of osteoclastic-inhibition and osteogenic-stimulation through strontium-releasing bioactive nanoscale cement imply biomaterial-enabled osteoporosis therapy. Biomaterials 2021, 276, 121025.
Crossref Google Scholar
[18]

Hu, M.; Xiao, F.; Ke, Q. F.; Li, Y.; Chen, X. D.; Guo, Y. P. Cerium-doped whitlockite nanohybrid scaffolds promote new bone regeneration via SMAD signaling pathway. Chem. Eng. J. 2019, 359, 1–12.
Crossref Google Scholar
[19]

Li, J. K.; Lv, F.; Li, J. X.; Li, Y. X.; Gao, J. D.; Luo, J.; Xue, F.; Ke, Q. F.; Xu, H. Cobalt-based metal-organic framework as a dual cooperative controllable release system for accelerating diabetic wound healing. Nano Res. 2020, 13, 2268–2279.
Crossref Google Scholar
[20]

Shen, X. K.; Hu, Y.; Xu, G. Q.; Chen, W. Z.; Xu, K.; Ran, Q. C.; Ma, P. P.; Zhang, Y. R.; Li, J. H.; Cai, K. Y. Regulation of the biological functions of osteoblasts and bone formation by Zn-incorporated coating on microrough titanium. ACS Appl. Mater. Interfaces 2014, 6, 16426–16440.
Crossref Google Scholar
[21]

Liu, Y. H.; Zhu, Z.; Pei, X. B.; Zhang, X.; Cheng, X. T.; Hu, S. S.; Gao, X. M.; Wang, J.; Chen, J. Y.; Wan, Q. B. ZIF-8-modified multifunctional bone-adhesive hydrogels promoting angiogenesis and osteogenesis for bone regeneration. ACS Appl. Mater. Interfaces 2020, 12, 36978–36995.
Crossref Google Scholar
[22]

Han, H. C.; Yang, J. J.; Li, X. Y.; Qi, Y.; Yang, Z. Y.; Han, Z. J.; Jiang, Y. Y.; Stenzel, M.; Li, H.; Yin, Y. X. et al. Shining light on transition metal sulfides: New choices as highly efficient antibacterial agents. Nano Res. 2021, 14, 2512–2534.
Crossref Google Scholar
[23]

Millward, D. J. Nutrition, infection and stunting: The roles of deficiencies of individual nutrients and foods, and of inflammation, as determinants of reduced linear growth of children. Nutr. Res. Rev. 2017, 30, 50–72.
Crossref Google Scholar
[24]

Ferreira, E. C. S.; Bortolin, R. H.; Freire-Neto, F. P.; Souza, K. S. C.; Bezerra, J. F.; Ururahy, M. A. G.; Ramos, A. M. O.; Himelfarb, S. T.; Abreu, B. J.; Didone, T. V. N. et al. Zinc supplementation reduces RANKL/OPG ratio and prevents bone architecture alterations in ovariectomized and type 1 diabetic rats. Nutr. Res. 2017, 40, 48–56.
Crossref Google Scholar
[25]

Amin, N.; Clark, C. C. T.; Taghizadeh, M.; Djafarnejad, S. Zinc supplements and bone health: The role of the RANKL-RANK axis as a therapeutic target. J. Trace Elem. Med. Biol. 2020, 57, 126417.
Crossref Google Scholar
[26]

Palmiter, R. D. Protection against zinc toxicity by metallothionein and zinc transporter 1. Proc. Natl. Acad. Sci. USA 2004, 101, 4918–4923.
Crossref Google Scholar
[27]

Liu, Y.; Yan, F.; Yang, W. L.; Lu, X. F.; Wang, W. B. Effects of zinc transporter on differentiation of bone marrow mesenchymal stem cells to osteoblasts. Biol. Trace Elem. Res. 2013, 154, 234–243.
Crossref Google Scholar
[28]

Huang, M.; Hill, R. G.; Rawlinson, S. C. F. Zinc bioglasses regulate mineralization in human dental pulp stem cells. Dent. Mater. 2017, 33, 543–552.
Crossref Google Scholar
[29]

Augustine, R.; Dan, P.; Sosnik, A.; Kalarikkal, N.; Tran, N.; Vincent, B.; Thomas, S.; Menu, P.; Rouxel, D. Electrospun poly(vinylidene fluoride-trifluoroethylene)/zinc oxide nanocomposite tissue engineering scaffolds with enhanced cell adhesion and blood vessel formation. Nano Res. 2017, 10, 3358–3376.
Crossref Google Scholar
[30]

Jang, H. L.; Jin, K.; Lee, J.; Kim, Y.; Nahm, S. H.; Hong, K. S.; Nam, K. T. Revisiting whitlockite, the second most abundant biomineral in bone: Nanocrystal synthesis in physiologically relevant conditions and biocompatibility evaluation. ACS Nano 2014, 8, 634–641.
Crossref Google Scholar
[31]

Yang, Z. C.; Yao, T. Y.; Zheng, X. Y.; Hui, J. F.; Fan, D. D. Eu3+/Tb3+-doped whitlockite nanocrystals: Controllable synthesis, cell imaging, and the degradation process in the bone reconstruction. Nano Res. 2022, 15, 1303–1309.
Crossref Google Scholar
[32]

Kizalaite, A.; Grigoraviciute-Puroniene, I.; Asuigui, D. R. C.; Stoll, S. L.; Cho, S. H.; Sekino, T.; Kareiva, A.; Zarkov, A. Dissolution-precipitation synthesis and characterization of zinc whitlockite with variable metal content. ACS Biomater. Sci. Eng. 2021, 7, 3586–3593.
Crossref Google Scholar
[33]

Zhu, Z.; Jiang, S. K.; Liu, Y. H.; Gao, X. M.; Hu, S. S.; Zhang, X.; Huang, C.; Wan, Q. B.; Wang, J.; Pei, X. B. Micro or nano: Evaluation of biosafety and biopotency of magnesium metal organic framework-74 with different particle sizes. Nano Res. 2020, 13, 511–526.
Crossref Google Scholar
[34]

Zhang, J. Y.; Chen, H. L.; Zhao, M.; Liu, G. T.; Wu, J. 2D nanomaterials for tissue engineering application. Nano Res. 2020, 13, 2019–2034.
Crossref Google Scholar
[35]

Chen, Y. Q.; Udduttula, A.; Xie, X. L.; Zhou, M.; Sheng, W. B.; Yu, F.; Weng, J.; Wang, D. L.; Teng, B.; Manivasagam, G. et al. A novel photocrosslinked phosphate functionalized chitosan-Sr5(PO4)2SiO4 composite hydrogels and in vitro biomineralization, osteogenesis, angiogenesis for bone regeneration application. Compos. B. Eng. 2021, 222, 109057.
Crossref Google Scholar
[36]

Cao, J.; Wang, P.; Liu, Y. N.; Zhu, C. H.; Fan, D. D. Double crosslinked HLC-CCS hydrogel tissue engineering scaffold for skin wound healing. Int. J. Biol. Macromol. 2020, 155, 625–635.
Crossref Google Scholar
[37]

Bao, Z. T.; Gu, Z. P.; Xu, J. B.; Zhao, M.; Liu, G. T.; Wu, J. Acid-responsive composite hydrogel platform with space-controllable stiffness and calcium supply for enhanced bone regeneration. Chem. Eng. J. 2020, 396, 125353.
Crossref Google Scholar
[38]

Genova, T.; Petrillo, S.; Zicola, E.; Roato, I.; Ferracini, R.; Tolosano, E.; Altruda, F.; Carossa, S.; Mussano, F.; Munaron, L. The crosstalk between osteodifferentiating stem cells and endothelial cells promotes angiogenesis and bone formation. Vasc. Pharmacol. 2020, 132, 106723.
Crossref Google Scholar
[39]

Wang, C. F.; Jeong, K. J.; Park, H. J.; Lee, M.; Ryu, S. C.; Hwang, D. Y.; Nam, K. H.; Han, I. H.; Lee, J. Synthesis and formation mechanism of bone mineral, whitlockite nanocrystals in tri-solvent system. J. Colloid Interface Sci. 2020, 569, 1–11.
Crossref Google Scholar
[40]
Wu, H. F. ; Hua, Y. C. ; Wu, J. J. ; Zeng, Q. ; Yang, X. ; Zhu, X. D. ; Zhang, X. D. The morphology of hydroxyapatite nanoparticles regulates clathrin-mediated endocytosis in melanoma cells and resultant anti-tumor efficiency. Nano Res., in press, https://doi.org/10.1007/s12274-022-4220-y.
[41]

Liu, X. J.; Chang, Z.; Luo, L.; Xu, T. H.; Lei, X. D.; Liu, J. F.; Sun, X. M. Hierarchical ZnxCo3−xO4 nanoarrays with high activity for electrocatalytic oxygen evolution. Chem. Mater. 2014, 26, 1889–1895.
Crossref Google Scholar
[42]

Zeng, H. F.; Li, X. Y.; Xie, F.; Teng, L.; Chen, H. F. Dextran-coated fluorapatite nanorods doped with lanthanides in labelling and directing osteogenic differentiation of bone marrow mesenchymal stem cells. J. Mater. Chem. B 2014, 2, 3609–3617.
Crossref Google Scholar
[43]

Stanić, V.; Dimitrijević, S.; Antonović, D. G.; Jokić, B. M.; Zec, S. P.; Tanasković, S. T.; Raičević, S. Synthesis of fluorine substituted hydroxyapatite nanopowders and application of the central composite design for determination of its antimicrobial effects. Appl. Surf. Sci. 2014, 290, 346–352.
Crossref Google Scholar
[44]

Sun, J. P.; Zheng, X. Y.; Li, H.; Fan, D. D.; Song, Z. P.; Ma, H. X.; Hua, X. F.; Hui, J. F. Monodisperse selenium-substituted hydroxyapatite: Controllable synthesis and biocompatibility. Mater. Sci. Eng. C 2017, 73, 596–602.
Crossref Google Scholar
[45]

Kim, S.; Gim, T.; Kang, S. M. Versatile, tannic acid-mediated surface PEGylation for marine antifouling applications. ACS Appl. Mater. Interfaces 2015, 7, 6412–6416.
Crossref Google Scholar
[46]

Shao, C. S.; Chen, L. J.; Tang, R. M.; Zhang, B.; Tang, J. J.; Ma, W. N. Polarized hydroxyapatite/BaTiO3 scaffolds with bio-inspired porous structure for enhanced bone penetration. Rare Met. 2022, 41, 67–77.
Crossref Google Scholar
[47]

Takeno, H.; Aoki, Y.; Kimura, K. Effects of silica and clay nanoparticles on the mechanical properties of poly(vinyl alcohol) nanocomposite hydrogels. Colloids Surf. A Physicochem. Eng. Asp. 2021, 630, 127592.
Crossref Google Scholar
[48]

Chiu, Y. C.; Cheng, M. H.; Engel, H.; Kao, S. W.; Larson, J. C.; Gupta, S.; Brey, E. M. The role of pore size on vascularization and tissue remodeling in PEG hydrogels. Biomaterials 2011, 32, 6045–6051.
Crossref Google Scholar
[49]

Stevens, L. R.; Gilmore, K. J.; Wallace, G. G.; Panhuis, M. I. H. Tissue engineering with gellan gum. Biomater. Sci. 2016, 4, 1276–1290.
Crossref Google Scholar
[50]

Armiento, A. R.; Hatt, L. P.; Rosenberg, G. S.; Thompson, K.; Stoddart, M. J. Functional biomaterials for bone regeneration: A lesson in complex biology. Adv. Funct. Mater. 2020, 30, 1909874.
Crossref Google Scholar
[51]

Milovanovic, M.; Isselbaecher, N.; Brandt, V.; Tiller, J. C. Improving the strength of ultrastiff organic–inorganic double-network hydrogels. Chem. Mater. 2021, 33, 8312–8322.
Crossref Google Scholar
[52]

Ito, A.; Kawamura, H.; Otsuka, M.; Ikeuchi, M.; Ohgushi, H.; Ishikawa, K.; Onuma, K.; Kanzaki, N.; Sogo, Y.; Ichinose, N. Zinc-releasing calcium phosphate for stimulating bone formation. Mater. Sci. Eng. C 2002, 22, 21–25.
Crossref Google Scholar
[53]

Singh, A.; Gill, G.; Kaur, H.; Amhmed, M.; Jakhu, H. Role of osteopontin in bone remodeling and orthodontic tooth movement: A review. Prog. Orthod. 2018, 19, 18.
Crossref Google Scholar
[54]

Tsao, Y. T.; Huang, Y. J.; Wu, H. H.; Liu, Y. A.; Liu, Y. S.; Lee, O. K. Osteocalcin mediates biomineralization during osteogenic maturation in human mesenchymal stromal cells. Int. J. Mol. Sci. 2017, 18, 159.
Crossref Google Scholar
[55]

Zhu, D. H.; Su, Y. C.; Young, M. L.; Ma, J.; Zheng, Y. F.; Tang, L. P. Biological responses and mechanisms of human bone marrow mesenchymal stem cells to Zn and Mg biomaterials. ACS Appl. Mater. Interfaces 2017, 9, 27453–27461.
Crossref Google Scholar
[56]

Chen, X.; Tan, B.; Wang, S.; Tang, R.; Bao, Z.; Chen, G.; Chen, S.; Tang, W.; Wang, Z.; Long, C. et al. Rationally designed protein cross-linked hydrogel for bone regeneration via synergistic release of magnesium and zinc ions. Biomaterials 2021, 274, 120895.
Crossref Google Scholar
[57]

Li, Y.; Xiong, W.; Zhang, C. C.; Gao, B.; Guan, H. F.; Cheng, H.; Fu, J. J.; Li, F. Enhanced osseointegration and antibacterial action of zinc-loaded titania-nanotube-coated titanium substrates: In vitro and in vivo studies. J. Biomed. Mater. Res. A 2014, 102, 3939–3950.
Crossref Google Scholar
[58]

Stanić, V.; Dimitrijević, S.; Antić-Stanković, J.; Mitrić, M.; Jokić, B.; Plećaš, I. B.; Raičević, S. Synthesis, characterization and antimicrobial activity of copper and zinc-doped hydroxyapatite nanopowders. Appl. Surf. Sci. 2010, 256, 6083–6089.
Crossref Google Scholar
Nano Research
Volume 16 Issue 1,
January 2023
Pages 757-770
DOI: 10.1007/s12274-022-4644-4
Cite this article:
Wang M, Yao J, Shen S, et al. A scaffold with zinc-whitlockite nanoparticles accelerates bone reconstruction by promoting bone differentiation and angiogenesis. Nano Research, 2023, 16(1): 757-770. https://doi.org/10.1007/s12274-022-4644-4
Topics:
Tissue regeneration

1161

Views

17

Crossref

18

Web of Science

19

Scopus

1

CSCD

Altmetrics
Received: 25 May 2022
Revised: 07 June 2022
Accepted: 08 June 2022
Published: 28 July 2022
© Tsinghua University Press 2022
Return