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Cited by 27Bone Tissue Engineering MaterialsDental Implant Techniques and OutcomesPeriodontal Regeneration and Treatments

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Osteoinductive micro-nano guided bone regeneration membrane for in situ bone defect repair

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Wang, Bingqian, Xie, Xinfang, Jiang, Wenbin, Zhan, Yichen, Zhang, Yifan, Guo, Yaqi, Wang, Zhenxing, Guo, Nengqiang, Guo, Ke, Sun, Jiaming·2024·Stem Cell Research & Therapy
DOI 10.1186/s13287-024-03745-wPMC PMC11077813
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Abstract

BACKGROUND: Biomaterials used in bone tissue engineering must fulfill the requirements of osteoconduction, osteoinduction, and osseointegration. However, biomaterials with good osteoconductive properties face several challenges, including inadequate vascularization, limited osteoinduction and barrier ability, as well as the potential to trigger immune and inflammatory responses. Therefore, there is an urgent need to develop guided bone regeneration membranes as a crucial component of tissue engineering strategies for repairing bone defects. METHODS: The mZIF-8/PLA membrane was prepared using electrospinning technology and simulated body fluid external mineralization method. Its ability to induce biomimetic mineralization was evaluated through TEM, EDS, XRD, FT-IR, zeta potential, and wettability techniques. The biocompatibility, osteoinduction properties, and osteo-immunomodulatory effects of the mZIF-8/PLA membrane were comprehensively evaluated by examining cell behaviors of surface-seeded BMSCs and macrophages, as well as the regulation of cellular genes and protein levels using PCR and WB. In vivo, the mZIF-8/PLA membrane's potential to promote bone regeneration and angiogenesis was assessed through Micro-CT and immunohistochemical staining. RESULTS: The mineralized deposition enhances hydrophilicity and cell compatibility of mZIF-8/PLA membrane. mZIF-8/PLA membrane promotes up-regulation of osteogenesis and angiogenesis related factors in BMSCs. Moreover, it induces the polarization of macrophages towards the M2 phenotype and modulates the local immune microenvironment. After 4-weeks of implantation, the mZIF-8/PLA membrane successfully bridges critical bone defects and almost completely repairs the defect area after 12-weeks, while significantly improving the strength and vascularization of new bone. CONCLUSIONS: The mZIF-8/PLA membrane with dual osteoconductive and immunomodulatory abilities could pave new research paths for bone tissue engineering.

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Fig. 1 Schematic of spontaneously induced biomimetic mineralization of electrospun ZIF-8/PLA membrane enhanced in situ bone defect repair. (a) Mineralization procedure of ZIF-8 in the body fluid microenvironment. (b) mZIF-8/PLA membrane with biomimetic mineralization capability, manufactured using electrospinning technology, was implanted into rat critical-sized skull defect models for in vivo bone regeneration evaluation. (c) Molecular mechanism of M2 polarization induced by the mZIF-8/PLA membrane
Fig. 1 Schematic of spontaneously induced biomimetic mineralization of electrospun ZIF-8/PLA membrane enhanced in situ bone defect repair. (a) Mineralization procedure of ZIF-8 in the body fluid microenvironment. (b) mZIF-8/PLA membrane with biomimetic mineralization capability, manufactured using electrospinning technology, was implanted into rat critical-sized skull defect models for in vivo bone regeneration evaluation. (c) Molecular mechanism of M2 polarization induced by the mZIF-8/PLA membraneCC BY · PubMed Central
Fig. 2 ZIF-8 induces biomimetic mineralization spontaneously. (a) TEM images of a typical structure of synthesized ZIF-8 particles. (b) EDS elements mapping showing morphology and component changes of ZIF-8 during mineralization process. (c) Comparison of XRD patterns of synthesized ZIF-8 and mineralized ZIF-8 (mineralization for 14 days). d FT-IR analysis of the original ZIF-8 and mineralized ZIF-8, together with standard phosphate absorption bands
Fig. 2 ZIF-8 induces biomimetic mineralization spontaneously. (a) TEM images of a typical structure of synthesized ZIF-8 particles. (b) EDS elements mapping showing morphology and component changes of ZIF-8 during mineralization process. (c) Comparison of XRD patterns of synthesized ZIF-8 and mineralized ZIF-8 (mineralization for 14 days). d FT-IR analysis of the original ZIF-8 and mineralized ZIF-8, together with standard phosphate absorption bandsCC BY · PubMed Central
Fig. 3 Characterization of the mineralization properties of the mZIF-8/PLA membrane. a, b) No significant changes between the PLA and mPLA membrane groups under SEM observation. c, d) SEM images of obvious crystal deposition after the mineralization process on the surface of ZIF-8/PLA membrane. Elemental mapping confirms the deposition involves Ca, P, and Zn elements
Fig. 3 Characterization of the mineralization properties of the mZIF-8/PLA membrane. a, b) No significant changes between the PLA and mPLA membrane groups under SEM observation. c, d) SEM images of obvious crystal deposition after the mineralization process on the surface of ZIF-8/PLA membrane. Elemental mapping confirms the deposition involves Ca, P, and Zn elementsCC BY · PubMed Central
Fig. 4 Characterizations of the material properties of the mZIF-8/PLA membrane. (a) Comparative FT-IR spectroscopic analysis of the PLA and ZIF-8/PLA membranes after immersion in SBF. (b) Zeta potential (ξ) measurements of the dispersion surface charge of the membranes can be altered by adding ZIF-8 particles. (c) Surface elemental compositions were determined using XPS. (d) Water contact angle test demonstrated that the hydrophily of PLA membrane after 7-day mineralization significantly increased due to the addition of ZIF-8
Fig. 4 Characterizations of the material properties of the mZIF-8/PLA membrane. (a) Comparative FT-IR spectroscopic analysis of the PLA and ZIF-8/PLA membranes after immersion in SBF. (b) Zeta potential (ξ) measurements of the dispersion surface charge of the membranes can be altered by adding ZIF-8 particles. (c) Surface elemental compositions were determined using XPS. (d) Water contact angle test demonstrated that the hydrophily of PLA membrane after 7-day mineralization significantly increased due to the addition of ZIF-8CC BY · PubMed Central
Fig. 5 Biocompatibility for BMSCs and the phenotype of macrophages cultured on the mZIF-8/PLA membrane. (a) Immunofluorescent staining for Calcein AM (green) and PI (red) in BMSCs from mPLA and mZIF-8/PLA group at day 3 and day 7. (b) Cell cytotoxicity assessment of BMSCs co-cultured in mPLA and mZIF-8/PLA groups showed no significant differences compared to the control group. (c) Cell viability result of BMSCs co-cultured with mZIF-8/PLA membrane shows a higher proliferating ability. (d) TNF𝛼 and IL10 production of 2 day–cultured macrophages by ELISA. (e) Surface markers IF staining and quantitative analysis of seeded macrophage (inducible nitric oxide synthase (iNOS) and CD206). (f) Flow cytometry demonstrating the percentages of CD86-positive and CD163-positive macrophages after cell seeding for 2 days. (g) CCR7, CD206, and VEGF of macrophages evaluated by RT–PCR. *p < 0.05, **p < 0.01, *** p < 0.001 (n = 6)
Fig. 5 Biocompatibility for BMSCs and the phenotype of macrophages cultured on the mZIF-8/PLA membrane. (a) Immunofluorescent staining for Calcein AM (green) and PI (red) in BMSCs from mPLA and mZIF-8/PLA group at day 3 and day 7. (b) Cell cytotoxicity assessment of BMSCs co-cultured in mPLA and mZIF-8/PLA groups showed no significant differences compared to the control group. (c) Cell viability result of BMSCs co-cultured with mZIF-8/PLA membrane shows a higher proliferating ability. (d) TNF𝛼 and IL10 production of 2 day–cultured macrophages by ELISA. (e) Surface markers IF staining and quantitative analysis of seeded macrophage (inducible nitric oxide synthase (iNOS) and CD206). (f) Flow cytometry demonstrating the percentages of CD86-positive and CD163-positive macrophages after cell seeding for 2 days. (g) CCR7, CD206, and VEGF of macrophages evaluated by RT–PCR. *p < 0.05, **p < 0.01, *** p < 0.001 (n = 6)CC BY · PubMed Central
Fig. 6 Pro-osteogenesis ability of BMSCs co-cultured with various membranes in vitro. (a) View of mPLA and mZIF-8/PLA after culturing with BMSCs in osteogenic induction medium in Alizarin Red staining at day 14. (b) Alizarin Red semi-quantification of calcium deposition to represent mineral deposition. (c) The mineralization ECM of BMSCs incubated with leaching solutions from different groups in Alizarin Red staining. d, e) ALP staining and quantification of ALP activity. f) Collagen content was estimated by determining the hydroxyproline content. g) Fluorescent images and quantitative analysis of OCN expression after 14 days of culture; Red (OCN), green (F-actin), and blue (nucleus). h) In the mZIF-8/PLA group, gene expression of Runx2 and Alp in BMSCs at day 5, Ocn, Col-1 and vegf in BMSCs at day 14, were significantly increased compared with the mPLA group. **p < 0.01, ***p < 0.001 (n = 6)
Fig. 6 Pro-osteogenesis ability of BMSCs co-cultured with various membranes in vitro. (a) View of mPLA and mZIF-8/PLA after culturing with BMSCs in osteogenic induction medium in Alizarin Red staining at day 14. (b) Alizarin Red semi-quantification of calcium deposition to represent mineral deposition. (c) The mineralization ECM of BMSCs incubated with leaching solutions from different groups in Alizarin Red staining. d, e) ALP staining and quantification of ALP activity. f) Collagen content was estimated by determining the hydroxyproline content. g) Fluorescent images and quantitative analysis of OCN expression after 14 days of culture; Red (OCN), green (F-actin), and blue (nucleus). h) In the mZIF-8/PLA group, gene expression of Runx2 and Alp in BMSCs at day 5, Ocn, Col-1 and vegf in BMSCs at day 14, were significantly increased compared with the mPLA group. **p < 0.01, ***p < 0.001 (n = 6)CC BY · PubMed Central
Fig. 7 New bone formation in vivo.a) Macroscopic observation of implantation area intraoperatively. b) 3D reconstructed images after micro-CT scanning of the calvarial defect area. Quantitative results of c) BV/TV and d) BMD. ***p < 0.001 (n = 8)
Fig. 7 New bone formation in vivo.a) Macroscopic observation of implantation area intraoperatively. b) 3D reconstructed images after micro-CT scanning of the calvarial defect area. Quantitative results of c) BV/TV and d) BMD. ***p < 0.001 (n = 8)CC BY · PubMed Central
Fig. 8 Histological and immunohistochemical analysis. (a) H&E staining (the margin and the center region of the defects). (b–e) H&E staining (b), Masson’s trichrome staining (c), OCN staining (D), and CD31 staining (e) images of the mPLA and mZIF-8/PLA bone guide membranes (*: new bone, &: membranes)
Fig. 8 Histological and immunohistochemical analysis. (a) H&E staining (the margin and the center region of the defects). (b–e) H&E staining (b), Masson’s trichrome staining (c), OCN staining (D), and CD31 staining (e) images of the mPLA and mZIF-8/PLA bone guide membranes (*: new bone, &: membranes)CC BY · PubMed Central

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Metadata

Authors
Wang, B., Xie, X., Jiang, W., Zhan, Y., Zhang, Y., Guo, Y., Wang, Z., Guo, N., Guo, K., & Sun, J.
Affiliations
  • Huazhong University of Science and Technology (CN)
  • Wuhan Union Hospital (CN)
Corresponding author
  • Guo, Nengqiang
  • Guo, Ke
  • Sun, Jiaming
ORCID
Venue
Stem Cell Research & Therapy
Publisher
Springer Science and Business Media LLC
Published
2024-05-07
Volume
15
Issue
1
Pages
135-135
ISSN
1757-6512 (ISSN-L)
DOI
10.1186/s13287-024-03745-w
PMC
PMC11077813
OpenAlex
W4396689525
Cited by
27
References
52
Citations by year
2026: 7 · 2025: 16 · 2024: 4
FWCI
2.96
Type
journal article
Language
en
Open access
Licence
Locations
  • Stem Cell Research & Therapy (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • National Key R&D Program of China (2019YFA0110500)
  • National Natural Science Foundation of China (82020108020, 82072198, 81873941, 81701922)
  • Health Commission of Hubei Province scientific research project (WJ2021Z008)
  • Jingshan Union Hospital program (2023-XHJS-004)
Topics
  • Physical Sciences › Engineering › Biomedical Engineering › Bone Tissue Engineering Materials
  • Health Sciences › Dentistry › Oral Surgery › Dental Implant Techniques and Outcomes
  • Health Sciences › Dentistry › Periodontics › Periodontal Regeneration and Treatments
Keywords
metal-organic framework derived materials, polylactic acid, biomimetic mineralization, osteoinduction, osteoimmunomodulation, macrophage polarization, M2 macrophages, bone marrow mesenchymal stem cells, angiogenesis, bone defect repair, critical-size bone defect, bone tissue engineering
MeSH terms
Animals, Biocompatible Materials, Bone Regeneration, Membranes, Artificial, Osteogenesis, Polyesters, Tissue Engineering, Guided Tissue Regeneration, Mice, Rats, Tissue Scaffolds, Mesenchymal Stem Cells

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