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Inflammatory Response of Human Peripheral Blood Mononuclear Cells and Osteoblasts Incubated With Metallic and Ceramic Submicron Particles

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Klinder, Annett, Seyfarth, Anika, Hansmann, Doris, Bader, Rainer, Jonitz-Heincke, Anika·2018·Frontiers in Immunology
DOI 10.3389/fimmu.2018.00831PMC PMC5996910
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Abstract

Inflammatory reactions associated with osteolysis and aseptic loosening are the result of wear particles generated at the articulating surfaces of implant components. The aim of the present study was to analyze the biological response of human osteoblasts and PBMCs after exposure to metallic and alumina ceramic particles regarding cellular differentiation, cytokine release and monocyte migration. Cells were exposed to particles (0.01 mg/ml, 0.05 mg/ml) from an alumina matrix composite (AMC) and a CoCr28Mo6 alloy with an average size of 0.5 µm over 48 h and 96 h. The expression rates of osteogenic (Col1A1, ALP) and pro-osteoclastic (RANK, Trap5b) differentiation markers as well as pro-osteolytic mediators (MMP-1, TIMP-1, IL-6, IL-8, MCP-1) were determined and soluble protein concentrations of active MMP-1, IL-6, IL-8 and pro-collagen type 1 in cell culture supernatants were evaluated. Additionally, the capacity of particle-treated osteoblasts to attract potentially pro-inflammatory cells to the site of particle exposure was investigated by migration assays using osteoblast-conditioned media. The cellular morphology and metabolism of human osteoblasts and adherent PBMCs were influenced by particle type and concentration. In human osteoblasts, Col1A1 expression rates and protein production were significantly reduced after exposing cells to the lower concentration of CoCr and AMC particles. Exposure to AMC particles (0.01 mg/ml) resulted in increased mRNA levels of RANK and Trap5b in adherent PBMCs. For MMP-1 gene expression, elevated levels were more prominent after incubation with CoCr compared to AMC particles in osteoblasts which was not reflected by the protein data. IL-6 and IL-8 mRNA and protein was induced in both cell types after treatment with AMC particles whereas exposure to CoCr particles resulted in significantly upregulated IL-6 and IL-8 protein contents in PBMCs only. Exposure of osteoblasts to CoCr particles reduced the chemoattractant potential of osteoblast-conditioned medium. Our results demonstrated distinct effects of AMC and CoCr particles in human osteoblasts and PBMCs. More complex cell models are required to further evaluate the impact of cellular interactions between different cell types during particle exposure.

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Figure 1 Representative FESEM pictures of AMC and CoCr particles. AMC particles showed a granular, irregular, and angulated appearance (left panel). Particles derived from a CoCr alloy revealed a flake-like to globular (cauliflowers) appearance (right panel). Bar: 1 µm.
Figure 1 Representative FESEM pictures of AMC and CoCr particles. AMC particles showed a granular, irregular, and angulated appearance (left panel). Particles derived from a CoCr alloy revealed a flake-like to globular (cauliflowers) appearance (right panel). Bar: 1 µm.CC BY · PubMed Central
Figure 2 Representative pictures of human PBMCs (A–E) and osteoblasts (F–J) after exposure to AMC and CoCr particles. Cells were treated with the respective particle type using different concentrations over a period of 48 h. Particle accumulations are highlighted with black arrows. Light microscopy revealed either particle- or concentration-dependent effect on cell density and morphology. Bar: 20 µm.
Figure 2 Representative pictures of human PBMCs (A–E) and osteoblasts (F–J) after exposure to AMC and CoCr particles. Cells were treated with the respective particle type using different concentrations over a period of 48 h. Particle accumulations are highlighted with black arrows. Light microscopy revealed either particle- or concentration-dependent effect on cell density and morphology. Bar: 20 µm.CC BY · PubMed Central
Figure 3 Cell viability of human PBMCs (A) and osteoblasts (B) after exposure to AMC and CoCr particles. Cells treated with the respective particle were analyzed using the WST-1 assay. Data are shown as box plots (n ≥ 3). Significances between groups were calculated with the Mann–Whitney U-test (*p < 0.05, treated vs. untreated; #p < 0.05, 0.01 vs. 0.05 mg/ml; °p < 0.05, 48 vs. 96 h).
Figure 3 Cell viability of human PBMCs (A) and osteoblasts (B) after exposure to AMC and CoCr particles. Cells treated with the respective particle were analyzed using the WST-1 assay. Data are shown as box plots (n ≥ 3). Significances between groups were calculated with the Mann–Whitney U-test (*p < 0.05, treated vs. untreated; #p < 0.05, 0.01 vs. 0.05 mg/ml; °p < 0.05, 48 vs. 96 h).CC BY · PubMed Central
Figure 4 Differentiation capacity of human PBMC cultures after exposure to AMC and CoCr particles in different concentrations. Cells were analyzed for gene expression levels of pro-osteoclastic differentiation marker by qRT-PCR (A,B). Data are shown as box plots (n = 4). Significances between groups were calculated with the Mann–Whitney U-test (*p < 0.05, treated vs. untreated; #p < 0.05, 0.01 vs. 0.05 mg/ml; °p < 0.05, 48 vs. 96 h). (C) Representative pictures of actin (green fluorescence) and cell nuclei (blue fluorescence) in PBMC cultures after 48 h of incubation with AMC and CoCr particles. Exposure to particles revealed an enhanced cell number with actin rings as well as formation of membranous ruffled border compared to untreated controls. Bar: 20 µm.
Figure 4 Differentiation capacity of human PBMC cultures after exposure to AMC and CoCr particles in different concentrations. Cells were analyzed for gene expression levels of pro-osteoclastic differentiation marker by qRT-PCR (A,B). Data are shown as box plots (n = 4). Significances between groups were calculated with the Mann–Whitney U-test (*p < 0.05, treated vs. untreated; #p < 0.05, 0.01 vs. 0.05 mg/ml; °p < 0.05, 48 vs. 96 h). (C) Representative pictures of actin (green fluorescence) and cell nuclei (blue fluorescence) in PBMC cultures after 48 h of incubation with AMC and CoCr particles. Exposure to particles revealed an enhanced cell number with actin rings as well as formation of membranous ruffled border compared to untreated controls. Bar: 20 µm.CC BY · PubMed Central
Figure 5 Differentiation capacity of human osteoblasts after exposure to different concentrations of AMC and CoCr particles. Cells were treated with the respective particle to evaluate gene expression levels of osteogenic differentiation marker by qRT-PCR (A,B). (C,D) Cell culture supernatants were used to evaluate the concentration of pro-collagen type 1 (C1CP per total protein content). Data are shown as box plots (n ≥ 3). Significances between groups were calculated with the Mann–Whitney U-test (*p < 0.05, treated vs. untreated; #p < 0.05, 0.01 vs. 0.05 mg/ml; °p < 0.05, 48 vs. 96 h).
Figure 5 Differentiation capacity of human osteoblasts after exposure to different concentrations of AMC and CoCr particles. Cells were treated with the respective particle to evaluate gene expression levels of osteogenic differentiation marker by qRT-PCR (A,B). (C,D) Cell culture supernatants were used to evaluate the concentration of pro-collagen type 1 (C1CP per total protein content). Data are shown as box plots (n ≥ 3). Significances between groups were calculated with the Mann–Whitney U-test (*p < 0.05, treated vs. untreated; #p < 0.05, 0.01 vs. 0.05 mg/ml; °p < 0.05, 48 vs. 96 h).CC BY · PubMed Central
Figure 6 MMP-1 and TIMP-1 expression rates in human osteoblasts following exposure to AMC and CoCr particles. Gene expression levels of MMP-1 and TIMP-1 by qRT-PCR (A,B) were determined in cells treated with the respective particle type. (C,D) Cell culture supernatants were used to evaluate the concentration of activated MMP-1 protein (per total protein content). Data are shown as median and minimum/maximum values (n = 4). Significances between groups were calculated with the Mann–Whitney U-test (*p < 0.05, treated vs. untreated; #p < 0.05, 0.01 vs. 0.05 mg/ml).
Figure 6 MMP-1 and TIMP-1 expression rates in human osteoblasts following exposure to AMC and CoCr particles. Gene expression levels of MMP-1 and TIMP-1 by qRT-PCR (A,B) were determined in cells treated with the respective particle type. (C,D) Cell culture supernatants were used to evaluate the concentration of activated MMP-1 protein (per total protein content). Data are shown as median and minimum/maximum values (n = 4). Significances between groups were calculated with the Mann–Whitney U-test (*p < 0.05, treated vs. untreated; #p < 0.05, 0.01 vs. 0.05 mg/ml).CC BY · PubMed Central
Figure 7 IL-6 and IL-8 expression rates in human PBMC cultures and osteoblasts following exposure to AMC and CoCr particles. PBMCs were treated with the respective particle to evaluate gene expression levels of IL-6 and IL-8 by qRT-PCR (A,B). (C–F) Cell culture supernatants of particle-exposed PBMCs and osteoblasts were used to evaluate the concentration of soluble IL-6 and IL-8 protein (per total protein content). Data are shown as median and minimum/maximum values (n = 4). Significances between groups were calculated with the Mann–Whitney U-test (*p < 0.05, treated vs. untreated; #p < 0.05, 0.01 vs. 0.05 mg/ml).
Figure 7 IL-6 and IL-8 expression rates in human PBMC cultures and osteoblasts following exposure to AMC and CoCr particles. PBMCs were treated with the respective particle to evaluate gene expression levels of IL-6 and IL-8 by qRT-PCR (A,B). (C–F) Cell culture supernatants of particle-exposed PBMCs and osteoblasts were used to evaluate the concentration of soluble IL-6 and IL-8 protein (per total protein content). Data are shown as median and minimum/maximum values (n = 4). Significances between groups were calculated with the Mann–Whitney U-test (*p < 0.05, treated vs. untreated; #p < 0.05, 0.01 vs. 0.05 mg/ml).CC BY · PubMed Central
Figure 8 Osteoblast-conditioned medium: influence on migration of human monocytes (A) and M-CSF protein content (B). (A) Cells were treated with 96 and 168 h osteoblast-conditioned medium and growth factor controls (positive controls) for 18 h. Cells in insert and well were counted and ratios calculated. Data are shown as box plots of ratios (n = 6) normalized to the negative control. Significances between groups were calculated with Friedman test with Dunn’s post-test (*p < 0.05). (B) Cell culture supernatants were used to evaluate the concentration of M-CSF (per total protein content). Data are shown as box plots (n = 4). Significances between groups were calculated with the Mann–Whitney U-test (*p < 0.05, treated vs. untreated; #p < 0.05, 96 vs. 168 h).
Figure 8 Osteoblast-conditioned medium: influence on migration of human monocytes (A) and M-CSF protein content (B). (A) Cells were treated with 96 and 168 h osteoblast-conditioned medium and growth factor controls (positive controls) for 18 h. Cells in insert and well were counted and ratios calculated. Data are shown as box plots of ratios (n = 6) normalized to the negative control. Significances between groups were calculated with Friedman test with Dunn’s post-test (*p < 0.05). (B) Cell culture supernatants were used to evaluate the concentration of M-CSF (per total protein content). Data are shown as box plots (n = 4). Significances between groups were calculated with the Mann–Whitney U-test (*p < 0.05, treated vs. untreated; #p < 0.05, 96 vs. 168 h).CC BY · PubMed Central

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References 52 · Cited by 32

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  1. Wengler, 2014, Hip and knee replacement in Germany and the USA: analysis of individual inpatient data from German and US hospitals for the years 2005 to 2011, Dtsch Arztebl Int, 111, 407, 10.3238/arztebl.2014.0407 · DOI
  2. Hughes, 2017, Arthroplasty registries around the world: valuable sources of hip implant revision risk data, Curr Rev Musculoskelet Med, 10, 240, 10.1007/s12178-017-9408-5 · DOI
  3. Sadoghi, 2013, Revision surgery after total joint arthroplasty: a complication-based analysis using worldwide arthroplasty registers, J Arthroplasty, 28, 1329, 10.1016/j.arth.2013.01.012 · DOI
  4. Man, 2017, Immunological responses to total hip arthroplasty, J Funct Biomater, 8, E33, 10.3390/jfb8030033 · DOI
  5. Bitar, 2015, Biological response to prosthetic debris, World J Orthop, 6, 172, 10.5312/wjo.v6.i2.172 · DOI
  6. Gallo, 2014, Contributions of human tissue analysis to understanding the mechanisms of loosening and osteolysis in total hip replacement, Acta Biomater, 10, 2354, 10.1016/j.actbio.2014.02.003 · DOI
  7. Goodman, 1998, Cellular profile and cytokine production at prosthetic interfaces. Study of tissues retrieved from revised hip and knee replacements, J Bone Joint Surg Br, 80, 531, 10.1302/0301-620X.80B3.0800531 · DOI
  8. Green, 2000, Effect of size and dose on bone resorption activity of macrophages by in vitro clinically relevant ultra high molecular weight polyethylene particles, J Biomed Mater Res, 53, 490, 10.1002/1097-4636(200009)53:5<490::AID-JBM7>3.0.CO;2-7 · DOI
  9. Gallo, 2013, Particle disease: biologic mechanisms of periprosthetic osteolysis in total hip arthroplasty, Innate Immun, 19, 213, 10.1177/1753425912451779 · DOI
  10. Nich, 2013, Macrophages—key cells in the response to wear debris from joint replacements, J Biomed Mater Res A, 101, 3033, 10.1002/jbm.a.34599 · DOI
  11. Jämsen, 2014, Characterization of macrophage polarizing cytokines in the aseptic loosening of total hip replacements, J Orthop Res, 32, 1241, 10.1002/jor.22658 · DOI
  12. Hallab, 2009, Biologic effects of implant debris, Bull NYU Hosp Jt Dis, 67, 182
  13. Davidson, 1994, Abrasive wear of ceramic, metal, and UHMWPE bearing surfaces from third-body bone, PMMA bone cement, and titanium debris, Biomed Mater Eng, 4, 213
  14. Sonntag, 2012, What’s next? Alternative materials for articulation in total joint replacement, Acta Biomater, 8, 2434, 10.1016/j.actbio.2012.03.029 · DOI
  15. Xing, 2002, The effect of polyethylene particle phagocytosis on the viability of mature human macrophages, J Biomed Mater Res, 61, 619, 10.1002/jbm.10078 · DOI
  16. Germain, 2003, Comparison of the cytotoxicity of clinically relevant cobalt-chromium and alumina ceramic wear particles in vitro, Biomaterials, 24, 469, 10.1016/S0142-9612(02)00360-5 · DOI
  17. Liu, 2015, The biological response to nanometre-sized polymer particles, Acta Biomater, 23, 38, 10.1016/j.actbio.2015.05.016 · DOI
  18. Neale, 2000, The effect of particle phagocytosis and metallic wear particles on osteoclast formation and bone resorption in vitro, J Arthroplasty, 15, 654, 10.1054/arth.2000.6622 · DOI
  19. Athanasou, 2016, The pathobiology and pathology of aseptic implant failure, Bone Joint Res, 5, 162, 10.1302/2046-3758.55.BJR-2016-0086 · DOI
  20. Lohmann, 2000, Phagocytosis of wear debris by osteoblasts affects differentiation and local factor production in a manner dependent on particle composition, Biomaterials, 21, 551, 10.1016/S0142-9612(99)00211-2 · DOI
  21. Lohmann, 2002, Ceramic and PMMA particles differentially affect osteoblast phenotype, Biomaterials, 23, 1855, 10.1016/S0142-9612(01)00312-X · DOI
  22. Fritz, 2006, Chemokine gene activation in human bone marrow-derived osteoblasts following exposure to particulate wear debris, J Biomed Mater Res A, 77, 192, 10.1002/jbm.a.30609 · DOI
  23. Fritz, 2002, Titanium particles induce the immediate early stress responsive chemokines IL-8 and MCP-1 in osteoblasts, J Orthop Res, 20, 490, 10.1016/S0736-0266(01)00154-1 · DOI
  24. Lochner, 2011, The potential role of human osteoblasts for periprosthetic osteolysis following exposure to wear particles, Int J Mol Med, 28, 1055, 10.3892/ijmm.2011.778 · DOI
  25. Braux, 2016, Strontium-substituted bioceramics particles: a new way to modulate MCP-1 and Gro-α production by human primary osteoblastic cells, Materials (Basel), 9, E985, 10.3390/ma9120985 · DOI
  26. Waugh, 2008, The interleukin-8 pathway in cancer, Clin Cancer Res, 14, 6735, 10.1158/1078-0432.CCR-07-4843 · DOI · Paper page
  27. Deshmane, 2009, Monocyte chemoattractant protein-1 (MCP-1): an overview, J Interferon Cytokine Res, 29, 313, 10.1089/jir.2008.0027 · DOI · Paper page
  28. Gallo, 2012, Advantages and disadvantages of ceramic on ceramic total hip arthroplasty: a review, Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub, 156, 204, 10.5507/bp.2012.063 · DOI
  29. Jeffers, 2012, Ceramic-on-ceramic bearings in hip arthroplasty: state of the art and the future, J Bone Joint Surg Br, 94, 735, 10.1302/0301-620X.94B6.28801 · DOI
  30. Laquerriere, 2003, Importance of hydroxyapatite particles characteristics on cytokines production by human monocytes in vitro, Biomaterials, 24, 2739, 10.1016/S0142-9612(03)00089-9 · DOI
  31. Laquerriere, 2004, MMP-2, MMP-9 and their inhibitors TIMP-2 and TIMP-1 production by human monocytes in vitro in the presence of different forms of hydroxyapatite particles, Biomaterials, 25, 2515, 10.1016/j.biomaterials.2003.09.034 · DOI
  32. Grandjean-Laquerriere, 2006, Influence of the zinc concentration of sol-gel derived zinc substituted hydroxyapatite on cytokine production by human monocytes in vitro, Biomaterials, 27, 3195, 10.1016/j.biomaterials.2006.01.024 · DOI
  33. Lange, 2011, Size dependent induction of proinflammatory cytokines and cytotoxicity of particulate beta-tricalciumphosphate in vitro, Biomaterials, 32, 4067, 10.1016/j.biomaterials.2011.02.039 · DOI
  34. Lange, 2009, Proinflammatory and osteoclastogenic effects of beta-tricalciumphosphate and hydroxyapatite particles on human mononuclear cells in vitro, Biomaterials, 30, 5312, 10.1016/j.biomaterials.2009.06.023 · DOI
  35. Laquerriere, 2001, Effect of hydroxyapatite sintering temperature on intracellular ionic concentrations of monocytes: a TEM-cryo-X-ray microanalysis study, J Biomed Mater Res, 58, 238, 10.1002/1097-4636(2001)58:3<238::AID-JBM1012>3.0.CO;2-I · DOI
  36. Jonitz-Heincke, 2017, The impact of metal ion exposure on the cellular behavior of human osteoblasts and PBMCs: in vitro analyses of osteolytic processes, Materials, 10, E734, 10.3390/ma10070734 · DOI
  37. Schulze, 2013, Cell viability, collagen synthesis and cytokine expression in human osteoblasts following incubation with generated wear particles using different bone cements, Int J Mol Med, 32, 227, 10.3892/ijmm.2013.1383 · DOI
  38. Jonitz-Heincke, 2016, Contribution of human osteoblasts and macrophages to bone matrix degradation and proinflammatory cytokine release after exposure to abrasive endoprosthetic wear particles, Mol Med Rep, 14, 1491, 10.3892/mmr.2016.5415 · DOI
  39. Goodman, 2013, The basic science of periprosthetic osteolysis, Instr Course Lect, 62, 201
  40. Yagil-Kelmer, 2004, Comparison of the response of primary human blood monocytes and the U937 human monocytic cell line to two different sizes of alumina ceramic particles, J Orthop Res, 22, 832, 10.1016/j.orthres.2003.10.022 · DOI
  41. Scharf, 2014, Molecular analysis of chromium and cobalt-related toxicity, Sci Rep, 4, 5729, 10.1038/srep05729 · DOI
  42. Kim, 2005, PGE2 induces the gene expression of bone matrix metalloproteinase-1 in mouse osteoblasts by cAMP-PKA signaling pathway, Int J Biochem Cell Biol, 37, 375, 10.1016/j.biocel.2004.07.013 · DOI
  43. Samelko, 2016, Cobalt alloy implant debris induces inflammation and bone loss primarily through danger signaling, not TLR4 activation: implications for DAMP-ening implant related inflammation, PLoS One, 11, e0160141, 10.1371/journal.pone.0160141 · DOI
  44. Burton, 2013, Orthopedic wear debris mediated inflammatory osteolysis is mediated in part by NALP3 inflammasome activation, J Orthop Res, 31, 73, 10.1002/jor.22190 · DOI
  45. Queally, 2009, Cobalt ions induce chemokine secretion in primary human osteoblasts, J Orthop Res, 27, 855, 10.1002/jor.20837 · DOI
  46. Johnson, 2014, The primary function of gp130 signaling in osteoblasts is to maintain bone formation and strength, rather than promote osteoclast formation, J Bone Miner Res, 29, 1492, 10.1002/jbmr.2159 · DOI
  47. Schmidt, 2003, IL-6 and PGE2 release by human osteoblasts on implant materials, Biomaterials, 24, 4191, 10.1016/S0142-9612(03)00317-X · DOI
  48. Goodman, 2010, Cellular chemotaxis induced by wear particles from joint replacements, Biomaterials, 31, 5045, 10.1016/j.biomaterials.2010.03.046 · DOI

Metadata

Authors
Klinder, A., Seyfarth, A., Hansmann, D., Bader, R., & Jonitz-Heincke, A.
Affiliations
Universitätsmedizin Rostock (DE)
ORCID
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2018-04-25
Volume
9
Pages
831-831
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2018.00831
PMC
PMC5996910
OpenAlex
W2801578735
Cited by
32
References
52
Citations by year
2026: 3 · 2025: 3 · 2024: 3 · 2023: 5 · 2022: 3 · 2021: 3 · 2020: 5 · 2019: 5 · 2018: 2
FWCI
3.90
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Immunology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
Deutsche Forschungsgemeinschaft (BA 3347/12-1)
Topics
  • Health Sciences › Medicine › Surgery › Orthopaedic implants and arthroplasty
  • Health Sciences › Medicine › Surgery › Orthopedic Infections and Treatments
  • Physical Sciences › Engineering › Biomedical Engineering › Bone Tissue Engineering Materials
Keywords
wear debris, osteolysis, aseptic loosening, alumina matrix composites, submicron particles, osteoblasts, peripheral blood mononuclear cells, inflammation, osteogenic differentiation, RANK, MMP-1, interleukin-6, interleukin-8, monocyte migration, chemoattractant activity
MeSH terms
Adult, Aged, Aged, 80 and over, Aluminum Oxide, Biocompatible Materials, Cell Survival, Cells, Cultured, Ceramics, Cobalt, Female, Humans, Leukocytes, Mononuclear, Male, Materials Testing, Middle Aged, Osteoblasts, Titanium, Interleukin-6, Interleukin-8, Culture Media, Conditioned, Matrix Metalloproteinase 1

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CoChat. (2026). Citation check: Inflammatory Response of Human Peripheral Blood Mononuclear Cells and Osteoblasts Incubated With Metallic and Ceramic Submicron Particles. https://app.cochat.ai/papers/10.3389/fimmu.2018.00831
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Klinder, A., Seyfarth, A., Hansmann, D., Bader, R., & Jonitz-Heincke, A. (2018). Inflammatory Response of Human Peripheral Blood Mononuclear Cells and Osteoblasts Incubated With Metallic and Ceramic Submicron Particles. Frontiers in Immunology. https://doi.org/10.3389/fimmu.2018.00831