Abstract: Inflammation is a key physiological process in the regeneration of bone tissue following injury. The acute inflammatory response, along with the timely resolution of inflammation, is essential for effective bone tissue repair. Exacerbation of either acute or chronic inflammation can lead to impaired bone regeneration, which is closely associated with interactions between immune cells and bone-related cells, as well as the regulatory roles of various inflammatory cytokines. In this review, we discuss the role of the immune microenvironment in bone regeneration and the negative impact of dysregulated inflammation on bone regeneration, and highlight on the need for timely elimination of inflammation. Additionally, the application of nanobiomaterials with immunomodulatory function in the treatment of inflammatory bone defects is discussed to clarify its current challenges and the future direction of its development.

免疫微环境在骨再生中的作用及免疫调节骨纳米生物材料的研究进展

[1]AlblowiJ, KayalRA, SiqueriaM, et al., 2009. High levels of tumor necrosis factor-α contribute to accelerated loss of cartilage in diabetic fracture healing. Am J Pathol, 175(4):1574-1585.

[2]AndersonJM, RodriguezA, ChangDT, 2008. Foreign body reaction to biomaterials. Semin Immunol, 20(2):86-100.

[3]Arango DuqueG, DescoteauxA, 2014. Macrophage cytokines: involvement in immunity and infectious diseases. Front Immunol, 5:491.

[4]BahneyCS, ZondervanRL, AllisonP, et al., 2019. Cellular biology of fracture healing. J Orthop Res, 37(1):35-50.

[5]BaiYJ, NiuYM, QinSG, et al., 2023. A new biomaterial derived from Aloe vera-acemannan from basic studies to clinical application. Pharmaceutics, 15(7):1913.

[6]BalistreriCR, CandoreG, AccardiG, et al., 2013. NF-κB pathway activators as potential ageing biomarkers: targets for new therapeutic strategies. Immun Ageing, 10:24.

[7]BastianO, PillayJ, AlblasJ, et al., 2011. Systemic inflammation and fracture healing. J Leukoc Biol, 89(5):669-673.

[8]BramhillJ, RossS, RossG, 2017. Bioactive nanocomposites for tissue repair and regeneration: a review. Int J Environ Res Public Health, 14(1):66.

[9]CaoLY, WerkmeisterJA, WangJ, et al., 2014. Bone regeneration using photocrosslinked hydrogel incorporating rhBMP-2 loaded 2-N,6-O-sulfated chitosan nanoparticles. Biomaterials, 35(9):2730-2742.

[10]ChenZT, BachhukaA, WeiF, et al., 2017a. Nanotopography-based strategy for the precise manipulation of osteoimmunomodulation in bone regeneration. Nanoscale, 9(46):18129-18152.

[11]ChenZT, BachhukaA, HanSW, et al., 2017b. Tuning chemistry and topography of nanoengineered surfaces to manipulate immune response for bone regeneration applications. ACS Nano, 11(5):4494-4506.

[12]ChenZT, HanSW, ShiMC, et al., 2018. Immunomodulatory effects of mesoporous silica nanoparticles on osteogenesis: from nanoimmunotoxicity to nanoimmunotherapy. Appl Mater Today, 10:184-193.

[13]ChungR, CoolJC, SchererMA, et al., 2006. Roles of neutrophil-mediated inflammatory response in the bony repair of injured growth plate cartilage in young rats. J Leukoc Biol, 80(6):1272-1280.

[14]ClaesL, RecknagelS, IgnatiusA, 2012. Fracture healing under healthy and inflammatory conditions. Nat Rev Rheumatol, 8(3):133-143.

[15]CottrellJ, O'ConnorJP, 2010. Effect of non-steroidal anti-inflammatory drugs on bone healing. Pharmaceuticals, 3(5):1668-1693.

[16]DavisonNL, SuJ, YuanH, et al., 2015. Influence of surface microstructure and chemistry on osteoinduction and osteoclastogenesis by biphasic calcium phosphate discs. Eur Cell Mater, 29:314-329.

[17]DingZC, ZengWN, RongX, et al., 2020. Do patients with diabetes have an increased risk of impaired fracture healing? A systematic review and meta-analysis. ANZ J Surg, 90(7-8):1259-1264.

[18]DonathMY, ShoelsonSE, 2011. Type 2 diabetes as an inflammatory disease. Nat Rev Immunol, 11(2):98-107.

[19]DudaGN, GeisslerS, ChecaS, et al., 2023. The decisive early phase of bone regeneration. Nat Rev Rheumatol, 19(2):78-95.

[20]EinhornTA, GerstenfeldLC, 2015. Fracture healing: mechanisms and interventions. Nat Rev Rheumatol, 11(1):45-54.

[21]EllisTN, BeamanBL, 2004. Interferon-γ activation of polymorphonuclear neutrophil function. Immunology, 112(1):2-12.

[22]FangHY, LinJ, QiuYW, et al., 2025. Epidemiology and pathogenesis of the link between rheumatoid arthritis and periodontitis. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 26(5):448-460.

[23]FernandoMR, ReyesJL, IannuzziJ, et al., 2014. The pro-inflammatory cytokine, interleukin-6, enhances the polarization of alternatively activated macrophages. PLoS One, 9(4):e94188.

[24]FerrariSL, AbrahamsenB, NapoliN, et al., 2018. Diagnosis and management of bone fragility in diabetes: an emerging challenge. Osteoporos Int, 29(12):2585-2596.

[25]FijanyA, SayadiLR, KhoshabN, et al., 2019. Mesenchymal stem cell dysfunction in diabetes. Mol Biol Rep, 46(1):1459-1475.

[26]FranceschiC, BonafèM, ValensinS, et al., 2000. Inflamm-aging: an evolutionary perspective on immunosenescence. Ann N Y Acad Sci, 908(1):244-254.

[27]FratzlP, GuptaHS, PaschalisEP, et al., 2004. Structure and mechanical quality of the collagen-mineral nano-composite in bone. J Mater Chem, 14(14):2115-2123.

[28]FrostHM, 1989. The biology of fracture healing. An overview for clinicians. Part II. Clin Orthop Relat Res, 248:294-309.

[29]FuXB, HanB, CaiS, et al., 2009. Migration of bone marrow-derived mesenchymal stem cells induced by tumor necrosis factor-α and its possible role in wound healing. Wound Repair Regen, 17(2):185-191.

[30]FuY, CuiSJ, LuoD, et al., 2021. Novel inorganic nanomaterial-based therapy for bone tissue regeneration. Nanomaterials, 11(3):789.

[31]GerstenfeldLC, ChoTJ, KonT, et al., 2003. Impaired fracture healing in the absence of TNF-α signaling: the role of TNF-α in endochondral cartilage resorption. J Bone Miner Res, 18(9):1584-1592.

[32]GoodnoughLH, GoodmanSB, 2022. Relationship of aging, inflammation, and skeletal stem cells and their effects on fracture repair. Curr Osteoporos Rep, 20(5):320-325.

[33]GulatiK, Abdal-HayA, IvanovskiS, 2022. Novel nano-engineered biomaterials for bone tissue engineering. Nanomaterials, 12(3):333.

[34]HardyR, CooperMS, 2009. Bone loss in inflammatory disorders. J Endocrinol, 201(3):309-320.

[35]HoffP, GaberT, StrehlC, et al., 2017. A pronounced inflammatory activity characterizes the early fracture healing phase in immunologically restricted patients. Int J Mol Sci, 18(3):583.

[36]HosseinpourS, WalshLJ, XuC, 2022. Modulating osteoimmune responses by mesoporous silica nanoparticles. ACS Biomater Sci Eng, 8(10):4110-4122.

[37]HozainS, CottrellJ, 2020. Cdllb+ targeted depletion of macrophages negatively affects bone fracture healing. Bone, 138:115479.

[38]HuW, FeiTY, LiuZC, et al., 2025. Single-cell RNA-sequencing-guided reactive oxygen species-scavenging hydrogel design for regeneration of osteoporotic bone. J Zhejiang Univ-Sci B, 26(12):1172-1191.

[39]HuangR, WangX, ZhouYH, et al., 2017. RANKL-induced M1 macrophages are involved in bone formation. Bone Res, 5:17019.

[40]HuangRL, SunYB, HoCK, et al., 2018. IL-6 potentiates BMP-2-induced osteogenesis and adipogenesis via two different BMPR1A-mediated pathways. Cell Death Dis, 9(2):144.

[41]HuangXF, XieMR, XieYL, et al., 2020. The roles of osteocytes in alveolar bone destruction in periodontitis. J Transl Med, 18:479.

[42]HurtgenBJ, WardCL, GargK, et al., 2016. Severe muscle trauma triggers heightened and prolonged local musculoskeletal inflammation and impairs adjacent tibia fracture healing. J Musculoskelet Neuronal Interact, 16(2):122-134.

[43]IgnjatovićN, AjdukovićZ, SavićV, et al., 2013. Nanoparticles of cobalt-substituted hydroxyapatite in regeneration of mandibular osteoporotic bones. J Mater Sci Mater Med, 24(2):343-354.

[44]JacobsR, FonteneleRC, LahoudP, et al., 2024. Radiographic diagnosis of periodontal diseases ‒ current evidence versus innovations. Periodontology 2000, 95(1):51-69.

[45]JiaoHL, XiaoE, GravesDT, 2015. Diabetes and its effect on bone and fracture healing. Curr Osteoporos Rep, 13(5):327-335.

[46]JimiE, HuangF, NakatomiC, 2019. NF-κB signaling regulates physiological and pathological chondrogenesis. Int J Mol Sci, 20(24):6275.

[47]JinJO, HanXZ, YuQ, 2013. Interleukin-6 induces the generation of IL-10-producing Tr1 cells and suppresses autoimmune tissue inflammation. J Autoimmun, 40:28-44.

[48]JosephsonAM, Bradaschia-CorreaV, LeeS, et al., 2019. Age-related inflammation triggers skeletal stem/progenitor cell dysfunction. Proc Natl Acad Sci USA, 116(14):6995-7004.

[49]JulierZ, ParkAJ, BriquezPS, et al., 2017. Promoting tissue regeneration by modulating the immune system. Acta Biomater, 53:13-28.

[50]KatsuyamaE, MiyamotoH, KobayashiT, et al., 2015. Interleukin-1 receptor-associated kinase-4 (IRAK4) promotes inflammatory osteolysis by activating osteoclasts and inhibiting formation of foreign body giant cells. J Biol Chem, 290(2):716-726.

[51]KoKI, CoimbraLS, TianC, et al., 2015. Diabetes reduces mesenchymal stem cells in fracture healing through a TNFαmediated mechanism. Diabetologia, 58(3):633-642.

[52]KoKI, SyversonAL, KralikRM, et al., 2019. Diabetes-induced NF-κB dysregulation in skeletal stem cells prevents resolution of inflammation. Diabetes, 68(11):2095-2106.

[53]KobayashiK, TakahashiN, JimiE, et al., 2000. Tumor necrosis factor α stimulates osteoclast differentiation by a mechanism independent of the ODF/RANKL‒RANK interaction. J Exp Med, 191(2):275-286.

[54]KolarP, Schmidt-BleekK, SchellH, et al., 2010. The early fracture hematoma and its potential role in fracture healing. Tissue Eng Part B Rev, 16(4):427-434.

[55]KolarP, GaberT, PerkaC, et al., 2011. Human early fracture hematoma is characterized by inflammation and hypoxia. Clin Orthop Relat Res, 469(11):3118-3126.

[56]KovtunA, BergdoltS, WiegnerR, et al., 2016. The crucial role of neutrophil granulocytes in bone fracture healing. Eur Cell Mater, 32:152-162.

[57]KuchlerU, SchwarzeUY, DobsakT, et al., 2014. Dental and periodontal phenotype in sclerostin knockout mice. Int J Oral Sci, 6(2):70-76.

[58]KushiokaJ, ChowSKH, ToyaM, et al., 2023. Bone regeneration in inflammation with aging and cell-based immunomodulatory therapy. Inflamm Regen, 43:29.

[59]KwonD, ChaBG, ChoY, et al., 2017. Extra-large pore mesoporous silica nanoparticles for directing in vivo M2 macrophage polarization by delivering IL-4. Nano Lett, 17(5):2747-2756.

[60]LeeJ, ByunH, Madhurakkat PerikamanaSK, et al., 2019. Current advances in immunomodulatory biomaterials for bone regeneration. Adv Healthc Mater, 8(4):1801106.

[61]LeiH, Schmidt-BleekK, DieneltA, et al., 2015. Regulatory T cell-mediated anti-inflammatory effects promote successful tissue repair in both indirect and direct manners. Front Pharmacol, 6:184.

[62]LimJC, KoKI, MattosM, et al., 2017. TNFα contributes to diabetes impaired angiogenesis in fracture healing. Bone, 99:26-38.

[63]LiuD, XuJK, FigliomeniL, et al., 2003. Expression of RANKL and OPG mRNA in periodontal disease: possible involvement in bone destruction. Int J Mol Med, 11(1):17-21.

[64]LöfflerJ, SassFA, FilterS, et al., 2019. Compromised bone healing in aged rats is associated with impaired M2 macrophage function. Front Immunol, 10:2443.

[65]LoiF, CórdovaLA, PajarinenJ, et al., 2016. Inflammation, fracture and bone repair. Bone, 86:119-130.

[66]LopezEM, LeclercK, RamsukhM, et al., 2022. Modulating the systemic and local adaptive immune response after fracture improves bone regeneration during aging. Bone, 157:116324.

[67]MahonOR, BroweDC, Gonzalez-FernandezT, et al., 2020. Nano-particle mediated M2 macrophage polarization enhances bone formation and MSC osteogenesis in an IL-10 dependent manner. Biomaterials, 239:119833.

[68]MantovaniA, CassatellaMA, CostantiniC, et al., 2011. Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol, 11(8):519-531.

[69]MarsellR, EinhornTA, 2011. The biology of fracture healing. Injury, 42(6):551-555.

[70]MartinoMM, MaruyamaK, KuhnGA, et al., 2016. Inhibition of IL-1R1/MyD88 signalling promotes mesenchymal stem cell-driven tissue regeneration. Nat Commun, 7:11051.

[71]MaruyamaM, RheeC, UtsunomiyaT, et al., 2020. Modulation of the inflammatory response and bone healing. Front Endocrinol, 11:386.

[72]MooneyJE, RolfeBE, OsborneGW, et al., 2010. Cellular plasticity of inflammatory myeloid cells in the peritoneal foreign body response. Am J Pathol, 176(1):369-380.

[73]NegiD, BhavyaK, PalD, et al., 2024. Acemannan coated, cobalt-doped biphasic calcium phosphate nanoparticles for immunomodulation regulated bone regeneration. Biomater Sci, 12(14):3672-3685.

[74]NewmanH, ShihYV, VargheseS, 2021. Resolution of inflammation in bone regeneration: from understandings to therapeutic applications. Biomaterials, 277:121114.

[75]OhSA, LiMO, 2013. TGF-β: guardian of T cell function. J Immunol, 191(8):3973-3979.

[76]OlivieriF, PrattichizzoF, GrillariJ, et al., 2018. Cellular senescence and inflammaging in age-related diseases. Mediators Inflamm, 2018(1):9076485.

[77]PaciosS, AndriankajaO, KangJ, et al., 2013. Bacterial infection increases periodontal bone loss in diabetic rats through enhanced apoptosis. Am J Pathol, 183(6):1928-1935.

[78]PajarinenJ, LinT, GibonE, et al., 2019. Mesenchymal stem cell-macrophage crosstalk and bone healing. Biomaterials, 196:80-89.

[79]QiaoW, XieHZ, FangJH, et al., 2021. Sequential activation of heterogeneous macrophage phenotypes is essential for biomaterials-induced bone regeneration. Biomaterials, 276:121038.

[80]ReljaB, YangB, BundkirchenK, et al., 2020. Different experimental multiple trauma models induce comparable inflammation and organ injury. Sci Rep, 10:20185.

[81]Rezaei EsfahroodZ, YadegariZ, VeysariSK, et al., 2018. Gingival crevicular fluid levels of sclerostin in chronic periodontitis and healthy subjects. J Korean Assoc Oral Maxillofac Surg, 44(6):289-292.

[82]SadekKM, el MoshyS, RadwanIA, et al., 2023. Molecular basis beyond interrelated bone resorption/regeneration in periodontal diseases: a concise review. Int J Mol Sci, 24(5):4599.

[83]SadowskaJM, WeiF, GuoJ, et al., 2018. Effect of nano-structural properties of biomimetic hydroxyapatite on osteoimmunomodulation. Biomaterials, 181:318-332.

[84]SalminenA, KauppinenA, KaarnirantaK, 2012. Emerging role of NF-κB signaling in the induction of senescence-associated secretory phenotype (SASP). Cell Signal, 24(4):835-845.

[85]SasiSP, YanX, EnderlingH, et al., 2012. Breaking the ‘harmony’ of TNF-α signaling for cancer treatment. Oncogene, 31(37):4117-4127.

[86]SaulD, KhoslaS, 2022. Fracture healing in the setting of endocrine diseases, aging, and cellular senescence. Endocr Rev, 43(6):984-1002.

[87]SchlundtC, el KhassawnaT, SerraA, et al., 2018. Macrophages in bone fracture healing: their essential role in endochondral ossification. Bone, 106:78-89.

[88]SchlundtC, ReinkeS, GeisslerS, et al., 2019. Individual effector/regulator T cell ratios impact bone regeneration. Front Immunol, 10:1954.

[89]ShemeshM, AddadiL, GeigerB, 2017. Surface microtopography modulates sealing zone development in osteoclasts cultured on bone. J Roy Soc Interface, 14(127):20160958.

[90]ShiMC, ChenZT, FarnaghiS, et al., 2016. Copper-doped mesoporous silica nanospheres, a promising immunomodulatory agent for inducing osteogenesis. Acta Biomater, 30:334-344.

[91]ShullMM, OrmsbyI, KierAB, et al., 1992. Targeted disruption of the mouse transforming growth factor-β1 gene results in multifocal inflammatory disease. Nature, 359(6397):693-699.

[92]TakeuchiT, YoshidaH, TanakaS, 2021. Role of interleukin-6 in bone destruction and bone repair in rheumatoid arthritis. Autoimmun Rev, 20(9):102884.

[93]TaniosM, BrickmanB, CageE, et al., 2022. Diabetes and impaired fracture healing: a narrative review of recent literature. Curr Osteoporos Rep, 20(5):229-239.

[94]TimmenM, HiddingH, WieskötterB, et al., 2014. Influence of antiTNF-alpha antibody treatment on fracture healing under chronic inflammation. BMC Musculoskelet Disord, 15:184.

[95]TrindadeR, AlbrektssonT, TengvallP, et al., 2016. Foreign body reaction to biomaterials: on mechanisms for buildup and breakdown of osseointegration. Clin Implant Dent Relat Res, 18(1):192-203.

[96]VeisehO, VegasAJ, 2019. Domesticating the foreign body response: recent advances and applications. Adv Drug Deliv Rev, 144:148-161.

[97]WangXP, LiX, YoshiyukiK, et al., 2016. Comprehensive mechanism analysis of mesoporous-silica-nanoparticle-induced cancer immunotherapy. Adv Healthc Mater, 5(10):1169-1176.

[98]WeckbachS, HohmannC, BraumuellerS, et al., 2013. Inflammatory and apoptotic alterations in serum and injured tissue after experimental polytrauma in mice: distinct early response compared with single trauma or “double-hit” injury. J Trauma Acute Care Surg, 74(2):489-498.

[99]WeiCX, LiZA, LiangXY, et al., 2025. Three-dimensional (3D) printing-assisted freeze-casting of processed pyritum-doped β-tricalcium phosphate biomimetic scaffold with angiogenesis and bone regeneration capability. J Zhejiang Univ-Sci B, 26(9):863-880.

[100]WeitzmannMN, 2017. Bone and the immune system. Toxicol Pathol, 45(7):911-924.

[101]XuC, XiaoL, CaoYX, et al., 2020. Mesoporous silica rods with cone shaped pores modulate inflammation and deliver BMP-2 for bone regeneration. Nano Res, 13(9):2323-2331.

[102]YangJK, ShuaiJ, SiowL, et al., 2024. MicroRNA-146a-loaded magnesium silicate nanospheres promote bone regeneration in an inflammatory microenvironment. Bone Res, 12:2.

[103]YangN, LiuY, 2021. The role of the immune microenvironment in bone regeneration. Int J Med Sci, 18(16):3697-3707.

[104]YangX, RicciardiBF, Hernandez-SoriaA, et al., 2007. Callus mineralization and maturation are delayed during fracture healing in interleukin-6 knockout mice. Bone, 41(6):928-936.

[105]YuD, ShenWY, DaiJH, et al., 2025. Treatment of large bone defects in load-bearing bone: traditional and novel bone grafts. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 26(5):421-447.

[106]YuasaM, MignemiNA, NymanJS, et al., 2015. Fibrinolysis is essential for fracture repair and prevention of heterotopic ossification. J Clin Invest, 125(8):3117-3131.

[107]ZaissMM, FreyB, HessA, et al., 2010. Regulatory T cells protect from local and systemic bone destruction in arthritis. J Immunol, 184(12):7238-7246.

[108]ZhangEH, MiraminiS, PatelM, et al., 2022. Role of TNF-α in early-stage fracture healing under normal and diabetic conditions. Comput Methods Programs Biomed, 213:106536.

[109]ZhangQ, ChenB, YanFH, et al., 2014. Interleukin-10 inhibits bone resorption: a potential therapeutic strategy in periodontitis and other bone loss diseases. Biomed Res Int, 2014:284836.

[110]ZhengXY, MaoCY, QiaoH, et al., 2017. Plumbagin suppresses chronic periodontitis in rats via down-regulation of TNF-α, IL-1β and IL-6 expression. Acta Pharmacol Sin, 38(8):1150-1160.