Strategies of Modulating Macrophage Behavior to Promote Bone Healing in Bone Tissue Engineering
Shan Qin1,2,3,4,5*
1(Stomatology Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China) 2(School of Stomatology, Zhejiang University School of Medicine, Hangzhou 310006, China) 3(Clinical Research Center for Oral Diseases of Zhejiang Province, Hangzhou 310006, China) 4(Key Laboratory of Oral Biomedical Research of Zhejiang Province, Hangzhou 310006, China) 5(Cancer Center of Zhejiang University, Hangzhou 310006, China)
Abstract：In bone tissue engineering, the biomaterial is implanted into the bone defect as a regeneration scaffold to help promote bone healing. With the development of osteoimmunology in recent years, people have realized that the immune response of macrophages determines whether the implantation is successful. Macrophages, which are diverse and plastic, can be polarized into M1-like (pro-inflammatory) and M2-like (anti-inflammatory) phenotypes according to environmental signals and play an important role in different stages of bone healing. Their behavior like migration, proliferation and polarization is sensitive to the properties of the material. This article reviews the current strategies of modulating the behavior of macrophages to promote bone healing by designing the physical properties, surface chemical properties, and biological properties of materials, including increasing the roughness of the material, macropores combining with nanostructures, appropriate electrical or mechanical signals, neutral or anionic surfaces, increasing hydrophilicity, using immunomodulatory materials or delivering immunological active substances to the defect area, etc., which provide ideas for the design of bone tissue engineering materials with good immunomodulatory properties.
单沁. 骨组织工程中调节巨噬细胞行为促进骨愈合的策略[J]. 中国生物医学工程学报, 2022, 41(5): 614-620.
Shan Qin,*. Strategies of Modulating Macrophage Behavior to Promote Bone Healing in Bone Tissue Engineering. Chinese Journal of Biomedical Engineering, 2022, 41(5): 614-620.
[1] Alvarez MM, Liu JC, Santiago TD, et al. Delivery strategies to control inflammatory response: modulating M1-M2 polarization in tissue engineering applications[J]. Journal of Controlled Release, 2016,240:349-363. [2] Vasconcelos DP, Artur PÁ, Mário AB, et al. The inflammasome in host response to biomaterials: bridging inflammation and tissue regeneration[J]. Acta Biomaterialia, 2019, 83:1-12. [3] Pajarinen J, Lin Tzuhua, Gibon E, et al. Mesenchymal stem cell-macrophage crosstalk and bone healing[J]. Biomaterials, 2019,196:80-89. [4] Zhu guanyin, Zhang Tianxu, Chen Miao, et al. Bone physiological microenvironment and healing mechanism: basis for future bone-tissue engineering scaffolds[J]. Bioactive Materials, 2021, 6(11):4110-4140. [5] Negrescu AM, Cimpean A. The state of the art and prospects for osteoimmunomodulatory biomaterials[J]. Materials (Basel), 2021, 14(6):1357-1390. [6] Niu Yiming, Wang Zhenzhen, Shi Yuchen, et al. Modulating macrophage activities to promote endogenous bone regeneration: biological mechanisms and engineering approaches [J]. Bioactive Materials, 2021, 6(1):244-261. [7] Chen Kaixuan, Jiao Yurui, Liu Ling, et al. Communications between bone marrow macrophages and bone cells in bone remodeling[J]. Frontiers in Cell and Developmental Biology, 2020, 8:598263. [8] Sinder BP, Pettit AR, Mccauley LK. Macrophages: their emerging roles in bone[J]. Journal of Bone and Mineral Research, 2015, 30(12):2140-2149. [9] Le BQ, Nurcombe V, Cool MK, et al. The Components of Bone and What They Can Teach Us about Regeneration[J]. Materials, 2018, 11(1):14-29. [10] Arora S, Dev K, Agarwal B, et al. Macrophages: their role, activation and polarization in pulmonary diseases[J]. Immunobiology, 2018, 223(4): 383-396. [11] Li Heng, Jiang Ting, Li Meng-Qi, et al. Transcriptional Regulation of Macrophages Polarization by MicroRNAs[J]. Frontiers in Immunology, 2018, 9: 1175. [12] Wang Lexun, Zhang Shengxi, Wu Huijuan, et al. M2b macrophage polarization and its roles in diseases[J]. Journal of Leukocyte Biology, 2019,106(2): 345-358. [13] Spiller KL, Sina N, Claire EW, et al. Sequential delivery of immunomodulatory cytokines to facilitate the M1-to-M2 transition of macrophages and enhance vascularization of bone scaffolds[J]. Biomaterials Guildford, 2015, 37:194-207. [14] Zhang Yang, Bse T, Unger R E, et al. Macrophage type modulates osteogenic differentiation of adipose tissue MSCs[J]. Cell and Tissue Research, 2017, 369(2):273-286. [15] Dutta B, Goswami R, Rahaman SO. TRPV4 Plays a role in matrix stiffness-induced macrophage polarization[J]. Frontiers in Immunology, 2020, 11:570195. [16] Sridharan R, Cavanagh B, Cameron AR, et al. Material stiffness influences the polarization state, function and migration mode of macrophages[J]. Acta Biomaterialia, 2019, 89:47-59. [17] Chen Mimi, Zhang Yu, Zhou Pinghui, et al. Substrate stiffness modulates bone marrow-derived macrophage polarization through NF-κB signaling pathway[J]. Bioactive Materials, 2020, 5(4):880-890. [18] Sridharan R, Ryan EJ, Kearney CJ, et al. Macrophage polarization in response to collagen scaffold stiffness is dependent on cross-linking agent used to modulate the stiffness[J]. ACS Biomaterials Science and Engineering, 2019,5(2):544-552. [19] Hind LE, Dembo M, Hammer DA. Macrophage motility is driven by frontal-towing with a force magnitude dependent on substrate stiffness[J]. Integr Biol (Camb),2015,7(4):447-453. [20] Lee J, Byun H, Perikamana SKM, et al. Current advances in immunomodulatory biomaterials for bone regeneration[J]. Advanced Healthcare Materials, 2019, 8(4): e1801106. [21] Hotchkiss KM, Reddy GB, Hyzy SL, et al. Titanium surface characteristics, including topography and wettability, alter macrophage activation[J]. Acta Biomater, 2016,31: 425-434. [22] Zhu Yizhou, Liang Hang, Liu Xiangmei, et al. Regulation of macrophage polarization through surface topography design to facilitate implant-to-bone osteointegration[J]. Science Advances, 2021, 7(14): eabf6654. [23] Cockerill I, Su Yingchao, Lee JH, et al. Micro-/nano-topography on bioresorbable zinc dictates cytocompatibility, bone cell differentiation, and macrophage polarization[J]. Nano Letters, 2020, 20(6):4594-4602. [24] Wissing TB, Bonito V, Haaften EEV, et al. Macrophage-driven biomaterial degradation depends on scaffold microarchitecture[J]. Frontiers in Bioengineering and Biotechnology, 2019, 7:87. [25] Xie Yajuan, Hu Cheng, Feng Yi, et al. Osteoimmunomodulatory effects of biomaterial modification strategies on macrophage polarization and bone regeneration[J]. Regenerative Biomaterials, 2020, 7(3):233-245. [26] Chen Zetao, Ni Siyu, Han Shengwei, et al. Nanoporous microstructures mediate osteogenesis by modulating the osteo-immune response of macrophages[J]. Nanoscale, 2016, 9(2):706-718. [27] Pan Houhua, Xie Youtao, Zhang Zequan, et al. Immunomodulation effect of a hierarchical macropore/nanosurface on osteogenesis and angiogenesis[J]. Biomedical Materials, 2017, 12(4):045006. [28] Dai Xiaohan, Heng BC, Bai Yunyang, et al. Restoration of electrical microenvironment enhances bone regeneration under diabetic conditions by modulating macrophage polarization[J]. Bioactive Materials, 2021, 6(7):2029-2038. [29] Hao Suisui, Meng Jie, Zhang Yu, et al. Macrophage phenotypic mechanomodulation of enhancing bone regeneration by superparamagnetic scaffold upon magnetization [J]. Biomaterials, 2017, 140:16-25. [30] Bygd HC, Forsmark KD, Bratlie KM. Altering in vivo macrophage responses with modified polymer properties[J]. Biomaterials, 2015, 56:187-197. [31] Hamlet SM, Lee RSB, Moon H. Hydrophilic titanium surface-induced macrophage modulation promotes pro-osteogenic signaling[J]. Clinical Oral Implants Research,2019,30(11):1085-1096. [32] Zhu Yu, Zhang Kun, Zhao Rui, et al. Bone regeneration with micro/nano hybrid-structured biphasic calcium phosphate bioceramics at segmental bone defect and the induced immunoregulation of MSCs[J]. Biomaterials, 2017:133-144. [33] Yang Fenghe, Niu Xufeng, Gu Xuenan, et al. Biodegradable magnesium-incorporated poly (l-lactic acid) microspheres for manipulation of drug release and alleviation of inflammatory response [J]. ACS Applied Materials & Interfaces, 2019, 11(26):23546-23557. [34] Julier Z, Park AJ, Briquez PS, et al. Promoting tissue regeneration by modulating the immune system[J]. Acta Biomaterialia, 2017,53:13-28. [35] Dziki JL, Wang DS, Pineda C, et al. Solubilized extracellular matrix bioscaffolds derived from diverse source tissues differentially influence macrophage phenotype[J]. Journal of Biomedical Materials Research Part A, 2017, 105(1):138-147. [36] Huleihel L, Hussey GS, Naranjo JD, et al. Matrix-bound nanovesicles within ECM bioscaffolds[J]. Science Advances, 2016, 2(6): e1600502. [37] Hussey GS, Dziki JL, Lee YC, et al. Matrix bound nanovesicle-associated IL-33 activates a pro-remodeling macrophage phenotype via a non-canonical, ST2-independent pathway[J]. Journal of Immunology & Regenerative Medicine, 2019, 3:26-35. [38] Huleihel L, Bartolacci JG, Dziki JL, et al. Matrix bound nanovesicles recapitulate extracellular matrix effects on macrophage phenotype[J]. Tissue Engineering Part A, 2017,23(21-22):1283-1294. [39] Kim Y, Tabata Y. Recruitment of mesenchymal stem cells and macrophages by dual release of stromal cell-derived factor-1 and a macrophage recruitment agent enhances wound closure[J]. Journal of Biomedical Materials Research Part A, 2016, 104(4):942-956. [40] Shi Mengchao, Chen Zetao, Farnaghi S, et al. Copper-doped mesoporous silica nanospheres, a promising immunomodulatory agent for inducing osteogenesis[J]. Acta Biomaterialia, 2016, 30:334-344. [41] Hu Zhiai, Ma Chi, Rong Xin, et al. Immunomodulatory ECM-like microspheres for accelerated bone regeneration in diabetes mellitus[J]. ACS Applied Materials & Interfaces, 2018, 10(3):2377-2390. [42] 王静旭, 夏海发, 姚尚龙. 促炎症消退介质通过调节免疫细胞促进炎症消退的机制研究进展[J]. 中华危重病急救医学, 2020, 32(7):873-876. [43] Yin Chengcheng, Zhao Qin, Li Wu, et al. Biomimetic Anti-inflammatory Nano-Capsule served as cytokines blocker and M2 polarization inducer for bone tissue repair[J]. Acta Biomaterialia, 2019, 102:416-426. [44] Spiller KL, Nassiri S, Witherel CE, et al. Sequential delivery of immunomodulatory cytokines to facilitate the M1-to-M2 transition of macrophages and enhance vascularization of bone scaffolds[J]. Biomaterials, 2015, 37:194-207. [45] Li Tao, Peng Mingzheng, Yang Zezheng, et al. 3D-printed IFN-γ-loading calcium silicate-β-tricalcium phosphate scaffold sequentially activates M1 and M2 polarization of macrophages to promote vascularization of tissue engineering bone[J]. Acta Biomaterialia, 2018, 71:96-107. [46] Seebach E, Freischmidt H, Holschbach J, et al. Mesenchymal stroma cells trigger early attraction of M1 macrophages and endothelial cells into fibrin hydrogels, stimulating long bone healing without long-term engraftment[J]. Acta Biomaterialia, 2014, 10(11):4730-4741. [47] Humbert P, Brennan MÁ, Davison N, et al. Immune modulation by transplanted calcium phosphate biomaterials and human mesenchymal stromal cells in bone regeneration [J]. Frontiers in Immunology, 2019, 10:663. [48] Liu Li, Guo Shujuan, Shi Weiwei, et al. BMSCs-derived small extracellular vesicles promote periodontal regeneration[J]. Tissue Engineering Part A, 2020, 27:13-14. [49] Cui Yigong, Fu Shenglong, Sun Dong, et al. EPC‐derived exosomes promote osteoclastogenesis through LncRNA‐MALAT1[J]. Journal of Cellular and Molecular Medicine, 2019, 23(6): 3843-3854. [50] Kang Miya, Huang C, Lu Yu, et al. Bone regeneration is mediated by macrophage extracellular vesicles[J]. Bone, 2020, 141:115627. [51] Murali VP, Holmes CA. Mesenchymal stromal cell-derived extracellular vesicles for bone regeneration therapy[J]. Bone Reports, 2021, 14:101093. [52] Xing Helin, Wang Xing, Xiao Gao, et al. Hierarchical assembly of nanostructured coating for siRNA-based dual therapy of bone regeneration and revascularization [J]. Biomaterials, 2020, 235:119784. [53] Nelson MC, O′Connell RM. MicroRNAs: at the interface of metabolic pathways and inflammatory responses by macrophages[J]. Frontiers in Immunology, 2020, 11:1797. [54] Essandoh K, Li Yutian, Huo Jiuzhou, et al. MiRNA-mediated macrophage polarization and its potential role in the regulation of inflammatory response[J]. Shock, 2016, 46(2):122-131. [55] Lee SWL, Paoletti C, Campisi M, et al. MicroRNA delivery through nanoparticles[J]. Journal of Controlled Release, 2019, 313:80-95.
