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Engineering of Immune Microenvironment for Enhanced Tissue Remodeling

  • Review Article
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Tissue Engineering and Regenerative Medicine Aims and scope

Abstract

The capability to restore the structure and function of tissues damaged by fatal diseases and trauma is essential for living organisms. Various tissue engineering approaches have been applied in lesions to enhance tissue regeneration after injuries and diseases in living organisms. However, unforeseen immune reactions by the treatments interfere with successful healing and reduce the therapeutic efficacy of the strategies. The immune system is known to play essential roles in the regulation of the microenvironment and recruitment of cells that directly or indirectly participate in tissue remodeling in defects. Accordingly, regenerative immune engineering has emerged as a novel approach toward efficiently inducing regeneration using engineering techniques that modulate the immune system. It is aimed at providing a favorable immune microenvironment based on the controlled balance between pro-inflammation and anti-inflammation. In this review, we introduce recent developments in immune engineering therapeutics based on various cell types and biomaterials. These developments could potentially overcome the therapeutic limitations of tissue remodeling.

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References

  1. Julier Z, Park AJ, Briquez PS, Martino MM. Promoting tissue regeneration by modulating the immune system. Acta Biomater. 2017;53:13–28.

    CAS  PubMed  Google Scholar 

  2. Ho J, Walsh C, Yue D, Dardik A, Cheema U. Current advancements and strategies in tissue engineering for wound healing: a comprehensive review. Adv Wound Care (New Rochelle). 2017;6:191–209.

    Google Scholar 

  3. Biondi M, Ungaro F, Quaglia F, Netti PA. Controlled drug delivery in tissue engineering. Adv Drug Deliv Rev. 2008;60:229–42.

    CAS  PubMed  Google Scholar 

  4. Shi Y, Hu G, Su J, Li W, Chen Q, Shou P, et al. Mesenchymal stem cells: a new strategy for immunosuppression and tissue repair. Cell Res. 2010;20:510–8.

    CAS  PubMed  Google Scholar 

  5. Godwin JW, Pinto AR, Rosenthal NA. Chasing the recipe for a pro-regenerative immune system. Semin Cell Dev Biol. 2017;61:71–9.

    CAS  PubMed  Google Scholar 

  6. Eming SA, Krieg T, Davidson JM. Inflammation in wound repair: molecular and cellular mechanisms. J Invest Dermatol. 2007;127:514–25.

    CAS  PubMed  Google Scholar 

  7. Andorko JI, Jewell CM. Designing biomaterials with immunomodulatory properties for tissue engineering and regenerative medicine. Bioeng Transl Med. 2017;2:139–55.

    PubMed  PubMed Central  Google Scholar 

  8. Boehler RM, Graham JG, Shea LD. Tissue engineering tools for modulation of the immune response. Biotechniques. 2011;51:239–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Ruytinx P, Proost P, Van Damme J, Struyf S. Chemokine-induced macrophage polarization in inflammatory conditions. Front Immunol. 2018;9:1930.

    PubMed  PubMed Central  Google Scholar 

  10. Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008;8:958–69.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Zhang Z, Tang J, Cui X, Qin B, Zhang J, Zhang L, et al. New insights and novel therapeutic potentials for macrophages in myocardial infarction. Inflammation. 2021;44:1696–712.

    CAS  PubMed  Google Scholar 

  12. Jung M, Ma Y, Iyer RP, DeLeon-Pennell KY, Yabluchanskiy A, Garrett MR, et al. IL-10 improves cardiac remodeling after myocardial infarction by stimulating M2 macrophage polarization and fibroblast activation. Basic Res Cardiol. 2017;112:33.

    PubMed  PubMed Central  Google Scholar 

  13. Shintani Y, Ito T, Fields L, Shiraishi M, Ichihara Y, Sato N, et al. IL-4 as a repurposed biological drug for myocardial infarction through augmentation of reparative cardiac macrophages: proof-of-concept data in mice. Sci Rep. 2017;7:6877.

    PubMed  PubMed Central  Google Scholar 

  14. Murray LA, Chen Q, Kramer MS, Hesson DP, Argentieri RL, Peng X, et al. TGF-beta driven lung fibrosis is macrophage dependent and blocked by Serum amyloid P. Int J Biochem Cell Biol. 2011;43:154–62.

    CAS  PubMed  Google Scholar 

  15. Pradere JP, Kluwe J, De Minicis S, Jiao JJ, Gwak GY, Dapito DH, et al. Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice. Hepatology. 2013;58:1461–73.

    CAS  PubMed  Google Scholar 

  16. Braga TT, Agudelo JS, Camara NO. Macrophages during the fibrotic process: M2 as friend and foe. Front Immunol. 2015;6:602.

    PubMed  PubMed Central  Google Scholar 

  17. Braga TT, Correa-Costa M, Guise YF, Castoldi A, de Oliveira CD, Hyane MI, et al. MyD88 signaling pathway is involved in renal fibrosis by favoring a TH 2 immune response and activating alternative M2 macrophages. Mol Med. 2012;18:1231–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Li D, Guabiraba R, Besnard AG, Komai-Koma M, Jabir MS, Zhang L, et al. IL-33 promotes ST2-dependent lung fibrosis by the induction of alternatively activated macrophages and innate lymphoid cells in mice. J Allergy Clin Immunol. 2014;134:1422-32.e11.

    Google Scholar 

  19. Wang J, Xu L, Xiang Z, Ren Y, Zheng X, Zhao Q, et al. Microcystin-LR ameliorates pulmonary fibrosis via modulating CD206+ M2-like macrophage polarization. Cell Death Dis. 2020;11:136.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Redente EF, Keith RC, Janssen W, Henson PM, Ortiz LA, Downey GP, et al. Tumor necrosis factor-α accelerates the resolution of established pulmonary fibrosis in mice by targeting profibrotic lung macrophages. Am J Respir Cell Mol Biol. 2014;50:825–37.

    PubMed  PubMed Central  Google Scholar 

  21. Toita R, Shimizu E, Murata M, Kang JH. Protective and healing effects of apoptotic mimic-induced M2-like macrophage polarization on pressure ulcers in young and middle-aged mice. J Control Release. 2021;330:705–14.

    CAS  PubMed  Google Scholar 

  22. Sen CK, Gordillo GM, Roy S, Kirsner R, Lambert L, Hunt TK, et al. Human skin wounds: a major and snowballing threat to public health and the economy. Wound Repair Regen. 2009;17:763–71.

    PubMed  PubMed Central  Google Scholar 

  23. Li M, Sun X, Zhao J, Xia L, Li J, Xu M, et al. CCL5 deficiency promotes liver repair by improving inflammation resolution and liver regeneration through M2 macrophage polarization. Cell Mol Immunol. 2020;17:753–64.

    CAS  PubMed  Google Scholar 

  24. Sun H, Sun S, Chen G, Xie H, Yu S, Lin X, et al. Ceramides and sphingosine-1-phosphate mediate the distinct effects of M1/M2-macrophage infusion on liver recovery after hepatectomy. Cell Death Dis. 2021;12:324.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Podaru MN, Fields L, Kainuma S, Ichihara Y, Hussain M, Ito T, et al. Reparative macrophage transplantation for myocardial repair: a refinement of bone marrow mononuclear cell-based therapy. Basic Res Cardiol. 2019;114:34.

    PubMed  PubMed Central  Google Scholar 

  26. Li Y, Li H, Pei J, Hu S, Nie Y. Transplantation of murine neonatal cardiac macrophage improves adult cardiac repair. Cell Mol Immunol. 2021;18:492–4.

    CAS  PubMed  Google Scholar 

  27. Mao R, Wang C, Zhang F, Zhao M, Liu S, Liao G, et al. Peritoneal M2 macrophage transplantation as a potential cell therapy for enhancing renal repair in acute kidney injury. J Cell Mol Med. 2020;24:3314–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Liu H, He Y, Lu C, Zhang P, Zhou C, Ni Y, et al. Efficacy of pulmonary transplantation of engineered macrophages secreting IL-4 on acute lung injury in C57BL/6J mice. Cell Death Dis. 2019;10:664.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Al Faraj A, Shaik AS, Alnafea M. Intrapulmonary administration of bone-marrow derived M1/M2 macrophages to enhance the resolution of LPS-induced lung inflammation: noninvasive monitoring using free-breathing MR and CT imaging protocols. BMC Med Imag. BMC Med Imaging. 2015;15:16.

    Google Scholar 

  30. Raphael I, Nalawade S, Eagar TN, Forsthuber TG. T cell subsets and their signature cytokines in autoimmune and inflammatory diseases. Cytokine. 2015;74:5–17.

    CAS  PubMed  Google Scholar 

  31. Koyasu S, Moro K. Type 2 innate immune responses and the natural helper cell. Immunology. 2011;132:475–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Li J, Tan J, Martino MM, Lui KO. Regulatory T-cells: potential regulator of tissue repair and regeneration. Front Immunol. 2018;9:585.

    PubMed  PubMed Central  Google Scholar 

  33. Epelman S, Liu PP, Mann DL. Role of innate and adaptive immune mechanisms in cardiac injury and repair. Nat Rev Immunol. 2015;15:117–29.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Blankesteijn WM, Creemers E, Lutgens E, Cleutjens JP, Daemen MJ, Smits JF. Dynamics of cardiac wound healing following myocardial infarction: observations in genetically altered mice. Acta Physiol Scand. 2001;173:75–82.

    CAS  PubMed  Google Scholar 

  35. Hofmann U, Beyersdorf N, Weirather J, Podolskaya A, Bauersachs J, Ertl G, et al. Activation of CD4+ T lymphocytes improves wound healing and survival after experimental myocardial infarction in mice. Circulation. 2012;125:1652–63.

    CAS  PubMed  Google Scholar 

  36. Weirather J, Hofmann UD, Beyersdorf N, Ramos GC, Vogel B, Frey A, et al. Foxp3+ CD4+ T cells improve healing after myocardial infarction by modulating monocyte/macrophage differentiation. Circ Res. 2014;115:55–67.

    CAS  PubMed  Google Scholar 

  37. Tang TT, Yuan J, Zhu ZF, Zhang WC, Xiao H, Xia N, et al. Regulatory T cells ameliorate cardiac remodeling after myocardial infarction. Basic Res Cardiol. 2012;107:232.

    PubMed  Google Scholar 

  38. Kuswanto W, Burzyn D, Panduro M, Wang KK, Jang YC, Wagers AJ, et al. Poor repair of skeletal muscle in aging mice reflects a defect in local, interleukin-33-dependent accumulation of regulatory T cells. Immunity. 2016;44:355–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Villalta SA, Rosenthal W, Martinez L, Kaur A, Sparwasser T, Tidball JG, et al. Regulatory T cells suppress muscle inflammation and injury in muscular dystrophy. Sci Transl Med. 2014;6:258ra142. 

    PubMed  PubMed Central  Google Scholar 

  40. Grassi F, Cattini L, Gambari L, Manferdini C, Piacentini A, Gabusi E, et al. T cell subsets differently regulate osteogenic differentiation of human mesenchymal stromal cells in vitro. J Tissue Eng Regen Med. 2016;10:305–14.

    CAS  PubMed  Google Scholar 

  41. Reinke S, Geissler S, Taylor WR, Schmidt-Bleek K, Juelke K, Schwachmeyer V, et al. Terminally differentiated CD8(+) T cells negatively affect bone regeneration in humans. Sci Transl Med. 2013;5:177ra36.

    PubMed  Google Scholar 

  42. Zhu L, Hua F, Ding W, Ding K, Zhang Y, Xu C. The correlation between the Th17/Treg cell balance and bone health. Immun Ageing. 2020;17:30.

    PubMed  PubMed Central  Google Scholar 

  43. Ono T, Okamoto K, Nakashima T, Nitta T, Hori S, Iwakura Y, et al. IL-17-producing gammadelta T cells enhance bone regeneration. Nat Commun. 2016;7:10928.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Li WJ, Luo Y, Xu HY, Ma QQ, Yao Q. Imbalance between T helper 1 and regulatory T cells plays a detrimental role in experimental Parkinson’s disease in mice. J Int Med Res. 2021;49:300060521998471.

    CAS  PubMed  Google Scholar 

  45. Cai Y, Xu TT, Lu CQ, Ma YY, Chang D, Zhang Y, et al. Endogenous regulatory T cells promote M2 macrophage phenotype in diabetic stroke as visualized by optical imaging. Transl Stroke Res. 2021;12:136–46.

    CAS  PubMed  Google Scholar 

  46. Xia Y, Cai W, Thomson AW, Hu X. Regulatory T cell therapy for ischemic stroke: how far from clinical translation? Transl Stroke Res. 2016;7:415–9.

    PubMed  PubMed Central  Google Scholar 

  47. Lane SW, Williams DA, Watt FM. Modulating the stem cell niche for tissue regeneration. Nat Biotechnol. 2014;32:795–803.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Qi K, Li N, Zhang Z, Melino G. Tissue regeneration: The crosstalk between mesenchymal stem cells and immune response. Cell Immunol. 2018;326:86–93.

    CAS  PubMed  Google Scholar 

  49. Markov A, Thangavelu L, Aravindhan S, Zekiy AO, Jarahian M, Chartrand MS, et al. Mesenchymal stem/stromal cells as a valuable source for the treatment of immune-mediated disorders. Stem Cell Res Ther. 2021;12:192.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Alves VBF, de Sousa BC, Fonseca MTC, Ogata H, Caliari-Oliveira C, Yaochite JNU, et al. A single administration of human adipose tissue-derived mesenchymal stromal cells (MSC) induces durable and sustained long-term regulation of inflammatory response in experimental colitis. Clin Exp Immunol. 2019;196:139–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Song WJ, Li Q, Ryu MO, Ahn JO, Bhang D, Jung YC, et al. TSG-6 secreted by human adipose tissue-derived mesenchymal stem cells ameliorates DSS-induced colitis by inducing M2 macrophage polarization in mice. Sci Rep. 2017;7:5187.

    PubMed  PubMed Central  Google Scholar 

  52. Mao F, Wu Y, Tang X, Kang J, Zhang B, Yan Y, et al. Exosomes derived from human umbilical cord mesenchymal stem cells relieve inflammatory bowel disease in mice. Biomed Res Int. 2017;2017:5356760.

    PubMed  PubMed Central  Google Scholar 

  53. Cai X, Zhang ZY, Yuan JT, Ocansey DKW, Tu Q, Zhang X, et al. hucMSC-derived exosomes attenuate colitis by regulating macrophage pyroptosis via the miR-378a-5p/NLRP3 axis. Stem Cell Res Ther. 2021;12:416.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Feng Z, Zhai Y, Zheng Z, Yang L, Luo X, Dong X, et al. Loss of A20 in BM-MSCs regulates the Th17/Treg balance in rheumatoid arthritis. Sci Rep. 2018;8:427.

    PubMed  PubMed Central  Google Scholar 

  55. Wei ST, Huang YC, Chiang JY, Lin CC, Lin YJ, Shyu WC, et al. Gain of CXCR7 function with mesenchymal stem cell therapy ameliorates experimental arthritis via enhancing tissue regeneration and immunomodulation. Stem Cell Res Ther. 2021;12:314.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Hu CX, Wu ZW, Li LJ. Mesenchymal stromal cells promote liver regeneration through regulation of immune cells. Int J Biol Sci. 2020;16:893–903.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Kyurkchiev D, Bochev I, Ivanova-Todorova E, Mourdjeva M, Oreshkova T, Belemezova K, et al. Secretion of immunoregulatory cytokines by mesenchymal stem cells. World J Stem Cells. 2014;6:552–70.

    PubMed  PubMed Central  Google Scholar 

  58. Liu QL, Chen XY, Liu C, Pan LJ, Kang XM, Li YL, et al. Mesenchymal stem cells alleviate experimental immune-mediated liver injury via chitinase 3-like protein 1-mediated T cell suppression. Cell Death Dis. 2021;12:240.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Chang PY, Zhang BY, Cui S, Qu C, Shao LH, Xu TK, et al. MSC-derived cytokines repair radiation-induced intra-villi microvascular injury. Oncotarget. 2017;8:87821–36.

    PubMed  PubMed Central  Google Scholar 

  60. Li Y, Sheng Q, Zhang C, Han C, Bai H, Lai P, et al. STAT6 up-regulation amplifies M2 macrophage anti-inflammatory capacity through mesenchymal stem cells. Int Immunopharmacol. 2021;91:107266.

    CAS  PubMed  Google Scholar 

  61. Ghafouri-Fard S, Niazi V, Hussen BM, Omrani MD, Taheri M, Basiri A. The emerging role of exosomes in the treatment of human disorders with a special focus on mesenchymal stem cells-derived exosomes. Front Cell Dev Biol. 2021;9:653296.

    PubMed  PubMed Central  Google Scholar 

  62. Du T, Ju GQ, Zhou J, Zhong L, Rong L, Chen WX, et al. Microvesicles derived from human umbilical cord mesenchyme promote M2 macrophage polarization and ameliorate renal fibrosis following partial nephrectomy via hepatocyte growth factor. Hum Cell. 2021;34:1103–13.

    CAS  PubMed  Google Scholar 

  63. D’Atri D, Zerrillo L, Garcia J, Oieni J, Lupu-Haber Y, Schomann T, et al. Nanoghosts: mesenchymal stem cells derived nanoparticles as a unique approach for cartilage regeneration. J Control Release. 2021;337:472–81.

    CAS  PubMed  Google Scholar 

  64. Yang J, Zhou CZ, Zhu R, Fan H, Liu XX, Duan XY, et al. miR-200b-containing microvesicles attenuate experimental colitis associated intestinal fibrosis by inhibiting epithelial-mesenchymal transition. J Gastroenterol Hepatol. 2017;32:1966–74.

    CAS  PubMed  Google Scholar 

  65. Zhou Y, Li P, Goodwin AJ, Cook JA, Halushka PV, Chang E, et al. Exosomes from endothelial progenitor cells improve outcomes of the lipopolysaccharide-induced acute lung injury. Crit Care. 2019;23:44.

    PubMed  PubMed Central  Google Scholar 

  66. Gong XH, Liu H, Wang SJ, Liang SW, Wang GG. Exosomes derived from SDF1-overexpressing mesenchymal stem cells inhibit ischemic myocardial cell apoptosis and promote cardiac endothelial microvascular regeneration in mice with myocardial infarction. J Cell Physiol. 2019;234:13878–93.

    CAS  PubMed  Google Scholar 

  67. Lu Y, Zhou Y, Zhang R, Wen L, Wu K, Li Y, et al. Bone mesenchymal stem cell-derived extracellular vesicles promote recovery following spinal cord injury via improvement of the integrity of the blood-spinal cord barrier. Front Neurosci. 2019;13:209.

    PubMed  PubMed Central  Google Scholar 

  68. Yao Y, Wang Y, Zhang Z, He L, Zhu J, Zhang M, et al. Chop deficiency protects mice against bleomycin-induced pulmonary fibrosis by attenuating M2 macrophage production. Mol Ther. 2016;24:915–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Singh A. Biomaterials innovation for next generation ex vivo immune tissue engineering. Biomaterials. 2017;130:104–10.

    CAS  PubMed  Google Scholar 

  70. Chocholata P, Kulda V, Babuska V. Fabrication of scaffolds for bone-tissue regeneration. Materials (Basel). 2019;12:568.

    CAS  PubMed Central  Google Scholar 

  71. Jeong J, Kim JH, Shim JH, Hwang NS, Heo CY. Bioactive calcium phosphate materials and applications in bone regeneration. Biomater Res. 2019;23:4.

    PubMed  PubMed Central  Google Scholar 

  72. Wang M, Yu Y, Dai K, Ma Z, Liu Y, Wang J, et al. Improved osteogenesis and angiogenesis of magnesium-doped calcium phosphate cement via macrophage immunomodulation. Biomater Sci. 2016;4:1574–83.

    CAS  PubMed  Google Scholar 

  73. Zhao Q, Shi M, Yin C, Zhao Z, Zhang J, Wang J, et al. Dual-wavelength photosensitive nano-in-micro scaffold regulates innate and adaptive immune responses for osteogenesis. Nanomicro Lett. 2021;13:28.

    Google Scholar 

  74. Luo M, Zhao F, Liu L, Yang Z, Tian T, Chen X, et al. IFN-gamma/SrBG composite scaffolds promote osteogenesis by sequential regulation of macrophages from M1 to M2. J Mater Chem B. 2021;9:1867–76.

    CAS  PubMed  Google Scholar 

  75. Blakney AK, Swartzlander MD, Bryant SJ. The effects of substrate stiffness on the in vitro activation of macrophages and in vivo host response to poly(ethylene glycol)-based hydrogels. J Biomed Mater Res A. 2012;100:1375–86.

    Google Scholar 

  76. Sridharan R, Cavanagh B, Cameron AR, Kelly DJ, O’Brien FJ. Material stiffness influences the polarization state, function and migration mode of macrophages. Acta Biomater. 2019;89:47–59.

    CAS  PubMed  Google Scholar 

  77. Hsieh JY, Keating MT, Smith TD, Meli VS, Botvinick EL, Liu WF. Matrix crosslinking enhances macrophage adhesion, migration, and inflammatory activation. APL Bioeng. 2019;3:016103.

    PubMed  PubMed Central  Google Scholar 

  78. Lee KY, Mooney DJ. Alginate: properties and biomedical applications. Prog Polym Sci. 2012;37:106–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Zhu YL, Ma ZJ, Kong LZ, He YH, Chan HF, Li HY. Modulation of macrophages by bioactive glass/sodium alginate hydrogel is crucial in skin regeneration enhancement. Biomaterials. 2020;256:120216.

    CAS  PubMed  Google Scholar 

  80. Zhu YL, Deng S, Ma ZJ, Kong LZ, Li HY, Chan HF. Macrophages activated by akermanite/alginate composite hydrogel stimulate migration of bone marrow-derived mesenchymal stem cells. Biomed Mater. 2021. https://doi.org/10.1088/1748-605X/abe80a.

    Article  PubMed  Google Scholar 

  81. Liang R, Shen X, Xie C, Gu Y, Li J, Wu H, et al. Silk gel recruits specific cell populations for scarless skin regeneration. Appl Mater Today. 2021;23:101004.

    Google Scholar 

  82. Lohmann N, Schirmer L, Atallah P, Wandel E, Ferrer RA, Werner C, et al. Glycosaminoglycan-based hydrogels capture inflammatory chemokines and rescue defective wound healing in mice. Sci Transl Med. 2017;9:eaai9044.

    PubMed  Google Scholar 

  83. Jiang LB, Ding SL, Ding W, Su DH, Zhang FX, Zhang TW, et al. Injectable sericin based nanocomposite hydrogel for multi-modal imaging-guided immunomodulatory bone regeneration. Chem Eng J. 2021;418:129323.

    CAS  Google Scholar 

  84. Li QF, Shen AF, Wang ZL. Enhanced osteogenic differentiation of BMSCs and M2-phenotype polarization of macrophages on a titanium surface modified with graphene oxide for potential implant applications. RSC Adv. 2020;10:16537–50.

    CAS  Google Scholar 

  85. Bordoni V, Reina G, Orecchioni M, Furesi G, Thiele S, Gardin C, et al. Stimulation of bone formation by monocyte-activator functionalized graphene oxide in vivo. Nanoscale. 2019;11:19408–21.

    CAS  PubMed  Google Scholar 

  86. Sun X, Ma ZJ, Zhao X, Jin WJ, Zhang CY, Ma J, et al. Three-dimensional bioprinting of multicell-laden scaffolds containing bone morphogenic protein-4 for promoting M2 macrophage polarization and accelerating bone defect repair in diabetes mellitus. Bioactive Mater. 2021;6:757–69.

    CAS  Google Scholar 

  87. Ou Q, Huang K, Fu C, Huang C, Fang Y, Gu Z, et al. Nanosilver-incorporated halloysite nanotubes/gelatin methacrylate hybrid hydrogel with osteoimmunomodulatory and antibacterial activity for bone regeneration. Chem Eng J. 2020;382:123019.

    CAS  Google Scholar 

  88. Huang L, Zhang J, Hu J, Zhao T, Gu Z. Biomimetic gelatin methacrylate/nano fish bone hybrid hydrogel for bone regeneration via osteoimmunomodulation. ACS Biomater Sci Eng. 2020;6:3270–4.

    CAS  PubMed  Google Scholar 

  89. Yan L, Han K, Pang B, Jin H, Zhao X, Xu X, et al. Surfactin-reinforced gelatin methacrylate hydrogel accelerates diabetic wound healing by regulating the macrophage polarization and promoting angiogenesis. Chem Eng J. 2021;414:128836.

    CAS  Google Scholar 

  90. Jiang GY, Li SH, Yu K, He B, Hong JQ, Xu TJ, et al. A 3D-printed PRP-GelMA hydrogel promotes osteochondral regeneration through M2 macrophage polarization in a rabbit model. Acta Biomater. 2021;128:150–62.

    CAS  PubMed  Google Scholar 

  91. Zhang W, Du A, Liu S, Lv M, Chen S. Research progress in decellularized extracellular matrix-derived hydrogels. Regen Ther. 2021;18:88–96.

    PubMed  PubMed Central  Google Scholar 

  92. Lee JS, Roh YH, Choi YS, Jin Y, Jeon EJ, Bong KW, et al. Tissue beads: tissue-specific extracellular matrix microbeads to potentiate reprogrammed cell-based therapy. Adv Func Mater. 2019;29:1807803.

    Google Scholar 

  93. Choi YS, Jeong E, Lee JS, Kim SK, Jo SH, Kim YG, et al. Immunomodulatory scaffolds derived from lymph node extracellular matrices. ACS Appl Mater Interfaces. 2021;13:14037–49.

    CAS  PubMed  Google Scholar 

  94. Cho AN, Jin Y, An Y, Kim J, Choi YS, Lee JS, et al. Microfluidic device with brain extracellular matrix promotes structural and functional maturation of human brain organoids. Nat Commun. 2021;12:4730.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Pati F, Jang J, Ha DH, Kim SW, Rhie JW, Shim JH, et al. Printing three-dimensional tissue analogues with decellularized extracellular matrix bioink. Nat Commun. 2014;5:3935.

    CAS  Google Scholar 

  96. Jakus AE, Laronda MM, Rashedi AS, Robinson CM, Lee C, Jordan SW, et al. “Tissue Papers” from organ-specific decellularized extracellular matrices. Adv Func Mater. 2017;27:1700992.

    Google Scholar 

  97. Qiu X, Liu S, Zhang H, Zhu B, Su Y, Zheng C, et al. Mesenchymal stem cells and extracellular matrix scaffold promote muscle regeneration by synergistically regulating macrophage polarization toward the M2 phenotype. Stem Cell Res Ther. 2018;9:88.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Hong JY, Seo Y, Davaa G, Kim HW, Kim SH, Hyun JK. Decellularized brain matrix enhances macrophage polarization and functional improvements in rat spinal cord injury. Acta Biomater. 2020;101:357–71.

    CAS  PubMed  Google Scholar 

  99. Tian G, Jiang S, Li J, Wei F, Li X, Ding Y, et al. Cell-free decellularized cartilage extracellular matrix scaffolds combined with interleukin 4 promote osteochondral repair through immunomodulatory macrophages: In vitro and in vivo preclinical study. Acta Biomater. 2021;127:131–45.

    CAS  PubMed  Google Scholar 

  100. Han X, Liao L, Zhu T, Xu Y, Bi F, Xie L, et al. Xenogeneic native decellularized matrix carrying PPARgamma activator RSG regulating macrophage polarization to promote ligament-to-bone regeneration. Mater Sci Eng C Mater Biol Appl. 2020;116:111224.

    CAS  PubMed  Google Scholar 

  101. Ko KW, Park SY, Lee EH, Yoo YI, Kim DS, Kim JY, et al. Integrated bioactive scaffold with polydeoxyribonucleotide and stem-cell-derived extracellular vesicles for kidney regeneration. ACS Nano. 2021;15:7575–85.

    CAS  PubMed  Google Scholar 

  102. Henderson CJ, Rognin E, Hall EA, Daly R. Design and model for ‘falling particle’ biosensors. Sens Actuators B Chem. 2021;329:129088.

  103. Shibata H, Heo YJ, Okitsu T, Matsunaga Y, Kawanishi T, Takeuchi S. Injectable hydrogel microbeads for fluorescence-based in vivo continuous glucose monitoring. Proc Natl Acad Sci U S A. 2010;107:17894–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Mankani MH, Kuznetsov SA, Fowler B, Kingman A, Robey PG. In vivo bone formation by human bone marrow stromal cells: effect of carrier particle size and shape. Biotechnol Bioeng. 2001;72:96–107.

    CAS  PubMed  Google Scholar 

  105. Liu X, Jin X, Ma PX. Nanofibrous hollow microspheres self-assembled from star-shaped polymers as injectable cell carriers for knee repair. Nat Mater. 2011;10:398–406.

    PubMed  PubMed Central  Google Scholar 

  106. Yin C, Zhao Q, Li W, Zhao Z, Wang J, Deng T, et al. Biomimetic anti-inflammatory nano-capsule serves as a cytokine blocker and M2 polarization inducer for bone tissue repair. Acta Biomater. 2020;102:416–26.

    CAS  PubMed  Google Scholar 

  107. Mao Y, Koga JI, Tokutome M, Matoba T, Ikeda G, Nakano K, et al. Nanoparticle-mediated delivery of pitavastatin to monocytes/macrophages inhibits left ventricular remodeling after acute myocardial infarction by inhibiting monocyte-mediated inflammation. Int Heart J. 2017;58:615–23.

    CAS  PubMed  Google Scholar 

  108. Yang Y, Guo L, Wang Z, Liu P, Liu X, Ding J, et al. Targeted silver nanoparticles for rheumatoid arthritis therapy via macrophage apoptosis and Re-polarization. Biomaterials. 2021;264:120390.

    CAS  PubMed  Google Scholar 

  109. Rutledge KE, Cheng Q, Jabbarzadeh E. Modulation of inflammatory response and induction of bone formation based on combinatorial effects of resveratrol. J Nanomed Nanotechnol. 2016;7:350.

    PubMed  PubMed Central  Google Scholar 

  110. Nagaoka K, Matoba T, Mao YJ, Nakano Y, Ikeda G, Egusa S, et al. A new therapeutic modality for acute myocardial infarction: nanoparticle-mediated delivery of pitavastatin induces cardioprotection from ischemia-reperfusion injury via activation of PI3K/Akt pathway and anti-inflammation in a rat model. PLoS One. 2015;10:e0132451. 

    PubMed  PubMed Central  Google Scholar 

  111. Shi M, Xia L, Chen Z, Lv F, Zhu H, Wei F, et al. Europium-doped mesoporous silica nanosphere as an immune-modulating osteogenesis/angiogenesis agent. Biomaterials. 2017;144:176–87.

    CAS  PubMed  Google Scholar 

  112. Shi M, Chen Z, Farnaghi S, Friis T, Mao X, Xiao Y, et al. Copper-doped mesoporous silica nanospheres, a promising immunomodulatory agent for inducing osteogenesis. Acta Biomater. 2016;30:334–44.

    CAS  PubMed  Google Scholar 

  113. Yang XS, Zhou FX, Yuan PY, Dou G, Liu XM, Liu SY, et al. T cell-depleting nanoparticles ameliorate bone loss by reducing activated T cells and regulating the Treg/Th17 balance. Bioact Mater. 2021;6:3150–63.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. NRF-2021R1A4A1028713). Figure 1 was created based on the figures in BioRender.com.

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Correspondence to Jung Seung Lee.

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Ko, G.R., Lee, J.S. Engineering of Immune Microenvironment for Enhanced Tissue Remodeling. Tissue Eng Regen Med 19, 221–236 (2022). https://doi.org/10.1007/s13770-021-00419-z

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