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Immunomodulatory Biomaterials and Emerging Analytical Techniques for Probing the Immune Micro-Environment

  • Review Article
  • Published:
Tissue Engineering and Regenerative Medicine Aims and scope

Abstract

After implantation of a biomaterial, both the host immune system and properties of the material determine the local immune response. Through triggering or modulating the local immune response, materials can be designed towards a desired direction of promoting tissue repair or regeneration. High-throughput sequencing technologies such as single-cell RNA sequencing (scRNA-seq) emerging as a powerful tool for dissecting the immune micro-environment around biomaterials, have not been fully utilized in the field of soft tissue regeneration. In this review, we first discussed the procedures of foreign body reaction in brief. Then, we summarized the influences that physical and chemical modulation of biomaterials have on cell behaviors in the micro-environment. Finally, we discussed the application of scRNA-seq in probing the scaffold immune micro-environment and provided some reference to designing immunomodulatory biomaterials. The foreign body response consists of a series of biological reactions. Immunomodulatory materials regulate immune cell activation and polarization, mediate divergent local immune micro-environments and possess different tissue engineering functions. The manipulation of physical and chemical properties of scaffolds can modulate local immune responses, resulting in different outcomes of fibrosis or tissue regeneration. With the advancement of technology, emerging techniques such as scRNA-seq provide an unprecedented understanding of immune cell heterogeneity and plasticity in a scaffold-induced immune micro-environment at high resolution. The in-depth understanding of the interaction between scaffolds and the host immune system helps to provide clues for the design of biomaterials to optimize regeneration and promote a pro-regenerative local immune micro-environment.

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References

  1. Anderson JM, Rodriguez A, Chang DT. Foreign body reaction to biomaterials. Semin Immunol. 2008;20:86–100.

    Article  CAS  Google Scholar 

  2. Kastellorizios M, Tipnis N, Burgess DJ. Foreign body reaction to subcutaneous implants. Adv Exp Med Biol. 2015;865:93–108.

    Article  CAS  Google Scholar 

  3. Nour S, Baheiraei N, Imani R, Khodaei M, Alizadeh A, Rabiee N, et al. A review of accelerated wound healing approaches: biomaterial- assisted tissue remodeling. J Mater Sci Mater Med. 2019;30:120.

    Article  Google Scholar 

  4. Massaro MS, Pálek R, Rosendorf J, Červenková L, Liška V, Moulisová V. Decellularized xenogeneic scaffolds in transplantation and tissue engineering: Immunogenicity versus positive cell stimulation. Mater Sci Eng C Mater Biol Appl. 2021;127:112203.

    Article  CAS  Google Scholar 

  5. Samojlik MM, Stabler CL. Designing biomaterials for the modulation of allogeneic and autoimmune responses to cellular implants in type 1 diabetes. Acta Biomater. 2021;133:87–101.

    Article  CAS  Google Scholar 

  6. Sadtler K, Singh A, Wolf MT, Wang X, Pardoll DM, Elisseeff JH. Design, clinical translation and immunological response of biomaterials in regenerative medicine. Nat Rev Mater. 2016;1:16040.

    Article  CAS  Google Scholar 

  7. Kang H, Yang B, Zhang K, Pan Q, Yuan W, Li G, et al. Immunoregulation of macrophages by dynamic ligand presentation via ligand-cation coordination. Nat Commun. 2019;10:1696.

    Article  Google Scholar 

  8. Liu W, Li J, Cheng M, Wang Q, Qian Y, Yeung KWK, et al. A surface-engineered polyetheretherketone biomaterial implant with direct and immunoregulatory antibacterial activity against methicillin-resistant Staphylococcus aureus. Biomaterials. 2019;208:8–20.

    Article  CAS  Google Scholar 

  9. Zhu R, Zhu X, Zhu Y, Wang Z, He X, Wu Z, et al. Immunomodulatory layered double hydroxide nanoparticles enable neurogenesis by targeting transforming growth factor-β receptor 2. ACS Nano. 2021;15:2812–30.

    Article  CAS  Google Scholar 

  10. Zheng YF, Gu XN, Witte F. Biodegradable metals. Mater Sci Eng R Rep. 2014;77:1–34.

    Article  Google Scholar 

  11. Alshemary AZ, Engin Pazarceviren A, Tezcaner A, Evis Z. Fe(3+) /SeO42(-) dual doped nano hydroxyapatite: A novel material for biomedical applications. J Biomed Mater Res B Appl Biomater. 2018;106:340–52.

    Article  CAS  Google Scholar 

  12. Rowley AT, Nagalla RR, Wang SW, Liu WF. Extracellular matrix-based strategies for immunomodulatory biomaterials engineering. Adv Healthc Mater. 2019;8:e1801578.

    Article  Google Scholar 

  13. Martin KE, García AJ. Macrophage phenotypes in tissue repair and the foreign body response: implications for biomaterial-based regenerative medicine strategies. Acta Biomater. 2021;133:4–16.

    Article  CAS  Google Scholar 

  14. Li J, Jiang X, Li H, Gelinsky M, Gu Z. Tailoring materials for modulation of macrophage fate. Adv Mater. 2021;33:e2004172.

    Article  Google Scholar 

  15. McWhorter FY, Davis CT, Liu WF. Physical and mechanical regulation of macrophage phenotype and function. Cell Mol Life Sci. 2015;72:1303–16.

    Article  CAS  Google Scholar 

  16. Hotchkiss KM, Reddy GB, Hyzy SL, Schwartz Z, Boyan BD, Olivares-Navarrete R. Titanium surface characteristics, including topography and wettability, alter macrophage activation. Acta Biomater. 2016;31:425–34.

    Article  CAS  Google Scholar 

  17. Jiang J, Li Z, Wang H, Wang Y, Carlson MA, Teusink MJ, et al. Expanded 3D nanofiber scaffolds: cell penetration, neovascularization, and host response. Adv Healthc Mater. 2016;5:2993–3003.

    Article  CAS  Google Scholar 

  18. Chu C, Liu L, Rung S, Wang Y, Ma Y, Hu C, et al. Modulation of foreign body reaction and macrophage phenotypes concerning microenvironment. J Biomed Mater Res Part A. 2020;108:127–35.

    Article  CAS  Google Scholar 

  19. Rodrigues M, Gurtner G. Black, white, and gray: macrophages in skin repair and disease. Curr Pathobiol Rep. 2017;5:333–42.

    Article  CAS  Google Scholar 

  20. Barman PK, Pang J, Urao N, Koh TJ. Skin wounding-induced monocyte expansion in mice is not abrogated by IL-1 receptor 1 deficiency. J Immunol. 2019;202:2720–7.

    Article  CAS  Google Scholar 

  21. Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest. 2012;122:787–95.

    Article  CAS  Google Scholar 

  22. Locati M, Curtale G, Mantovani A. Diversity, mechanisms, and significance of macrophage plasticity. Annu Rev Pathol. 2020;15:123–47.

    Article  CAS  Google Scholar 

  23. Bosurgi L, Cao YG, Cabeza-Cabrerizo M, Tucci A, Hughes LD, Kong Y, et al. Macrophage function in tissue repair and remodeling requires IL-4 or IL-13 with apoptotic cells. Science. 2017;356:1072–6.

    Article  CAS  Google Scholar 

  24. Shook B, Xiao E, Kumamoto Y, Iwasaki A, Horsley V. CD301b+ macrophages are essential for effective skin wound healing. J Invest Dermatol. 2016;136:1885–91.

    Article  CAS  Google Scholar 

  25. Shook BA, Wasko RR, Rivera-Gonzalez GC, Salazar-Gatzimas E, López-Giráldez F, Dash BC, et al. Myofibroblast proliferation and heterogeneity are supported by macrophages during skin repair. Science. 2018;362:eaar2971.

    Article  Google Scholar 

  26. Stuart T, Butler A, Hoffman P, Hafemeister C, Papalexi E, Mauck WM, et al. Comprehensive integration of single-cell data. Cell. 2019;177:1888-902e21.

    Article  CAS  Google Scholar 

  27. Wu H, Han S, Wu B, Du X, Sheng Z, Lin J, et al. Single-cell mass cytometry reveals in vivo immunological response to surgical biomaterials. Appl Mater Today. 2019;16:169–78.

    Article  Google Scholar 

  28. Perciani CT, MacParland SA. Lifting the veil on macrophage diversity in tissue regeneration and fibrosis. Sci Immunol. 2019;4:eaaz0749.

    Article  CAS  Google Scholar 

  29. Young AMH, Kumasaka N, Calvert F, Hammond TR, Knights A, Panousis N, et al. A map of transcriptional heterogeneity and regulatory variation in human microglia. Nat Genet. 2021;53:861–8.

    Article  CAS  Google Scholar 

  30. Franz S, Rammelt S, Scharnweber D, Simon JC. Immune responses to implants - a review of the implications for the design of immunomodulatory biomaterials. Biomaterials. 2011;32:6692–709.

    Article  CAS  Google Scholar 

  31. Rahmati M, Silva EA, Reseland JE, Heyward CA, Haugen HJ. Biological responses to physicochemical properties of biomaterial surface. Chem Soc Rev. 2020;49:5178–224.

    Article  CAS  Google Scholar 

  32. Frazão LP, de Vieira CJ, Neves NM. In vivo evaluation of the biocompatibility of biomaterial device. Adv Exp Med Biol. 2020;1250:109–24.

    Article  Google Scholar 

  33. Rodrigues M, Kosaric N, Bonham CA, Gurtner GC. Wound healing: a cellular perspective. Physiol Rev. 2019;99:665–706.

    Article  CAS  Google Scholar 

  34. Klopfleisch R, Jung F. The pathology of the foreign body reaction against biomaterials. J Biomed Mater Res A. 2017;105:927–40.

    Article  CAS  Google Scholar 

  35. Veiseh O, Vegas AJ. Domesticating the foreign body response: recent advances and applications. Adv Drug Deliv Rev. 2019;144:148–61.

    Article  CAS  Google Scholar 

  36. Galli SJ, Borregaard N, Wynn TA. Phenotypic and functional plasticity of cells of innate immunity: macrophages, mast cells and neutrophils. Nat Immunol. 2011;12:1035–44.

    Article  CAS  Google Scholar 

  37. Sorokin L. The impact of the extracellular matrix on inflammation. Nat Rev Immunol. 2010;10:712–23.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  39. Klopfleisch R. Macrophage reaction against biomaterials in the mouse model - Phenotypes, functions and markers. Acta Biomater. 2016;43:3–13.

    Article  CAS  Google Scholar 

  40. Lai YS, Wahyuningtyas R, Aui SP, Chang KT. Autocrine VEGF signalling on M2 macrophages regulates PD-L1 expression for immunomodulation of T cells. J Cell Mol Med. 2019;23:1257–67.

    CAS  Google Scholar 

  41. Ferrante CJ, Pinhal-Enfield G, Elson G, Cronstein BN, Hasko G, Outram S, et al. The adenosine-dependent angiogenic switch of macrophages to an M2-like phenotype is independent of interleukin-4 receptor alpha (IL-4Rα) signaling. Inflammation. 2013;36:921–31.

    Article  CAS  Google Scholar 

  42. Okuno Y, Nakamura-Ishizu A, Kishi K, Suda T, Kubota Y. Bone marrow-derived cells serve as proangiogenic macrophages but not endothelial cells in wound healing. Blood. 2011;117:5264–72.

    Article  CAS  Google Scholar 

  43. Brodbeck WG, Shive MS, Colton E, Nakayama Y, Matsuda T, Anderson JM. Influence of biomaterial surface chemistry on the apoptosis of adherent cells. J Biomed Mater Res. 2001;55:661–8.

    Article  CAS  Google Scholar 

  44. Anderson JM, McNally AK. Biocompatibility of implants: lymphocyte/macrophage interactions. Semin Immunopathol. 2011;33:221–33.

    Article  CAS  Google Scholar 

  45. Li AG, Quinn MJ, Siddiqui Y, Wood MD, Federiuk IF, Duman HM, et al. Elevation of transforming growth factor beta (TGFbeta) and its downstream mediators in subcutaneous foreign body capsule tissue. J Biomed Mater Res A. 2007;82:498–508.

    Article  Google Scholar 

  46. Robotti F, Sterner I, Bottan S, Monne Rodriguez JM, Pellegrini G, Schmidt T, et al. Microengineered biosynthesized cellulose as anti-fibrotic in vivo protection for cardiac implantable electronic devices. Biomaterials. 2020;229:119583.

    Article  CAS  Google Scholar 

  47. Cherry C, Maestas DR, Han J, Andorko JI, Cahan P, Fertig EJ, et al. Computational reconstruction of the signalling networks surrounding implanted biomaterials from single-cell transcriptomics. Nat Biomed Eng. 2021;5:1228–38.

    Article  CAS  Google Scholar 

  48. Li CGC, Fitzpatric V, Ibrahim A, Zwierstra MJ, et al. Design of biodegradable, implantable devices towards clinical translation. Nat Rev Mater. 2019;5:61–81.

    Article  Google Scholar 

  49. Gieseck RL, Wilson MS, Wynn TA. Type 2 immunity in tissue repair and fibrosis. Nat Rev Immunol. 2018;18:62–76.

    Article  CAS  Google Scholar 

  50. Sadtler K, Estrellas K, Allen BW, Wolf MT, Fan H, Tam AJ, et al. Developing a pro-regenerative biomaterial scaffold microenvironment requires T helper 2 cells. Science. 2016;352:366–70.

    Article  CAS  Google Scholar 

  51. Chung L, Maestas D R, Jr., Lebid A, Mageau A, Rosson G D, Wu X, et al. Interleukin 17 and senescent cells regulate the foreign body response to synthetic material implants in mice and humans. Sci Transl Med. 2020;12(539).

  52. Sadtler K, Wolf MT, Ganguly S, Moad CA, Chung L, Majumdar S, et al. Divergent immune responses to synthetic and biological scaffolds. Biomaterials. 2019;192:405–15.

    Article  CAS  Google Scholar 

  53. Farah S, Doloff JC, Muller P, Sadraei A, Han HJ, Olafson K, et al. Long-term implant fibrosis prevention in rodents and non-human primates using crystallized drug formulations. Nat Mater. 2019;18:892–904.

    Article  CAS  Google Scholar 

  54. Chu C, Deng J, Sun X, Qu Y, Man Y. Collagen membrane and immune response in guided bone regeneration: recent progress and perspectives. Tissue Eng Part B Rev. 2017;23:421–35.

    Article  CAS  Google Scholar 

  55. Zhang S, Liu Y, Zhang X, Zhu D, Qi X, Cao X, et al. Prostaglandin E2 hydrogel improves cutaneous wound healing via M2 macrophages polarization. Theranostics. 2018;8:5348–61.

    Article  CAS  Google Scholar 

  56. Veiseh O, Doloff JC, Ma M, Vegas AJ, Tam HH, Bader AR, et al. Size- and shape-dependent foreign body immune response to materials implanted in rodents and non-human primates. Nat Mater. 2015;14:643–51.

    Article  CAS  Google Scholar 

  57. Luu TU, Gott SC, Woo BW, Rao MP, Liu WF. Micro- and Nanopatterned topographical cues for regulating macrophage cell shape and phenotype. ACS Appl Mater Interface. 2015;7:28665–72.

    Article  CAS  Google Scholar 

  58. Guo R, Merkel AR, Sterling JA, Davidson JM, Guelcher SA. Substrate modulus of 3D-printed scaffolds regulates the regenerative response in subcutaneous implants through the macrophage phenotype and Wnt signaling. Biomaterials. 2015;73:85–95.

    Article  CAS  Google Scholar 

  59. Sun G. Pro-regenerative hydrogel restores scarless skin during cutaneous wound healing. Adv Healthc Mater. 2017;6:1700659.

    Article  Google Scholar 

  60. McWhorter FY, Wang T, Nguyen P, Chung T, Liu WF. Modulation of macrophage phenotype by cell shape. Proc Natl Acad Sci U S A. 2013;110:17253–8.

    Article  CAS  Google Scholar 

  61. Friedemann M, Kalbitzer L, Franz S, Moeller S, Schnabelrauch M, Simon JC, et al. Instructing human macrophage polarization by stiffness and glycosaminoglycan functionalization in 3D collagen networks. Adv Healthc Mater. 2017;6:1600967.

    Article  Google Scholar 

  62. Abebayehu D, Spence AJ, McClure MJ, Haque TT, Rivera KO, Ryan JJ. Polymer scaffold architecture is a key determinant in mast cell inflammatory and angiogenic responses. J Biomed Mater Res Part A. 2019;107:884–92.

    Article  CAS  Google Scholar 

  63. Swartzlander MD, Barnes CA, Blakney AK, Kaar JL, Kyriakides TR, Bryant SJ. Linking the foreign body response and protein adsorption to PEG-based hydrogels using proteomics. Biomaterials. 2015;41:26–36.

    Article  CAS  Google Scholar 

  64. Alapure BV, Lu Y, He M, Chu CC, Peng H, Muhale F, et al. Accelerate healing of severe burn wounds by mouse bone marrow mesenchymal stem cell-seeded biodegradable hydrogel scaffold synthesized from arginine-based poly(ester amide) and chitosan. Stem Cell Dev. 2018;27:1605–20.

    Article  CAS  Google Scholar 

  65. Sok MCP, Baker N, McClain C, Lim HS, Turner T, Hymel L, et al. Dual delivery of IL-10 and AT-RvD1 from PEG hydrogels polarize immune cells towards pro-regenerative phenotypes. Biomaterials. 2021;268:120475.

    Article  CAS  Google Scholar 

  66. Yan H, Hjorth M, Winkeljann B, Dobryden I, Lieleg O, Crouzier T. Glyco-modification of mucin hydrogels to investigate their immune activity. ACS Appl Mater Interface. 2020;12:19324–36.

    Article  CAS  Google Scholar 

  67. Dong L, Li L, Song Y, Fang Y, Liu J, Chen P, et al. MSC-derived immunomodulatory extracellular matrix functionalized electrospun fibers for mitigating foreign-body reaction and tendon adhesion. Acta Biomater. 2021;133:280–96.

    Article  CAS  Google Scholar 

  68. He M, Sun L, Fu X, McDonough SP, Chu CC. Biodegradable amino acid-based poly(ester amine) with tunable immunomodulating properties and their in vitro and in vivo wound healing studies in diabetic rats’ wounds. Acta Biomater. 2019;84:114–32.

    Article  CAS  Google Scholar 

  69. Jiang Y, Zhao W, Xu S, Wei J, Lasaosa FL, He Y, et al. Bioinspired design of mannose-decorated globular lysine dendrimers promotes diabetic wound healing by orchestrating appropriate macrophage polarization. Biomaterials. 2022;280:121323.

    Article  CAS  Google Scholar 

  70. Welch NG, Mukherjee S, Hossain MA, Praveen P, Werkmeister JA, Wade JD, et al. Coatings releasing the relaxin peptide analogue B7–33 reduce fibrotic encapsulation. ACS Appl Mater Interface. 2019;11:45511–9.

    Article  CAS  Google Scholar 

  71. Chu C, Deng J, Xiang L, Wu Y, Wei X, Qu Y, et al. Evaluation of epigallocatechin-3-gallate (EGCG) cross-linked collagen membranes and concerns on osteoblasts. Mater Sci Eng C Mater Biol Appl. 2016;67:386–94.

    Article  CAS  Google Scholar 

  72. Chu C, Deng J, Cao C, Man Y, Qu Y. Evaluation of epigallocatechin-3-gallate modified collagen membrane and concerns on schwann cells. Biomed Res Int. 2017;2017:9641801.

    Article  Google Scholar 

  73. Chu C, Deng J, Hou Y, Xiang L, Wu Y, Qu Y, et al. Application of PEG and EGCG modified collagen-base membrane to promote osteoblasts proliferation. Mater Sci Eng C Mater Biol Appl. 2017;76:31–6.

    Article  CAS  Google Scholar 

  74. Chu C, Deng J, Man Y, Qu Y. Green tea extracts epigallocatechin-3-gallate for different treatments. Biomed Res Int. 2017;2017:5615647.

    Article  Google Scholar 

  75. Chu C, Deng J, Man Y, Qu Y. Evaluation of nanohydroxyapaptite (nano-HA) coated epigallocatechin-3-gallate (EGCG) cross-linked collagen membranes. Mater Sci Eng C Mater Biol Appl. 2017;78:258–64.

    Article  CAS  Google Scholar 

  76. Chu C, Liu L, Wang Y, Wei S, Wang Y, Man Y, et al. Macrophage phenotype in the epigallocatechin-3-gallate (EGCG)-modified collagen determines foreign body reaction. J Tissue Eng Regen Med. 2018;12:1499–507.

    Article  CAS  Google Scholar 

  77. Chu C, Wang Y, Wang Y, Yang R, Liu L, Rung S, et al. Evaluation of epigallocatechin-3-gallate (EGCG) modified collagen in guided bone regeneration (GBR) surgery and modulation of macrophage phenotype. Mater Sci Eng C Mater Biol Appl. 2019;99:73–82.

    Article  CAS  Google Scholar 

  78. Chu C, Liu L, Wang Y, Yang R, Hu C, Rung S, et al. Evaluation of epigallocatechin-3-gallate (EGCG)-modified scaffold determines macrophage recruitment. Mater Sci Eng C Mater Biol Appl. 2019;100:505–13.

    Article  CAS  Google Scholar 

  79. Guo Y, Wang X, Shen Y, Dong K, Shen L, Alzalab AAA. Research progress, models and simulation of electrospinning technology: a review. J Mater Sci. 2022;57:58–104.

    Article  CAS  Google Scholar 

  80. Garg K, Pullen NA, Oskeritzian CA, Ryan JJ, Bowlin GL. Macrophage functional polarization (M1/M2) in response to varying fiber and pore dimensions of electrospun scaffolds. Biomaterials. 2013;34:4439–51.

    Article  CAS  Google Scholar 

  81. Law JX, Liau LL, Saim A, Yang Y, Idrus R. Electrospun collagen nanofibers and their applications in skin tissue engineering. Tissue Eng Regen Med. 2017;14:699–718.

    Article  Google Scholar 

  82. Sharma R, Kumar S, Bhawna S, Gupta A, Dheer N, Jain P. An insight of nanomaterials in tissue engineering from fabrication to applications. Tissue Eng Regen Med. 2022;19:927–60.

    Article  CAS  Google Scholar 

  83. Venugopal D, Vishwakarma S, Kaur I, Samavedi S. Electrospun fiber-based strategies for controlling early innate immune cell responses: towards immunomodulatory mesh designs that facilitate robust tissue repair. Acta Biomater. 2022. https://doi.org/10.1016/j.actbio.2022.06.004.

    Article  Google Scholar 

  84. da Silva EZ, Jamur MC, Oliver C. Mast cell function: a new vision of an old cell. J Histochem Cytochem Off J Histochem Soc. 2014;62:698–738.

    Article  Google Scholar 

  85. Zandstra J, Hiemstra C, Petersen AH, Zuidema J, van Beuge MM, Rodriguez S, et al. Microsphere size influences the foreign body reaction. Eur Cell Mater. 2014;28:335–47.

    Article  CAS  Google Scholar 

  86. Chen S, Shi J, Zhang M, Chen Y, Wang X, Zhang L, et al. Mesenchymal stem cell-laden anti-inflammatory hydrogel enhances diabetic wound healing. Sci Rep. 2015;5:18104.

    Article  CAS  Google Scholar 

  87. Sontyana AG, Mathew AP, Cho KH, Uthaman S, Park IK. Biopolymeric in situ hydrogels for tissue engineering and bioimaging applications. Tissue Eng Regen Med. 2018;15:575–90.

    Article  Google Scholar 

  88. Samuel CS, Royce SG, Hewitson TD, Denton KM, Cooney TE, Bennett RG. Anti-fibrotic actions of relaxin. Br J Pharmacol. 2017;174:962–76.

    Article  CAS  Google Scholar 

  89. Supp DM, Boyce ST. Engineered skin substitutes: practices and potentials. Clin Dermatol. 2005;23:403–12.

    Article  Google Scholar 

  90. Price RD, Das-Gupta V, Leigh IM, Navsaria HA. A comparison of tissue-engineered hyaluronic acid dermal matrices in a human wound model. Tissue Eng. 2006;12:2985–95.

    Article  CAS  Google Scholar 

  91. Burd A, Chiu T. Allogenic skin in the treatment of burns. Clin Dermatol. 2005;23:376–87.

    Article  Google Scholar 

  92. Shevchenko RV, James SL, James SE. A review of tissue-engineered skin bioconstructs available for skin reconstruction. J R Soc Interface. 2010;7:229–58.

    Article  CAS  Google Scholar 

  93. Naves LB, Dhand C, Almeida L, Rajamani L, Ramakrishna S. In vitro skin models and tissue engineering protocols for skin graft applications. Essay Biochem. 2016;60:357–69.

    Article  Google Scholar 

  94. Schmitt CM, Moest T, Lutz R, Wehrhan F, Neukam FW, Schlegel KA. Long-term outcomes after vestibuloplasty with a porcine collagen matrix (Mucograft®) versus the free gingival graft: a comparative prospective clinical trial. Clin Oral Implant Res. 2016;27:e125–33.

    Article  Google Scholar 

  95. Ghanaati S, Schlee M, Webber MJ, Willershausen I, Barbeck M, Balic E, et al. Evaluation of the tissue reaction to a new bilayered collagen matrix in vivo and its translation to the clinic. Biomed Mater. 2011;6:015010.

    Article  Google Scholar 

  96. Mohammadi MH, Obregon R, Ahadian S, Ramon-Azcon J, Radisic M. Engineered muscle tissues for disease modeling and drug screening applications. Curr Pharm Des. 2017;23:2991–3004.

    Article  CAS  Google Scholar 

  97. Lim WL, Liau LL, Ng MH, Chowdhury SR, Law JX. Current progress in tendon and ligament tissue engineering. Tissue Eng Regen Med. 2019;16:549–71.

    Article  CAS  Google Scholar 

  98. Palit S, Heuser C, de Almeida GP, Theis FJ, Zielinski CE. Meeting the challenges of high-dimensional single-cell data analysis in immunology. Front Immunol. 2019;10:1515.

    Article  CAS  Google Scholar 

  99. See P, Lum J, Chen J, Ginhoux F. A single-cell sequencing guide for immunologists. Front Immunol. 2018;9:2425.

    Article  Google Scholar 

  100. Spitzer MH, Nolan GP. Mass cytometry: single cells, many features. Cell. 2016;165:780–91.

    CAS  Google Scholar 

  101. Zhang T, Lei T, Yan R, Zhou B, Fan C, Zhao Y, et al. Systemic and single cell level responses to 1 nm size biomaterials demonstrate distinct biological effects revealed by multi-omics atlas. Bioact Mater. 2022;18:199–212.

    Article  CAS  Google Scholar 

  102. Chen G, Ning B, Shi T. Single-cell RNA-Seq technologies and related computational data analysis. Front Genet. 2019;10:317.

    Article  CAS  Google Scholar 

  103. Li X, Wang CY. From bulk, single-cell to spatial RNA sequencing. Int J Oral Sci. 2021;13:36.

    Article  Google Scholar 

  104. Mereu E, Lafzi A, Moutinho C, Ziegenhain C, McCarthy DJ, Alvarez-Varela A, et al. Benchmarking single-cell RNA-sequencing protocols for cell atlas projects. Nat Biotechnol. 2020;38:747–55.

    Article  CAS  Google Scholar 

  105. Luecken MD, Theis FJ. Current best practices in single-cell RNA-seq analysis: a tutorial. Mol Syst Biol. 2019;15:e8746.

    Article  Google Scholar 

  106. Svensson V, Vento-Tormo R, Teichmann SA. Exponential scaling of single-cell RNA-seq in the past decade. Nat Protoc. 2018;13:599–604.

    Article  CAS  Google Scholar 

  107. Papalexi E, Satija R. Single-cell RNA sequencing to explore immune cell heterogeneity. Nat Rev Immunol. 2018;18:35–45.

    Article  CAS  Google Scholar 

  108. Levitin HM, Yuan J, Sims PA. Single-cell transcriptomic analysis of tumor heterogeneity. Trends in Cancer. 2018;4:264–8.

    Article  CAS  Google Scholar 

  109. Liu X, Chen W, Zhu G, Yang H, Li W, Luo M, et al. Single-cell RNA sequencing identifies an Il1rn(+)/Trem1(+) macrophage subpopulation as a cellular target for mitigating the progression of thoracic aortic aneurysm and dissection. Cell Discov. 2022;8:11.

    Article  CAS  Google Scholar 

  110. Guerrero-Juarez CF, Dedhia PH, Jin S, Ruiz-Vega R, Ma D, Liu Y, et al. Single-cell analysis reveals fibroblast heterogeneity and myeloid-derived adipocyte progenitors in murine skin wounds. Nat Commun. 2019;10:650.

    Article  CAS  Google Scholar 

  111. Tan L, Sandrock I, Odak I, Aizenbud Y, Wilharm A, Barros-Martins J, et al. Single-cell transcriptomics identifies the adaptation of scart1(+) vgamma6(+) T cells to skin residency as activated effector cells. Cell Rep. 2019;27:3657-71.e4.

    Article  CAS  Google Scholar 

  112. Zeis P, Lian M, Fan X, Herman JS, Hernandez DC, Gentek R, et al. In situ maturation and tissue adaptation of type 2 innate lymphoid cell progenitors. Immunity. 2020;53:775-92.e9.

    Article  CAS  Google Scholar 

  113. Joost S, Zeisel A, Jacob T, Sun X, La Manno G, Lonnerberg P, et al. Single-cell transcriptomics reveals that differentiation and spatial signatures shape epidermal and hair follicle heterogeneity. Cell Syst. 2016;3:221-37.e9.

    Article  CAS  Google Scholar 

  114. Joost S, Annusver K, Jacob T, Sun X, Dalessandri T, Sivan U, et al. The molecular anatomy of mouse skin during hair growth and rest. Cell Stem Cell. 2020;26:441-57.e7.

    Article  CAS  Google Scholar 

  115. Wright SC, Canizal MCA, Benkel T, Simon K, Le Gouill C, Matricon P, et al. FZD5 is a galphaq-coupled receptor that exhibits the functional hallmarks of prototypical GPCRs. Sci Signal. 2018;11:eaar5536.

    Article  CAS  Google Scholar 

  116. Williams DW, Greenwell-Wild T, Brenchley L, Dutzan N, Overmiller A, Sawaya AP, et al. Human oral mucosa cell atlas reveals a stromal-neutrophil axis regulating tissue immunity. Cell. 2021;184:4090-104.e15.

    Article  CAS  Google Scholar 

  117. Jaitin DA, Kenigsberg E, Keren-Shaul H, Elefant N, Paul F, Zaretsky I, et al. Massively parallel single-cell RNA-seq for marker-free decomposition of tissues into cell types. Science. 2014;343:776–9.

    Article  CAS  Google Scholar 

  118. Björklund ÅK, Forkel M, Picelli S, Konya V, Theorell J, Friberg D, et al. The heterogeneity of human CD127+ innate lymphoid cells revealed by single-cell RNA sequencing. Nat Immunol. 2016;17:451–60.

    Article  Google Scholar 

  119. Gaublomme JT, Yosef N, Lee Y, Gertner RS, Yang LV, Wu C, et al. Single-cell genomics unveils critical regulators of Th17 Cell pathogenicity. Cell. 2015;163:1400–12.

    Article  CAS  Google Scholar 

  120. Chen B, Zhu L, Yang S, Su W. Unraveling the heterogeneity and ontogeny of dendritic cells using single-cell RNA Sequencing. Front Immunol. 2021;12:711329.

    Article  CAS  Google Scholar 

  121. Huang J, Fan C, Chen Y, Ye J, Yang Y, Tang C, et al. Single-cell RNA-seq reveals functionally distinct biomaterial degradation-related macrophage populations. Biomaterials. 2021;277:121116.

    Article  CAS  Google Scholar 

  122. Henn D, Chen K, Fehlmann T, Trotsyuk AA, Sivaraj D, Maan ZN, et al. Xenogeneic skin transplantation promotes angiogenesis and tissue regeneration through activated trem2(+) macrophages. Sci Adv. 2021;7:eabi4528.

    Article  CAS  Google Scholar 

  123. Sommerfeld SD, Cherry C, Schwab RM, Chung L, Maestas DR, Laffont P, et al. Interleukin-36 gamma-producing macrophages drive IL-17-mediated fibrosis. Sci Immunol. 2019;4:eaax4783.

    Article  CAS  Google Scholar 

  124. Hu C, Chu C, Liu L, Wang C, Jin S, Yang R, et al. Dissecting the microenvironment around biosynthetic scaffolds in murine skin wound healing. Sci Adv. 2021;7:eabf0787.

    Article  CAS  Google Scholar 

  125. Moore EM, Maestas DR, Cherry CC, Garcia JA, Comeau HY, Davenport Huyer L, et al. Biomaterials direct functional B cell response in a material-specific manner. Sci Adv. 2021;7:eabi5830.

    Article  Google Scholar 

  126. Andrews TS, Kiselev VY, McCarthy D, Hemberg M. Tutorial: guidelines for the computational analysis of single-cell RNA sequencing data. Nat Protoc. 2021;16:1–9.

    Article  CAS  Google Scholar 

  127. Aldridge S, Teichmann SA. Single cell transcriptomics comes of age. Nat Commun. 2020;11:4307.

    Article  CAS  Google Scholar 

  128. Peng G, Suo S, Cui G, Yu F, Wang R, Chen J, et al. Molecular architecture of lineage allocation and tissue organization in early mouse embryo. Nature. 2019;572:528–32.

    Article  CAS  Google Scholar 

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Acknowledgements

C.H. acknowledges funding through National Natural Science Foundation of China (81970965), Research Funding from West China School/Hospital of Stomatology Sichuan University, No. RCDWJS2022-(3) and Sichuan University postdoctoral interdisciplinary Innovation Fund.

National Natural Science Foundation of China, 81,970,965,Chen Hu, Research Funding from West China School/Hospital of Stomatology Sichuan University, No. RCDWJS2022-(3), Chen Hu, National Postdoctoral Program for Innovative Talents.

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  1. Nanyan Bian and Chenyu Chu have contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, Sichuan, China

    Nanyan Bian, Chenyu Chu, Shengan Rung, Vicha Huangphattarakul, Yi Man & Chen Hu

  2. Department of Oral Implantology, West China Hospital of Stomatology, Sichuan University, 14#, 3rd section, Renmin South Road, Chengdu, 610041, Sichuan, China

    Chenyu Chu, Shengan Rung, Vicha Huangphattarakul, Yi Man, Jie Lin & Chen Hu

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  1. Nanyan Bian
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Bian, N., Chu, C., Rung, S. et al. Immunomodulatory Biomaterials and Emerging Analytical Techniques for Probing the Immune Micro-Environment. Tissue Eng Regen Med 20, 11–24 (2023). https://doi.org/10.1007/s13770-022-00491-z

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