Emerging non-antibiotic strategies for implant-associated biofilm infections by reprogramming the dysregulated immune microenvironment

1. Kariuki, S. Global burden of antimicrobial resistance and forecasts to 2050. Lancet 404, 1172–1173 (2024).

   Google Scholar 

2. Weiner-Lastinger, L. M. et al. Antimicrobial-resistant pathogens associated with adult healthcare-associated infections: Summary of data reported to the National Healthcare Safety Network, 2015-2017. Infect. Control Hospital Epidemiol 41, 1–18 (2020).

   Google Scholar 

3. Azad, M. A. & Patel, R. Practical guidance for clinical microbiology laboratories: microbiologic diagnosis of implant-associated infections. Clin. Microbiol. Rev. 37, e0010423 (2024).

   Google Scholar 

4. Martin, K. E. & García, A. J. Macrophage phenotypes in tissue repair and the foreign body response: Implications for biomaterial-based regenerative medicine strategies. Acta Biomater 133, 4–16 (2021).

   Google Scholar 

5. Gristina, A. G. Biomaterial-centered infection: microbial adhesion versus tissue integration. Science 237, 1588–1595 (1987).

   Google Scholar 

6. Salthouse, D., Novakovic, K., Hilkens, C. M. U. & Ferreira, A. M. Interplay between biomaterials and the immune system: Challenges and opportunities in regenerative medicine. Acta Biomater 155, 1–18 (2023).

   Google Scholar 

7. Yin, W., Wang, Y., Liu, L. & He, J. Biofilms: the microbial “protective clothing” in extreme environments. Int. J. Mol. Sci. 20, 3423 (2019).

   Google Scholar 

8. Ul Haq, I., Khan, T. A. & Krukiewicz, K. Etiology, pathology, and host-impaired immunity in medical implant-associated infections. J. Infect. Public Health 17, 189–203 (2024).

   Google Scholar 

9. Sokhi, U. K. et al. Immune response to persistent Staphyloccocus Aureus periprosthetic joint infection in a mouse tibial implant model. J. Bone Miner. Res. 37, 577–594 (2022).

   Google Scholar 

10. Schmidmaier, G., Lucke, M., Wildemann, B., Haas, N. P. & Raschke, M. Prophylaxis and treatment of implant-related infections by antibiotic-coated implants: a review. Injury 37, S105–S112 (2006).

    Google Scholar 

11. Parmanik, A. et al. Current treatment strategies against multidrug-resistant bacteria: a review. Curr. Microbiol. 79, 388 (2022).

    Google Scholar 

12. Qiu, Y., Zhang, N., An, Y. H. & Wen, X. Biomaterial strategies to reduce implant-associated infections. Int. J. Artif. Organs 30, 828–841 (2007).

    Google Scholar 

13. Dini, C. et al. Progress in designing therapeutic antimicrobial hydrogels targeting implant-associated infections: paving the way for a sustainable platform applied to biomedical devices. Adv. Healthc. Mater. 14, 2402926 (2025).

    Google Scholar 

14. Amin Yavari, S., Castenmiller, S. M., van Strijp, J. A. G. & Croes, M. Combating implant infections: shifting focus from bacteria to host. Adv. Mater. 32, 2002962 (2020).

    Google Scholar 

15. Bazaka, K., Jacob, M. V., Crawford, R. J. & Ivanova, E. P. Efficient surface modification of biomaterial to prevent biofilm formation and the attachment of microorganisms. Appl. Microbiol. Biotechnol. 95, 299–311 (2012).

    Google Scholar 

16. Li, S. et al. Advancement in smart bone implants: the latest multifunctional strategies and synergistic mechanisms for tissue repair and regeneration. Bioact. Mater. 51, 333–382 (2025).

    Google Scholar 

17. Yang, D. et al. Nanotherapeutics with immunoregulatory functions for the treatment of bacterial infection. Biomater. Res. 27, 73 (2023).

    Google Scholar 

18. Dhaliwal, J. S. et al. Microbial biofilm decontamination on dental implant surfaces: a mini review. Front. Cell Infect. Microbiol. 11, 736186 (2021).

    Google Scholar 

19. Oliva, A. et al. Challenges in the microbiological diagnosis of implant-associated infections: a summary of the current knowledge. Front. Microbiol. 12, 750460 (2021).

    Google Scholar 

20. Bajaj, P., Schweller, R. M., Khademhosseini, A., West, J. L. & Bashir, R. 3D biofabrication strategies for tissue engineering and regenerative medicine. Annu. Rev. Biomed. Eng. 16, 247–276 (2014).

    Google Scholar 

21. Trindade, R., Albrektsson, T., Tengvall, P. & Wennerberg, A. Foreign body reaction to biomaterials: on mechanisms for buildup and breakdown of osseointegration. Clin. Implant Dent. Relat. Res. 18, 192–203 (2016).

    Google Scholar 

22. Li, J. et al. Remodeling of the osteoimmune microenvironment after biomaterials implantation in murine tibia: Single-cell transcriptome analysis. Bioact. Mater. 22, 404–422 (2023).

    Google Scholar 

23. Klopfleisch, R. & Jung, F. The pathology of the foreign body reaction against biomaterials. J. Biomed. Mater. Res. Part A 105, 927–940 (2017).

    Google Scholar 

24. Gorbet, M. B. & Sefton, M. V. Biomaterial-associated thrombosis: roles of coagulation factors, complement, platelets and leukocytes. Biomaterials 25, 5681–5703 (2004).

    Google Scholar 

25. Wilson, C. J., Clegg, R. E., Leavesley, D. I. & Pearcy, M. J. Mediation of biomaterial-cell interactions by adsorbed proteins: a review. Tissue Eng 11, 1–18 (2005).

    Google Scholar 

26. Balabiyev, A. et al. Fibrin polymer on the surface of biomaterial implants drives the foreign body reaction. Biomaterials 277, 121087 (2021).

    Google Scholar 

27. Yang, D. et al. The molecular mechanism of mediation of adsorbed serum proteins to endothelial cells adhesion and growth on biomaterials. Biomaterials 34, 5747–58 (2013).

    Google Scholar 

28. Godwin, J.W., Pinto, A.R. & Rosenthal, N.A. Seminars in Cell & Developmental Biology Vol. 61 71–79 (Elsevier, 2017).

29. Al-Saffar, N., Iwaki, H. & Revell, P. A. Direct activation of mast cells by prosthetic biomaterial particles. J. Mater. Sci. Mater. Med. 9, 849–853 (1998).

    Google Scholar 

30. Avula, M. N., Rao, A. N., McGill, L. D., Grainger, D. W. & Solzbacher, F. Foreign body response to subcutaneous biomaterial implants in a mast cell-deficient Kit(w-Sh) murine model. Acta Biomater 10, 1856–1863 (2014).

    Google Scholar 

31. Ozpinar, E. W., Frey, A. L., Cruse, G. & Freytes, D. O. Mast cell-biomaterial interactions and tissue repair. Tissue Eng. Part B Rev 27, 590–603 (2021).

    Google Scholar 

32. Tecchio, C. & Cassatella, M. A. Neutrophil-derived chemokines on the road to immunity. Semin. Immunol. 28, 119–128 (2016).

    Google Scholar 

33. Scapini, P. et al. The neutrophil as a cellular source of chemokines. Immunol. Rev. 177, 195–203 (2000).

    Google Scholar 

34. Anderson, J. M. Biological responses to materials. Annu. Rev. Mater. Res. 31, 81–110 (2001).

    Google Scholar 

35. Maduka, C. V. et al. Immunometabolic cues recompose and reprogram the microenvironment around implanted biomaterials. Nat. Biomed. Eng. 8, 1308–1321 (2024).

    Google Scholar 

36. Seong, S. Y. & Matzinger, P. Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses. Nat. Rev. Immunol. 4, 469–478 (2004).

    Google Scholar 

37. Mohiuddin, M., Pan, H. A., Hung, Y. C. & Huang, G. S. Control of growth and inflammatory response of macrophages and foam cells with nanotopography. Nanoscale Res. Lett. 7, 394 (2012).

    Google Scholar 

38. Chang, S., Popowich, Y., Greco, R. S. & Haimovich, B. Neutrophil survival on biomaterials is determined by surface topography. J. Vasc. Surg. 37, 1082–1090 (2003).

    Google Scholar 

39. Williams, D. F. The plasticity of biocompatibility. Biomaterials 296, 122077 (2023).

    Google Scholar 

40. Soehnlein, O., Lindbom, L. & Weber, C. Mechanisms underlying neutrophil-mediated monocyte recruitment. Blood 114, 4613–4623 (2009).

    Google Scholar 

41. Guilliams, M., Mildner, A. & Yona, S. Developmental and functional heterogeneity of monocytes. Immunity 49, 595–613 (2018).

    Google Scholar 

42. Auffray, C., Sieweke, M. H. & Geissmann, F. Blood monocytes: development, heterogeneity, and relationship with dendritic cells. Annu. Rev. Immunol. 27, 669–692 (2009).

    Google Scholar 

43. Sprangers, S., de Vries, T. J. & Everts, V. Monocyte heterogeneity: consequences for monocyte-derived immune cells. J. Immunol. Res. 2016, 1475435 (2016).

    Google Scholar 

44. Krieger, J. R. et al. Spatially localized recruitment of anti-inflammatory monocytes by SDF-1α-releasing hydrogels enhances microvascular network remodeling. Biomaterials 77, 280–290 (2016).

    Google Scholar 

45. Mamilos, A. et al. Macrophages: from simple phagocyte to an integrative regulatory cell for inflammation and tissue regeneration-a review of the literature. Cells 12, 276 (2023).

    Google Scholar 

46. Wynn, T. A. & Vannella, K. M. Macrophages in tissue repair, regeneration, and fibrosis. Immunity 44, 450–462 (2016).

    Google Scholar 

47. Li, J., Jiang, X., Li, H., Gelinsky, M. & Gu, Z. Tailoring materials for modulation of macrophage fate. Adv. Mater. 33, e2004172 (2021).

    Google Scholar 

48. Moore, E. M. & West, J. L. Harnessing macrophages for vascularization in tissue engineering. Ann. Biomed. Eng. 47, 354–365 (2019).

    Google Scholar 

49. Du, Q. et al. Targeting macrophage polarization for reinstating homeostasis following tissue damage. Int. J. Mol. Sci. 25, 7278 (2024).

    Google Scholar 

50. Martinez, F. O., Helming, L. & Gordon, S. Alternative activation of macrophages: an immunologic functional perspective. Annu. Rev. Immunol. 27, 451–483 (2009).

    Google Scholar 

51. Tarique, A. A. et al. Phenotypic, functional, and plasticity features of classical and alternatively activated human macrophages. Am. J. Respir. Cell Mol. Biol. 53, 676–688 (2015).

    Google Scholar 

52. Martinez, F. O. & Gordon, S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep 6, 13 (2014).

    Google Scholar 

53. Kadl, A. et al. Identification of a novel macrophage phenotype that develops in response to atherogenic phospholipids via Nrf2. Circ. Res. 107, 737–746 (2010).

    Google Scholar 

54. Castanheira, F. V. S. & Kubes, P. Neutrophils and NETs in modulating acute and chronic inflammation. Blood 133, 2178–2185 (2019).

    Google Scholar 

55. Morandini, L. et al. Reduction of neutrophil extracellular traps accelerates inflammatory resolution and increases bone formation on titanium implants. Acta Biomater 166, 670–684 (2023).

    Google Scholar 

56. Fetz, A. E. & Bowlin, G. L. Neutrophil extracellular traps: inflammation and biomaterial preconditioning for tissue engineering. Tissue Eng. Part B Rev 28, 437–450 (2022).

    Google Scholar 

57. Kizhakkedathu, J. N. & Conway, E. M. Biomaterial and cellular implants: foreign surfaces where immunity and coagulation meet. Blood 139, 1987–1998 (2022).

    Google Scholar 

58. Shanbhag, A., Yang, J., Lilien, J. & Black, J. Decreased neutrophil respiratory burst on exposure to cobalt-chrome alloy and polystyrene in vitro. J. Biomed. Mater. Res. 26, 185–195 (1992).

    Google Scholar 

59. Brodbeck, W. G. et al. Biomaterial adherent macrophage apoptosis is increased by hydrophilic and anionic substrates in vivo. Proc. Natl. Acad. Sci. USA 99, 10287–10292 (2002).

    Google Scholar 

60. McNally, A. K. & Anderson, J. M. Macrophage fusion and multinucleated giant cells of inflammation. Adv. Exp. Med. Biol. 713, 97–111 (2011).

    Google Scholar 

61. Stewart, C. L., Hook, A. L., Zelzer, M., Marlow, M. & Piccinini, A. M. Cellular and microenvironmental cues that promote macrophage fusion and foreign body response. Front. Immunol. 15, 1411872 (2024).

    Google Scholar 

62. Ahmadzadeh, K., Vanoppen, M., Rose, C. D., Matthys, P. & Wouters, C. H. Multinucleated giant cells: current insights in phenotype, biological activities, and mechanism of formation. Front. Cell Dev. Biol. 10, 873226 (2022).

    Google Scholar 

63. Cai, F., Jiang, B. & He, F. Formation and biological activities of foreign body giant cells in response to biomaterials. Acta Biomater. 188, 1–26 (2024).

    Google Scholar 

64. Carnicer-Lombarte, A., Chen, S. T., Malliaras, G. G. & Barone, D. G. Foreign body reaction to implanted biomaterials and its impact in nerve neuroprosthetics. Front. Bioeng. Biotechnol. 9, 622524 (2021).

    Google Scholar 

65. Lo Schiavo, A., Ruocco, E., Russo, T. & Brancaccio, G. Locus minoris resistentiae: an old but still valid way of thinking in medicine. Clin. Dermatol. 32, 553–556 (2014).

    Google Scholar 

66. Schoberleitner, I. et al. SMI-capsular fibrosis and biofilm dynamics: molecular mechanisms, clinical implications, and antimicrobial approaches. Int. J. Mol. Sci. 25, 11675 (2024).

    Google Scholar 

67. Donlan, R. M. Biofilms and device-associated infections. Emerg. Infect. Dis. 7, 277–281 (2001).

    Google Scholar 

68. Bouhrour, N., Nibbering, P. H. & Bendali, F. Medical device-associated biofilm infections and multidrug-resistant pathogens. Pathogens 13, 393 (2024).

    Google Scholar 

69. Zhang, S. et al. Immunomodulatory biomaterials against bacterial infections: progress, challenges, and future perspectives. Innovation 4, 100503 (2023).

    Google Scholar 

70. Vishwakarma, A. et al. Engineering immunomodulatory biomaterials to tune the inflammatory response. Trends Biotechnol 34, 470–482 (2016).

    Google Scholar 

71. Gristina, A. G., Naylor, P. & Myrvik, Q. Infections from biomaterials and implants: a race for the surface. Med. Prog. Technol. 14, 205–224 (1988).

    Google Scholar 

72. Shiels, S. M., Mangum, L. H. & Wenke, J. C. Revisiting the “race for the surface” in a pre-clinical model of implant infection. Eur. Cell Mater. 39, 77–95 (2020).

    Google Scholar 

73. Miramini, S. et al. The status and challenges of replicating the mechanical properties of connective tissues using additive manufacturing. J. Mech. Behav. Biomed. Mater. 103, 103544 (2020).

    Google Scholar 

74. Wagner, C. & Hänsch, G.M. Mechanisms of Bacterial Colonization of Implants and Host Response, in A Modern Approach to Biofilm-Related Orthopaedic Implant Infections: Advances in Microbiology, Infectious Diseases and Public Health, Vol. 5 (ed Drago, L.) 15–27 (Springer International Publishing, Cham, 2017).s

75. Rather, M. A., Gupta, K. & Mandal, M. Microbial biofilm: formation, architecture, antibiotic resistance, and control strategies. Braz. J. Microbiol. 52, 1701–1718 (2021).

    Google Scholar 

76. Subbiahdoss, G., Kuijer, R., Grijpma, D. W., van der Mei, H. C. & Busscher, H. J. Microbial biofilm growth vs. tissue integration:“the race for the surface” experimentally studied. Acta Biomater 5, 1399–1404 (2009).

    Google Scholar 

77. Mao, Y. & Schwarzbauer, J. E. Fibronectin fibrillogenesis, a cell-mediated matrix assembly process. Matrix Biol 24, 389–399 (2005).

    Google Scholar 

78. Kline, K. A., Fälker, S., Dahlberg, S., Normark, S. & Henriques-Normark, B. Bacterial adhesins in host-microbe interactions. Cell Host Microbe 5, 580–592 (2009).

    Google Scholar 

79. Carniello, V., Peterson, B. W., van der Mei, H. C. & Busscher, H. J. Physico-chemistry from initial bacterial adhesion to surface-programmed biofilm growth. Adv. Colloid Interface Sci 261, 1–14 (2018).

    Google Scholar 

80. Zhao, A., Sun, J. & Liu, Y. Understanding bacterial biofilms: From definition to treatment strategies. Front. Cell Infect. Microbiol. 13, 1137947 (2023).

    Google Scholar 

81. Bos, R., van der Mei, H. C. & Busscher, H. J. Physico-chemistry of initial microbial adhesive interactions–its mechanisms and methods for study. FEMS Microbiol. Rev. 23, 179–230 (1999).

    Google Scholar 

82. Garcı́a, A. J. & Boettiger, D. Integrin–fibronectin interactions at the cell-material interface: initial integrin binding and signaling. Biomaterials 20, 2427–2433 (1999).

    Google Scholar 

83. Stones, D. H. & Krachler, A. M. Fatal attraction: how bacterial adhesins affect host signaling and what we can learn from them. Int. J. Mol. Sci. 16, 2626–2640 (2015).

    Google Scholar 

84. Patti, J. M., Allen, B. L., McGavin, M. J. & Höök, M. MSCRAMM-mediated adherence of microorganisms to host tissues. Annu. Rev. Microbiol. 48, 585–617 (1994).

    Google Scholar 

85. Bowden, M. G. et al. Evidence for the “dock, lock, and latch” ligand binding mechanism of the staphylococcal microbial surface component recognizing adhesive matrix molecules (MSCRAMM) SdrG. J. Biol. Chem. 283, 638–647 (2008).

    Google Scholar 

86. Proft, T. & Baker, E. Pili in Gram-negative and Gram-positive bacteria—structure, assembly and their role in disease. Cell. Mol. Life Sci. 66, 613–635 (2009).

    Google Scholar 

87. Telford, J. L., Barocchi, M. A., Margarit, I., Rappuoli, R. & Grandi, G. Pili in gram-positive pathogens. Nat. Rev. Microbiol. 4, 509–519 (2006).

    Google Scholar 

88. Heilmann, C., Hussain, M., Peters, G. & Götz, F. Evidence for autolysin-mediated primary attachment of Staphylococcus epidermidis to a polystyrene surface. Mol. Microbiol. 24, 1013–1024 (1997).

    Google Scholar 

89. Bose, J. L., Lehman, M. K., Fey, P. D. & Bayles, K. W. Contribution of the Staphylococcus aureus Atl AM and GL murein hydrolase activities in cell division, autolysis, and biofilm formation. PLoS ONE 7, e42244 (2012).

    Google Scholar 

90. Paganelli, F. L. et al. Enterococcus faecium biofilm formation: identification of major autolysin AtlAEfm, associated Acm surface localization, and AtlAEfm-independent extracellular DNA Release. mBio 4, e00154 (2013).

    Google Scholar 

91. Biswas, R. et al. Activity of the major staphylococcal autolysin Atl. FEMS Microbiol. Lett. 259, 260–268 (2006).

    Google Scholar 

92. Stinemetz, E. K. et al. Processing of the major autolysin of E. faecalis, AtlA, by the zinc-metalloprotease, GelE, impacts AtlA septal localization and cell separation. PLoS ONE 12, e0186706 (2017).

    Google Scholar 

93. Dickschat, J. S. Quorum sensing and bacterial biofilms. Nat. Prod. Rep. 27, 343–369 (2010).

    Google Scholar 

94. Bjarnsholt, T., Høiby, N., Donelli, G., Imbert, C. & Försberg, Å. Understanding biofilms–are we there yet? FEMS Immunol. Med. Microbiol. 65, 125–126 (2012).

    Google Scholar 

95. Karygianni, L., Ren, Z., Koo, H. & Thurnheer, T. Biofilm matrixome: extracellular components in structured microbial communities. Trends Microbiol 28, 668–681 (2020).

    Google Scholar 

96. Arciola, C. R., Campoccia, D., Ravaioli, S. & Montanaro, L. Polysaccharide intercellular adhesin in biofilm: structural and regulatory aspects. Front. Cell Infect. Microbiol. 5, 7 (2015).

    Google Scholar 

97. Nguyen, H. T. T., Nguyen, T. H. & Otto, M. The staphylococcal exopolysaccharide PIA – Biosynthesis and role in biofilm formation, colonization, and infection. Comput. Struct. Biotechnol. J. 18, 3324–3334 (2020).

    Google Scholar 

98. Sabaté Brescó, M. et al. Pathogenic mechanisms and host interactions in Staphylococcus epidermidis device-related infection. Front. Microbiol. 8, 1401 (2017).

    Google Scholar 

99. Xia, G., Kohler, T. & Peschel, A. The wall teichoic acid and lipoteichoic acid polymers of Staphylococcus aureus. Int. J. Med. Microbiol. 300, 148–154 (2010).

    Google Scholar 

100. Le, K. Y., Dastgheyb, S., Ho, T. V. & Otto, M. Molecular determinants of staphylococcal biofilm dispersal and structuring. Front. Cell Infect. Microbiol. 4, 167 (2014).

     Google Scholar 

101. Schwartz, K., Syed, A. K., Stephenson, R. E., Rickard, A. H. & Boles, B. R. Functional amyloids composed of phenol soluble modulins stabilize Staphylococcus aureus biofilms. PLoS Pathog 8, e1002744 (2012).

     Google Scholar 

102. Srivastava, D. & Waters, C. M. A tangled web: regulatory connections between quorum sensing and cyclic Di-GMP. J. Bacteriol. 194, 4485–4493 (2012).

     Google Scholar 

103. Oppenheimer-Shaanan, Y., Steinberg, N. & Kolodkin-Gal, I. Small molecules are natural triggers for the disassembly of biofilms. Trends Microbiol 21, 594–601 (2013).

     Google Scholar 

104. Sikdar, R. & Elias, M. Quorum quenching enzymes and their effects on virulence, biofilm, and microbiomes: a review of recent advances. Expert Rev. Anti Infect. Ther. 18, 1221–1233 (2020).

     Google Scholar 

105. Paluch, E., Rewak-Soroczyńska, J., Jędrusik, I., Mazurkiewicz, E. & Jermakow, K. Prevention of biofilm formation by quorum quenching. Appl. Microbiol. Biotechnol. 104, 1871–1881 (2020).

     Google Scholar 

106. Missiakas, D. & Winstel, V. Selective host cell death by Staphylococcus aureus: a strategy for bacterial persistence. Front. Immunol. 11, 621733 (2020).

     Google Scholar 

107. Thakur, A., Mikkelsen, H. & Jungersen, G. Intracellular pathogens: host immunity and microbial persistence strategies. J. Immunol. Res. 2019, 1356540 (2019).

     Google Scholar 

108. Mohamed, W. et al. Intracellular proliferation of S. aureus in osteoblasts and effects of rifampicin and gentamicin on S. aureus intracellular proliferation and survival. Eur. Cell Mater. 28, 258–268 (2014).

     Google Scholar 

109. Campoccia, D. et al. Orthopedic implant infections: Incompetence of Staphylococcus epidermidis, Staphylococcus lugdunensis, and Enterococcus faecalis to invade osteoblasts. J. Biomed. Mater. Res. A 104, 788–801 (2016).

     Google Scholar 

110. Spaan, A. N., van Strijp, J. A. G. & Torres, V. J. Leukocidins: staphylococcal bi-component pore-forming toxins find their receptors. Nat. Rev. Microbiol. 15, 435–447 (2017).

     Google Scholar 

111. Melehani, J. H., James, D. B., DuMont, A. L., Torres, V. J. & Duncan, J. A. Staphylococcus aureus Leukocidin A/B (LukAB) Kills Human Monocytes via Host NLRP3 and ASC when Extracellular, but Not Intracellular. PLoS Pathog 11, e1004970 (2015).

     Google Scholar 

112. Scherr, T. D. et al. Staphylococcus aureus biofilms induce macrophage dysfunction through leukocirdin AB and alpha-toxin. mBio 6, e01021–15 (2015).

     Google Scholar 

113. Thurlow, L. R. et al. Staphylococcus aureus biofilms prevent macrophage phagocytosis and attenuate inflammation in vivo. J. Immunol. 186, 6585–6596 (2011).

     Google Scholar 

114. Hanke, M. L., Heim, C. E., Angle, A., Sanderson, S. D. & Kielian, T. Targeting macrophage activation for the prevention and treatment of Staphylococcus aureus biofilm infections. J. Immunol. 190, 2159–2168 (2013).

     Google Scholar 

115. Heim, C. E. et al. IL-12 promotes myeloid-derived suppressor cell recruitment and bacterial persistence during Staphylococcus aureus orthopedic implant infection. J. Immunol. 194, 3861–3872 (2015).

     Google Scholar 

116. Abdul Hamid, A. I. et al. Differential early in vivo dynamics and functionality of recruited polymorphonuclear neutrophils after infection by planktonic or biofilm Staphylococcus aureus. Front. Microbiol. 12, 728429 (2021).

     Google Scholar 

117. Gries, C. M. & Kielian, T. Staphylococcal biofilms and immune polarization during prosthetic joint infection. JAAOS 25, S20–S24 (2017).

     Google Scholar 

118. Bertrand, B. P., Heim, C. E., Koepsell, S. A. & Kielian, T. Elucidating granulocytic myeloid-derived suppressor cell heterogeneity during Staphylococcus aureus biofilm infection. J. Leukoc. Biol. 115, 620–632 (2024).

     Google Scholar 

119. Meyle, E. et al. Destruction of bacterial biofilms by polymorphonuclear neutrophils: relative contribution of phagocytosis, DNA release, and degranulation. Int. J. Artif. Organs 33, 608–620 (2010).

     Google Scholar 

120. Cavallo, I. et al. Bacterial biofilm in chronic wounds and possible therapeutic approaches. Biology 13, 109 (2024).

     Google Scholar 

121. Gaida, M. et al. Polymorphonuclear neutrophils in osteomyelitis: link to osteoclast generation and bone resorption. Eur. J. Inflamm. 10, 413–426 (2012).

     Google Scholar 

122. Stewart, P. S. & Franklin, M. J. Physiological heterogeneity in biofilms. Nat. Rev. Microbiol. 6, 199–210 (2008).

     Google Scholar 

123. Wilde, A. D. et al. Bacterial hypoxic responses revealed as critical determinants of the host-pathogen outcome by TnSeq analysis of Staphylococcus aureus invasive infection. PLoS Pathog 11, e1005341 (2015).

     Google Scholar 

124. Li, M., Yu, J., Guo, G. & Shen, H. Interactions between macrophages and biofilm during Staphylococcus aureus-associated implant infection: difficulties and solutions. J. Innate Immun. 15, 499–515 (2023).

     Google Scholar 

125. Menousek, J. et al. Transcriptional profiling of phagocytic leukocytes and microglia reveals a critical role for reactive oxygen species in biofilm containment during Staphylococcus aureus craniotomy infection. J. Immunol. 209, 1973–1986 (2022).

     Google Scholar 

126. Horn, C. M. et al. Granulocytic myeloid-derived suppressor cell activity during biofilm infection is regulated by a glycolysis/HIF1a axis. J. Clin. Invest. 134, e174051 (2024).

     Google Scholar 

127. Pomeyie, K. et al. Macrophage immunometabolism dysregulation and inflammatory disorders. Biomed. Pharmacother. 188, 118142 (2025).

     Google Scholar 

128. Viola, A., Munari, F., Sánchez-Rodríguez, R., Scolaro, T. & Castegna, A. The metabolic signature of macrophage responses. Front. Immunol. 10, 1462 (2019).

     Google Scholar 

129. Yamada, K. J. et al. Monocyte metabolic reprogramming promotes pro-inflammatory activity and Staphylococcus aureus biofilm clearance. PLoS Pathog 16, e1008354 (2020).

     Google Scholar 

130. Bertrand, B. P. et al. Metabolic diversity of human macrophages: potential influence on Staphylococcus aureus intracellular survival. Infect. Immun. 92, e00474–00423 (2024).

     Google Scholar 

131. Bosch, M. E. et al. Staphylococcus aureus ATP synthase promotes biofilm persistence by influencing innate immunity. mBio 11, e01581–20 (2020).

     Google Scholar 

132. Heim, C. E. et al. Lactate production by Staphylococcus aureus biofilm inhibits HDAC11 to reprogramme the host immune response during persistent infection. Nat. Microbiol. 5, 1271–1284 (2020).

     Google Scholar 

133. Wang, Y. et al. Interleukin-1β and tumor necrosis factor are essential in controlling an experimental orthopedic implant-associated infection. J. Orthop. Res. 38, 1800–1809 (2020).

     Google Scholar 

134. Hanke, M. L., Angle, A. & Kielian, T. MyD88-dependent signaling influences fibrosis and alternative macrophage activation during Staphylococcus aureus biofilm infection. PLoS ONE 7, e42476 (2012).

     Google Scholar 

135. Van Roy, Z., Kak, G., Fallet, R. W. & Kielian, T. Interferon-gamma receptor signaling regulates innate immunity during Staphylococcus aureus craniotomy infection. J. Neuroinflammation 22, 46 (2025).

     Google Scholar 

136. Trinchieri, G. Proinflammatory and immunoregulatory functions of interleukin-12. Int. Rev. Immunol. 16, 365–396 (1998).

     Google Scholar 

137. Prabhakara, R. et al. Suppression of the inflammatory immune response prevents the development of chronic biofilm infection due to methicillin-resistant Staphylococcus aureus. Infect. Immun. 79, 5010–5018 (2011).

     Google Scholar 

138. Heim, C. E., Vidlak, D. & Kielian, T. Interleukin-10 production by myeloid-derived suppressor cells contributes to bacterial persistence during Staphylococcus aureus orthopedic biofilm infection. J. Leukoc. Biol. 98, 1003–1013 (2015).

     Google Scholar 

139. Gallo, J., Holinka, M. & Moucha, C. S. Antibacterial surface treatment for orthopaedic implants. Int. J. Mol. Sci. 15, 13849–13880 (2014).

     Google Scholar 

140. Linklater, D. P. et al. Mechano-bactericidal actions of nanostructured surfaces. Nat. Rev. Microbiol. 19, 8–22 (2021).

     Google Scholar 

141. Fröjd, V. et al. In situ analysis of multispecies biofilm formation on customized titanium surfaces. Mol. Oral. Microbiol. 26, 241–252 (2011).

     Google Scholar 

142. Arnold, J. & Bailey, G. Surface finishes on stainless steel reduce bacterial attachment and early biofilm formation: scanning electron and atomic force microscopy study. Poult. Sci. 79, 1839–1845 (2000).

     Google Scholar 

143. Medilanski, E., Kaufmann, K., Wick, L. Y., Wanner, O. & Harms, H. Influence of the surface topography of stainless steel on bacterial adhesion. Biofouling 18, 193–203 (2002).

     Google Scholar 

144. Truong, V. K. et al. Self-organised nanoarchitecture of titanium surfaces influences the attachment of Staphylococcus aureus and Pseudomonas aeruginosa bacteria. Appl. Microbiol. Biotechnol. 99, 6831–6840 (2015).

     Google Scholar 

145. Vasudevan, R., Kennedy, A. J., Merritt, M., Crocker, F. H. & Baney, R. H. Microscale patterned surfaces reduce bacterial fouling-microscopic and theoretical analysis. Colloids Surf. B Biointerfaces 117, 225–232 (2014).

     Google Scholar 

146. Gu, H. et al. How Escherichia coli lands and forms cell clusters on a surface: a new role of surface topography. Sci. Rep. 6, 29516 (2016).

     Google Scholar 

147. Vadillo-Rodríguez, V., Guerra-García-Mora, A. I., Perera-Costa, D., Gónzalez-Martín, M. L. & Fernández-Calderón, M. C. Bacterial response to spatially organized microtopographic surface patterns with nanometer scale roughness. Colloids Surf. B Biointerfaces 169, 340–347 (2018).

     Google Scholar 

148. Cheng, Y., Feng, G. & Moraru, C. I. Micro- and nanotopography sensitive bacterial attachment mechanisms: a review. Front. Microbiol. 10, 191 (2019).

     Google Scholar 

149. Díaz, C., Schilardi, P. & de Mele, M. F. Influence of surface sub-micropattern on the adhesion of pioneer bacteria on metals. Artif. Organs 32, 292–298 (2008).

     Google Scholar 

150. Díaz, C., Schilardi, P. L. & Salvarezza, R. C. & Fernández Lorenzo de Mele, M. Nano/microscale order affects the early stages of biofilm formation on metal surfaces. Langmuir 23, 11206–11210 (2007).

     Google Scholar 

151. Hou, S., Gu, H., Smith, C. & Ren, D. Microtopographic patterns affect Escherichia coli biofilm formation on poly(dimethylsiloxane) surfaces. Langmuir 27, 2686–2691 (2011).

     Google Scholar 

152. Encinas, N. et al. Submicrometer-sized roughness suppresses bacteria adhesion. ACS Appl. Mater. Interfaces 12, 21192–21200 (2020).

     Google Scholar 

153. Wang, X. et al. Electrophoresis-deposited mesoporous graphitic carbon nitride surfaces with efficient bactericidal properties. ACS Appl. Bio Mater 3, 2255–2262 (2020).

     Google Scholar 

154. Hu, W. et al. Graphene-based antibacterial paper. ACS Nano 4, 4317–4323 (2010).

     Google Scholar 

155. Akhavan, O. & Ghaderi, E. Toxicity of graphene and graphene oxide nanowalls against bacteria. ACS Nano 4, 5731–5736 (2010).

     Google Scholar 

156. Liu, S. et al. Antibacterial activity of graphite, graphite oxide, graphene oxide, and reduced graphene oxide: membrane and oxidative stress. ACS Nano 5, 6971–6980 (2011).

     Google Scholar 

157. Deng, Y., Sun, M. & Shaevitz, J. W. Measuring peptidoglycan elasticity and stress-stiffening of live bacterial cells. Biophys. J. 100, 514a–515a (2011).

     Google Scholar 

158. Truong, V. K. et al. The susceptibility of Staphylococcus aureus CIP 65.8 and Pseudomonas aeruginosa ATCC 9721 cells to the bactericidal action of nanostructured Calopteryx haemorrhoidalis damselfly wing surfaces. Appl. Microbiol. Biotechnol. 101, 4683–4690 (2017).

     Google Scholar 

159. Jahed, Z. et al. Cell responses to metallic nanostructure arrays with complex geometries. Biomaterials 35, 9363–9371 (2014).

     Google Scholar 

160. Pham, V. T. et al. “Race for the surface”: eukaryotic cells can win. ACS Appl. Mater. Interfaces 8, 22025–22031 (2016).

     Google Scholar 

161. Luo, Y. et al. Anti-infective application of graphene-like silicon nanosheets via membrane destruction. Adv. Healthc. Mater. 9, 1901375 (2020).

     Google Scholar 

162. Wu, S. et al. Plasma-modified biomaterials for self-antimicrobial applications. ACS Appl. Mater. Interfaces 3, 2851–2860 (2011).

     Google Scholar 

163. Hasan, J. et al. Selective bactericidal activity of nanopatterned superhydrophobic cicada Psaltoda claripennis wing surfaces. Appl. Microbiol. Biotechnol. 97, 9257–9262 (2013).

     Google Scholar 

164. Mainwaring, D. E. et al. The nature of inherent bactericidal activity: insights from the nanotopology of three species of dragonfly. Nanoscale 8, 6527–6534 (2016).

     Google Scholar 

165. Li, X. Bactericidal mechanism of nanopatterned surfaces. Phys. Chem. Chem. Phys. 18, 1311–1316 (2016).

     Google Scholar 

166. Ivanova, E. P. et al. Natural bactericidal surfaces: mechanical rupture of Pseudomonas aeruginosa cells by cicada wings. Small 8, 2489–2494 (2012).

     Google Scholar 

167. Su, Q. et al. Strategies and applications of antibacterial surface-modified biomaterials. Bioact. Mater. 53, 114–140 (2025).

     Google Scholar 

168. Chen, Z. et al. Tuning chemistry and topography of nanoengineered surfaces to manipulate immune response for bone regeneration applications. ACS Nano 11, 4494–4506 (2017).

     Google Scholar 

169. Cloutier, M., Mantovani, D. & Rosei, F. Antibacterial coatings: challenges, perspectives, and opportunities. Trends Biotechnol 33, 637–652 (2015).

     Google Scholar 

170. Ellinas, K., Tserepi, A. & Gogolides, E. Durable superhydrophobic and superamphiphobic polymeric surfaces and their applications: a review. Adv. Colloid Interface Sci 250, 132–157 (2017).

     Google Scholar 

171. Salwiczek, M. et al. Emerging rules for effective antimicrobial coatings. Trends Biotechnol 32, 82–90 (2014).

     Google Scholar 

172. Song, Q. et al. Contact-killing antibacterial mechanisms of polycationic coatings: a review. Prog. Org. Coat. 188, 108214 (2024).

     Google Scholar 

173. Banerjee, I., Pangule, R. C. & Kane, R. S. Antifouling coatings: recent developments in the design of surfaces that prevent fouling by proteins, bacteria, and marine organisms. Adv. Mater. 23, 690–718 (2011).

     Google Scholar 

174. Olmo, J. A.-D., Ruiz-Rubio, L., Pérez-Alvarez, L., Sáez-Martínez, V. & Vilas-Vilela, J. L. Antibacterial coatings for improving the performance of biomaterials. Coatings 10, 139 (2020).

     Google Scholar 

175. Liu, S., Tang, J., Ji, F., Lin, W. & Chen, S. Recent advances in zwitterionic hydrogels: preparation, property, and biomedical application. Gels 8, 46 (2022).

     Google Scholar 

176. Junter, G. A., Thébault, P. & Lebrun, L. Polysaccharide-based antibiofilm surfaces. Acta Biomater 30, 13–25 (2016).

     Google Scholar 

177. Cui, X. et al. Bacterial inhibition and osteoblast adhesion on Ti alloy surfaces modified by poly(PEGMA-r-Phosmer) coating. ACS Appl. Mater. Interfaces 10, 23674–23681 (2018).

     Google Scholar 

178. Kang, S. et al. Development of anti-biofouling interface on hydroxyapatite surface by coating zwitterionic MPC polymer containing calcium-binding moieties to prevent oral bacterial adhesion. Acta Biomater 40, 70–77 (2016).

     Google Scholar 

179. Shao, H. et al. Advances in the superhydrophilicity-modified titanium surfaces with antibacterial and pro-osteogenesis properties: a review. Front. Bioeng. Biotechnol. 10, 1000401 (2022).

     Google Scholar 

180. Chen, Q., Liu, D., Gong, Y., Xiao, Q. & Li, Z. A. Modification of titanium surfaces via surface-initiated atom transfer radical polymerization to graft PEG-RGD polymer brushes to inhibit bacterial adhesion and promote osteoblast cell attachment. J. Wuhan Univ. Technol. Mater. Sci. Ed. 32, 1225–1231 (2017).

     Google Scholar 

181. Kugel, A., Stafslien, S. & Chisholm, B. J. Antimicrobial coatings produced by “tethering” biocides to the coating matrix: a comprehensive review. Prog. Org. Coat. 72, 222–252 (2011).

     Google Scholar 

182. Alkhalifa, S. et al. Analysis of the destabilization of bacterial membranes by quaternary ammonium compounds: a combined experimental and computational study. ChemBioChem 21, 1510–1516 (2020).

     Google Scholar 

183. Jennings, M. C., Minbiole, K. P. & Wuest, W. M. Quaternary ammonium compounds: an antimicrobial mainstay and platform for innovation to address bacterial resistance. ACS Infect. Dis. 1, 288–303 (2015).

     Google Scholar 

184. Salajkova, S. et al. Wide-antimicrobial spectrum of picolinium salts. Molecules 25, 2254 (2020).

     Google Scholar 

185. Sun, Z. et al. The overview of antimicrobial peptide-coated implants against oral bacterial infections. Aggregate 4, e309 (2023).

     Google Scholar 

186. Costa, F., Carvalho, I. F., Montelaro, R. C., Gomes, P. & Martins, M. C. L. Covalent immobilization of antimicrobial peptides (AMPs) onto biomaterial surfaces. Acta Biomater 7, 1431–1440 (2011).

     Google Scholar 

187. Brogden, K. A. Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria? Nat. Rev. Microbiol. 3, 238–250 (2005).

     Google Scholar 

188. Chen, J. et al. Antimicrobial titanium surface via click-immobilization of peptide and its in vitro/vivo activity. ACS Biomater. Sci. Eng. 5, 1034–1044 (2019).

     Google Scholar 

189. Lee, H., Dellatore, S. M., Miller, W. M. & Messersmith, P. B. Mussel-inspired surface chemistry for multifunctional coatings. Science 318, 426–430 (2007).

     Google Scholar 

190. Iqbal, Z., Lai, E. P. C. & Avis, T. J. Antimicrobial effect of polydopamine coating on Escherichia coli. J. Mater. Chem. 22, 21608–21612 (2012).

     Google Scholar 

191. Fu, Y. et al. Polydopamine antibacterial materials. Mater. Horiz. 8, 1618–1633 (2021).

     Google Scholar 

192. Su, L., Yu, Y., Zhao, Y., Liang, F. & Zhang, X. Strong antibacterial polydopamine coatings prepared by a shaking-assisted method. Sci. Rep. 6, 24420 (2016).

     Google Scholar 

193. Rienzo, M. A. D. et al. Antimicrobial properties of sophorolipids produced by Candida Bombicola ATCC 22214 against gram positive and Gram-negative bacteria. N. Biotechnol. 31, S66–S67 (2014).

     Google Scholar 

194. Elshikh, M. et al. Rhamnolipids and lactonic sophorolipids: natural antimicrobial surfactants for oral hygiene. J. Appl. Microbiol. 123, 1111–1123 (2017).

     Google Scholar 

195. Tambone, E. et al. Rhamnolipid coating reduces microbial biofilm formation on titanium implants: an in vitro study. BMC Oral. Health 21, 49 (2021).

     Google Scholar 

196. Holinka, J., Pilz, M., Kubista, B., Presterl, E. & Windhager, R. Effects of selenium coating of orthopaedic implant surfaces on bacterial adherence and osteoblastic cell growth. Bone Jt. J. 95-b, 678–682 (2013).

     Google Scholar 

197. Tsuchiya, H. et al. Innovative antimicrobial coating of titanium implants with iodine. J. Orthop. Sci. 17, 595–604 (2012).

     Google Scholar 

198. Sasamoto, T. et al. Antibacterial fluorinated diamond-like carbon coating promotes osteogenesis—comparison with titanium alloy. Appl. Sci. 11, 9451 (2021).

     Google Scholar 

199. Zhou, J., Li, B. & Han, Y. F-doped TiO₂ microporous coating on titanium with enhanced antibacterial and osteogenic activities. Sci. Rep. 8, 17858 (2018).

     Google Scholar 

200. Tran, P. A. et al. Selenium nanoparticles as anti-infective implant coatings for trauma orthopedics against methicillin-resistant Staphylococcus aureus and epidermidis: in vitro and in vivo assessment. Int. J. Nanomed. 14, 4613–4624 (2019).

     Google Scholar 

201. Xu, W., Lin, Z., Cortez-Jugo, C., Qiao, G. G. & Caruso, F. Antimicrobial phenolic materials: from assembly to function. Angew. Chem. Int. Ed. 64, e202423654 (2025).

     Google Scholar 

202. Polaquini, C. R. et al. Antibacterial activity of a new monocarbonyl analog of curcumin MAC 4 is associated with divisome disruption. Bioorg. Chem. 109, 104668 (2021).

     Google Scholar 

203. Caturla, N., Vera-Samper, E., Villalaín, J., Mateo, C. R. & Micol, V. The relationship between the antioxidant and the antibacterial properties of galloylated catechins and the structure of phospholipid model membranes. Free Radic. Biol. Med. 34, 648–662 (2003).

     Google Scholar 

204. Kushram, P., Majumdar, U. & Bose, S. Hydroxyapatite coated titanium with curcumin and epigallocatechin gallate for orthopedic and dental applications. Biomater. Adv. 155, 213667 (2023).

     Google Scholar 

205. Grainger, D. W. Controlled-release and local delivery of therapeutic antibodies. Expert Opin. Biol. Ther. 4, 1029–1044 (2004).

     Google Scholar 

206. Rojas, I. A., Slunt, J. B. & Grainger, D. W. Polyurethane coatings release bioactive antibodies to reduce bacterial adhesion. J. Control Release 63, 175–189 (2000).

     Google Scholar 

207. Chen, X., Zhou, J., Qian, Y. & Zhao, L. Antibacterial coatings on orthopedic implants. Mater. Today Bio 19, 100586 (2023).

     Google Scholar 

208. Cai, J. & Liu, R. Introduction to antibacterial biomaterials. Biomater. Sci. 8, 6812–6813 (2020).

     Google Scholar 

209. Lemire, J. A., Harrison, J. J. & Turner, R. J. Antimicrobial activity of metals: mechanisms, molecular targets and applications. Nat. Rev. Microbiol. 11, 371–384 (2013).

     Google Scholar 

210. Yang, N. et al. Silver-quercetin-loaded honeycomb-like Ti-based interface combats infection-triggered excessive inflammation via specific bactericidal and macrophage reprogramming. Bioact. Mater. 43, 48–66 (2025).

     Google Scholar 

211. Huang, Q. et al. The Cu-containing TiO₂ coatings with modulatory effects on macrophage polarization and bactericidal capacity prepared by micro-arc oxidation on titanium substrates. Colloids Surf. B Biointerfaces 170, 242–250 (2018).

     Google Scholar 

212. Zhao, D. W. et al. Calcium-zinc phosphate chemical conversion coating facilitates the osteointegration of biodegradable zinc alloy implants by orchestrating macrophage phenotype. Adv. Health. Mater. 12, e2202537 (2023).

     Google Scholar 

213. Yang, K. et al. Iron metabolism interference-enhanced sonodynamic therapy of methicillin-resistant Staphylococcus aureus-induced osteomyelitis by CaCO₃-Ga-PPIX@PEG nanospheres. Nano Today 56, 102299 (2024).

     Google Scholar 

214. Haidari, H. et al. Ultrasmall AgNP-impregnated biocompatible hydrogel with highly effective biofilm elimination properties. ACS Appl. Mater. Interfaces 12, 41011–41025 (2020).

     Google Scholar 

215. Zawadzka, K. et al. Surface area or diameter – which factor really determines the antibacterial activity of silver nanoparticles grown on TiO₂ coatings? N. J. Chem. 38, 3275–3281 (2014).

     Google Scholar 

216. Jia, Z. et al. Constructing multilayer silk protein/nanosilver biofunctionalized hierarchically structured 3D printed Ti6Al4 V Scaffold for repair of infective bone defects. ACS Biomater. Sci. Eng. 5, 244–261 (2019).

     Google Scholar 

217. Sobolev, A. et al. Bioactive coating on Ti alloy with high osseointegration and antibacterial Ag nanoparticles. ACS Appl Mater. Interfaces 11, 39534–39544 (2019).

     Google Scholar 

218. Jacobs, A., Renaudin, G., Forestier, C., Nedelec, J. M. & Descamps, S. Biological properties of copper-doped biomaterials for orthopedic applications: a review of antibacterial, angiogenic and osteogenic aspects. Acta Biomater 117, 21–39 (2020).

     Google Scholar 

219. Vincent, M., Hartemann, P. & Engels-Deutsch, M. Antimicrobial applications of copper. Int. J. Hyg. Environ. Health 219, 585–591 (2016).

     Google Scholar 

220. Song, X. et al. Cu-decorated graphene oxide coatings with enhanced antibacterial activity for surface modification of implant. Mater. Res. Bull. 141, 111345 (2021).

     Google Scholar 

221. Wu, H. et al. Preparation, antibacterial effects and corrosion resistant of porous Cu–TiO₂ coatings. Appl. Surf. Sci. 308, 43–49 (2014).

     Google Scholar 

222. Hadidi, M. et al. Electrophoretic-deposited hydroxyapatite-copper nanocomposite as an antibacterial coating for biomedical applications. Surf. Coat. Technol. 321, 171–179 (2017).

     Google Scholar 

223. Wen, Z. et al. Mesoporous TiO(2) coatings regulate ZnO nanoparticle loading and Zn²⁺ release on titanium dental implants for sustained osteogenic and antibacterial activity. ACS Appl. Mater. Interfaces 15, 15235–15249 (2023).

     Google Scholar 

224. Jin, G. et al. Osteogenic activity and antibacterial effect of zinc ion implanted titanium. Colloids Surf. B Biointerfaces 117, 158–165 (2014).

     Google Scholar 

225. Hu, H. et al. Antibacterial activity and increased bone marrow stem cell functions of Zn-incorporated TiO₂ coatings on titanium. Acta Biomater 8, 904–915 (2012).

     Google Scholar 

226. Li, F., Liu, F., Huang, K. & Yang, S. Advancement of gallium and gallium-based compounds as antimicrobial agents. Front. Bioeng. Biotechnol. 10, 827960 (2022).

     Google Scholar 

227. Wang, M. Q. et al. A 3D printed Ga containing scaffold with both anti-infection and bone homeostasis-regulating properties for the treatment of infected bone defects. J. Mater. Chem. B 9, 4735–4745 (2021).

     Google Scholar 

228. Cochis, A., Azzimonti, B., Chiesa, R., Rimondini, L. & Gasik, M. Metallurgical gallium additions to titanium alloys demonstrate a strong time-increasing antibacterial activity without any cellular toxicity. ACS Biomater. Sci. Eng. 5, 2815–2820 (2019).

     Google Scholar 

229. Anggård, E. Nitric oxide: mediator, murderer, and medicine. Lancet 343, 1199–1206 (1994).

     Google Scholar 

230. Pacher, P., Beckman, J. S. & Liaudet, L. Nitric oxide and peroxynitrite in health and disease. Physiol. Rev. 87, 315–424 (2007).

     Google Scholar 

231. Radi, R. Nitric oxide, oxidants, and protein tyrosine nitration. Proc. Natl. Acad. Sci. USA 101, 4003–4008 (2004).

     Google Scholar 

232. Schairer, D. O., Chouake, J. S., Nosanchuk, J. D. & Friedman, A. J. The potential of nitric oxide releasing therapies as antimicrobial agents. Virulence 3, 271–279 (2012).

     Google Scholar 

233. Hou, Z. et al. Nitric oxide-mediated dual-functional smart titanium implant coating for antibacterial and osseointegration promotion in implant-associated infections. Adv. Healthc. Mater. 14, 2500997 (2025).

     Google Scholar 

234. Su, Z. et al. Bioresponsive nano-antibacterials for H₂S-sensitized hyperthermia and immunomodulation against refractory implant-related infections. Sci. Adv. 8, eabn1701 (2022).

     Google Scholar 

235. Wu, S. et al. CO-loaded hemoglobin/EGCG nanoparticles functional coatings for inflammation modulation of vascular implants. Regener. Biomater. 12, rbae148 (2024).

     Google Scholar 

236. Zhou, M. et al. Interfacial delivery of carbon monoxide via smart titanium implant coating for enhanced soft tissue integration with switchable antibacterial and immunomodulatory properties. Bioact. Mater. 40, 318–333 (2024).

     Google Scholar 

237. VanEpps, J. S. & Younger, J. G. Implantable device-related infection. Shock 46, 597–608 (2016).

     Google Scholar 

238. Zimmerli, W. Clinical presentation and treatment of orthopaedic implant-associated infection. J. Intern. Med. 276, 111–119 (2014).

     Google Scholar 

239. Lesens, O. et al. Should we expand the indications for the DAIR (debridement, antibiotic therapy, and implant retention) procedure for Staphylococcus aureus prosthetic joint infections? A multicenter retrospective study. Eur. J. Clin. Microbiol. Infect. Dis. 37, 1949–1956 (2018).

     Google Scholar 

240. Mosaei, H. & Zenkin, N. Inhibition of RNA polymerase by rifampicin and rifamycin-like molecules. EcoSal Plus 9, https://doi.org/10.1128/ecosalplus.ESP-0017-2019 (2020).

241. Zimmerli, W. & Sendi, P. Role of rifampin against Staphylococcal biofilm infections in vitro, in animal models, and in orthopedic-device-related infections. Antimicrob. Agents Chemother. 63, e01746–18 (2019).

     Google Scholar 

242. Mei, L., Zhang, Y., Wang, K., Chen, S. & Song, T. Nanomaterials at the forefront of antimicrobial therapy by photodynamic and photothermal strategies. Mater. Today Bio 29, 101354 (2024).

     Google Scholar 

243. Nestoros, E., Sharma, A., Kim, E., Kim, J. S. & Vendrell, M. Smart molecular designs and applications of activatable organic photosensitizers. Nat. Rev. Chem. 9, 46–60 (2025).

     Google Scholar 

244. Priyadarshi, N. et al. Advances in photothermal therapy for cancer and bacterial cells ablation using various nanomaterials. Adv. Colloid Interface Sci 342, 103541 (2025).

     Google Scholar 

245. Wang, X. et al. Photodynamic and photothermal bacteria targeting nanosystems for synergistically combating bacteria and biofilms. J. Nanobiotechnol. 23, 40 (2025).

     Google Scholar 

246. Yu, Y.-L. et al. Elimination of methicillin-resistant Staphylococcus aureus biofilms on titanium implants via photothermally-triggered nitric oxide and immunotherapy for enhanced osseointegration. Mil. Med. Res. 10, 21 (2023).

     Google Scholar 

247. Xie, J. et al. Supramolecular nanoplatform for biofilm eradication and anti-inflammatory by phototherapies and macrophage repolarization. Adv. Healthc. Mater. 14, 2501162 (2025).

     Google Scholar 

248. Hu, J. et al. Surface modification of titanium substrate via combining photothermal therapy and quorum-sensing-inhibition strategy for improving osseointegration and treating biofilm-associated bacterial infection. Bioact. Mater. 18, 228–241 (2022).

     Google Scholar 

249. Maleki, A. et al. Titanium-based nanoarchitectures for sonodynamic therapy-involved multimodal treatments. Small 19, e2206253 (2023).

     Google Scholar 

250. Williams, R. G. & Pitt, W. G. In vitro response of Escherichia coli to antibiotics and ultrasound at various insonation intensities. J. Biomater. Appl. 12, 20–30 (1997).

     Google Scholar 

251. Qian, Z., Sagers, R. D. & Pitt, W. G. Investigation of the mechanism of the bioacoustic effect. J. Biomed. Mater. Res. 44, 198–205 (1999).

     Google Scholar 

252. Duco, W., Grosso, V., Zaccari, D. & Soltermann, A. T. Generation of ROS mediated by mechanical waves (ultrasound) and its possible applications. Methods 109, 141–148 (2016).

     Google Scholar 

253. Dong, Y. et al. Antibiofilm effect of ultrasound combined with microbubbles against Staphylococcus epidermidis biofilm. Int. J. Med. Microbiol. 307, 321–328 (2017).

     Google Scholar 

254. Qian, X., Zheng, Y. & Chen, Y. Micro/nanoparticle-augmented sonodynamic therapy (SDT): breaking the depth shallow of photoactivation. Adv. Mater. 28, 8097–8129 (2016).

     Google Scholar 

255. Smith, N. B., Temkin, J. M., Shapiro, F. & Hynynen, K. Thermal effects of focused ultrasound energy on bone tissue. Ultrasound Med. Biol. 27, 1427–1433 (2001).

     Google Scholar 

256. Guan, S. et al. Metastructure “trap” coating by acoustic confinement effect for antibacterial sonothermal therapy. Adv. Funct. Mater. 34, 2316093 (2024).

     Google Scholar 

257. Guan, S. et al. Metainterface heterostructure enhances sonodynamic therapy for disrupting secondary biofilms. ACS Nano 18, 15114–15129 (2024).

     Google Scholar 

258. Su, Z. et al. Biodegradable oxygen-evolving metalloantibiotics for spatiotemporal sono-metalloimmunotherapy against orthopaedic biofilm infections. Nat. Commun. 15, 8058 (2024).

     Google Scholar 

259. Xiu, W. et al. Ultrasound-stimulated “exocytosis” by cell-like microbubbles enhances antibacterial species penetration and immune activation against implant infection. Adv. Sci. 11, e2307048 (2024).

     Google Scholar 

260. Zhang, C. et al. Synthesis of iron nanometallic glasses and their application in cancer therapy by a localized Fenton reaction. Angew. Chem. Int. Ed. Engl. 55, 2101–2106 (2016).

     Google Scholar 

261. Jia, C., Guo, Y. & Wu, F. G. Chemodynamic therapy via Fenton and Fenton-like nanomaterials: strategies and recent advances. Small 18, e2103868 (2022).

     Google Scholar 

262. Pan, T. et al. Engineering efficient artificial nanozyme based on chitosan grafted Fe-doped-carbon dots for bacteria biofilm eradication. J. Hazard Mater. 435, 128996 (2022).

     Google Scholar 

263. Wang, Z. et al. Oxygen-independent sulfate radical and Fe²⁺-modified implants for fast sterilization and osseointegration of infectious bone defects. ACS Nano 19, 18804–18823 (2025).

     Google Scholar 

264. Guo, G. et al. Space-selective chemodynamic therapy of CuFe₅O₈ nanocubes for implant-related infections. ACS Nano 14, 13391–13405 (2020).

     Google Scholar 

265. Zhou, H. et al. Ultrasensitive chemodynamic therapy: bimetallic peroxide triggers high pH-activated, synergistic effect/H₂O₂ self-supply-mediated cascade Fenton chemistry. Adv. Health. Mater. 10, e2002126 (2021).

     Google Scholar 

266. Liu, Y., Chi, S., Cao, Y. & Liu, Z. Glutathione-responsive biodegradable core–shell nanoparticles that self-generate H₂O₂ and deliver doxorubicin for chemo–chemodynamic therapy. ACS Appl. Nano Mater 5, 2592–2602 (2022).

     Google Scholar 

267. Hedayatnasab, Z., Abnisa, F. & Daud, W. M. A. W. Review on magnetic nanoparticles for magnetic nanofluid hyperthermia application. Mater. Des. 123, 174–196 (2017).

     Google Scholar 

268. Alumutairi, L., Yu, B., Filka, M., Nayfach, J. & Kim, M. H. Mild magnetic nanoparticle hyperthermia enhances the susceptibility of Staphylococcus aureus biofilm to antibiotics. Int. J. Hyperth. 37, 66–75 (2020).

     Google Scholar 

269. Xu, C., Akakuru, O. U., Zheng, J. & Wu, A. Applications of iron oxide-based magnetic nanoparticles in the diagnosis and treatment of bacterial infections. Front. Bioeng. Biotechnol. 7, 141 (2019).

     Google Scholar 

270. Yang, N. et al. Magnesium implants with alternating magnetic field-enhanced hydrogen release and proton depletion for anti-infection treatment and tissue repair. Bioact. Mater. 38, 374–383 (2024).

     Google Scholar 

271. Xu, Y. et al. Urchin-like Fe₃O₄@Bi₂S₃ nanospheres enable the destruction of biofilm and efficiently antibacterial activities. ACS Appl. Mater. interfaces 16, 3215–3231 (2024).

     Google Scholar 

272. Arciola, C. R., Campoccia, D. & Montanaro, L. Implant infections: adhesion, biofilm formation and immune evasion. Nat. Rev. Microbiol. 16, 397–409 (2018).

     Google Scholar 

273. Brandquist, N. D. & Kielian, T. Immune dysfunction during S. aureus biofilm-associated implant infections: opportunities for novel therapeutic strategies. npj Biofilms Microbiomes 11, 144 (2025).

     Google Scholar 

274. Van Roy, Z. & Kielian, T. Immune-based strategies for the treatment of biofilm infections. Biofilm 9, 100264 (2025).

     Google Scholar 

275. Hu, Y. et al. Environment-responsive therapeutic platforms for the treatment of implant infection. Adv. Healthc. Mater. 12, e2300985 (2023).

     Google Scholar 

276. Alam, F. et al. Lactate biosensing: the emerging point-of-care and personal health monitoring. Biosens. Bioelectron. 117, 818–829 (2018).

     Google Scholar 

277. Abikhzer, G. et al. EANM/SNMMI guideline/procedure standard for [¹⁸F]FDG hybrid PET use in infection and inflammation in adults v2.0. Eur. J. Nucl. Med. Mol. Imaging 52, 510–538 (2025).

     Google Scholar 

278. Kim, D.-H., Kim, M.S. & Hwang, J. in Design and Quality for Biomedical Technologies V, Vol. 8215 27–33 (SPIE, 2012).

279. Gil, B. et al. Wireless implantable bioelectronics with a direct electron transfer lactate enzyme for detection of surgical site infection in orthopaedics. Biosens. Bioelectron. 263, 116571 (2024).

     Google Scholar 

280. Yang, K. et al. Self-adaptive antibiofilm effect and immune regulation by hollow Cu₂MoS₄ nanospheres for treatment of implant infections. ACS Appl. Mater. Interfaces 15, 18720–18733 (2023).

     Google Scholar 

281. Han, J. et al. The current status of stimuli-responsive nanotechnologies on orthopedic titanium implant surfaces. J. Nanobiotechnol. 21, 277 (2023).

     Google Scholar 

282. Hao, Z., Li, X., Zhang, R. & Zhang, L. Stimuli-responsive hydrogels for antibacterial applications. Adv. Healthc. Mater. 13, 2400513 (2024).

     Google Scholar 

Download references