THE WAR UNDER THE SKIN - BIOFILM AND INFLAMMATION IN CHRONIC WOUNDS
Keywords:
chronic wounds, biofilm, inflammation, wound healingAbstract
The skin, the largest organ in the body, protects against external stimuli and microorganisms. A balanced skin microbiota, including both commensal and pathogenic microorganisms, is essential for skin health. Disruptions in this balance can lead to infections and inflammation, which are key factors in delayed wound healing. Biofilm formation further complicates the process. In chronic wounds, healing is often impaired during the inflammatory phase due to persistent activation of the immune response. This leads to increased immune cell activation, along with heightened activity of matrix metalloproteinases (MMPs), collagenase, and elastase, while tissue inhibitors of matrix metalloproteinases (TIMPs) decrease. Host factors such as wound depth, duration, local hypoxia, and immune responses contribute to healing delays. Microbial factors, including bacterial diversity, microbial load, and pathogenicity, also play a significant role. Biofilms are more resistant to antimicrobial therapy than free-floating bacteria. Its formation in chronic wounds triggers sustained inflammation, marked by elevated inflammatory mediators like IL-6, IL-10, IL-17A, and TNF-α. Biofilms not only prolong inflammation but also cause oxidative stress and protease-mediated degradation of essential receptors and cytokines, accelerating wound bed senescence. The presence and persistence of biofilm in chronic wounds affect the host’s immune response. Understanding this relationship offers more opportunities for successful treatment.
References
Pereira RF, Barrias CC, Granja PL, Bartolo PJ. Advanced biofabrication strategies for skin regeneration and repair. Nanomedicine.2013; 8: 603-621. doi: 10.2217/nnm.13.50
Lejeune P. Contamination of abiotic surfaces: What a colonizing bacterium sees and howto blur it. Trends Microbiol. 2003; 11(4): 179-184.doi: 10.1016/s0966-842x(03)00047-7.
Rendueles O, Ghigo JM. Multi-species biofilms: How to avoid unfriendly neighbors. FEMS Microbiol. Rev. 2012; 36(5): 972-989.doi: 10.1111/j.1574-6976.2012.00328.x.
Sender R, Fuchs S, Milo R. Are We Really Vastly Outnumbered? Revisiting the Ratio of Bacterial to Host Cells in Humans. Cell. 2016;40:164:337. doi: 10.1016/j.cell.2016.01.013
Grice EA, Segre JA. The skin microbiome. Nat Rev Microbiol. 2011; 9:244–53. doi: 10.1038/nrmicro2537
Byrd AL, Belkaid Y, Segre JA. The human skin microbiome. Nat Rev Microbiol. 2018; 16:143–55. doi: 10.1038/nrmicro.2017.157
Leaper D, Assadian O, Edmiston CE. Approach to chronic wound infections. Br. J. Dermatol. 2015; 173(2):351-358.doi: 10.1111/bjd.13677
Bertozzi N, Simonacci F, Grieco MP, Grignaffini E, Raposio E. The biological and clinical basis for the use of adipose-derived stem cells in the field of wound healing. Ann Med Surg. 2017;41–48. doi:10.1016/j.amsu.2017.06.058
Daeschlein G. Antimicrobial and antiseptic strategies in wound management. Int Wound J. 2013;10:9–14. doi: 10.1111/iwj.12175
Bowler PG, Duerden BI, Armstrong DG. Wound Microbiology and Associated Approaches to Wound Management. Clin Microbiol Rev. 2001;14:244–69. doi: 10.1128/CMR.14.2.244-269.2001
Guo S, DiPietro LA. Factors Affecting Wound Healing. J Dental Res. 2010;89:219–29. doi: 10.1177/0022034509359125
Orsted HL, Keast DH, Forest-Laland L, Kuhnke JL, O’Sullivan-Drombolis D, Jin S, et al. Best practice recommendations for the prevention and management of wounds. In: Foundations of Best Practice for Skin and Wound Management. A supplement of Wound Care Canada. 2017; 74 pp.
Negut I, Grumezescu V, Grumezescu A. Treatment Strategies for Infected Wounds. Molecules. 2018; 23:2392. doi: 10.3390/molecules23092392
Kingsley A. The wound infection continuum and its application to clinical practice. Ostomy Manage. 2003; 49:1–7.
Bowler PG, Duerden BI, Armstrong DG. Wound Microbiology and Associated Approaches to Wound Management. Clin Microbiol Rev. 2001; 14:244–69. 10.1128/CMR.14.2.244-269.2001
Leaper D, Assadian O, Edmiston CE. Approach to chronic wound infections. Br. J. Dermatol. 2015; 173(2):351-358.doi: 10.1111/bjd.13677
Percival SL, Hill KE, Williams DW, Hooper SJ, Thomas DW, Costerton JW. A review of the scientific evidence for biofilms in wounds. Wound Repair Regen. 2012;20 (5):647-57. https://doi.org/10.1111/j.1524-475X.2012.00836.x
Peyyala R, Ebersole JL. Multispecies biofilms and host responses: “discriminating the trees from the forest.” Cytokine. 2013;61(1):15–25. doi: 10.1016/j.cyto.2012.10.006.
Wang J, Windbergs M. Functional electrospun fibers for the treatment of human skin wounds. Eur J Pharm Biopharm. 2017;119: 283-299.
Zahedi P, Rezaeian I, Ranaei-Siadat SO,Jafari SH, Supaphol P. A review on wound dressings with an emphasis on electrospun nanofibrous polymeric bandages. Polym Adv Technol. 2010; 21 :77-95.10.1002/pat.1625
Landén NX, Li D, Ståhle M. Transition from inflammation to proliferation: a critical step during wound healing. Cell Mol Life Sci. 2016;73:3861–85. doi: 10.1007/s00018-016-2268-0
Nguyen AV, Soulika AM. The Dynamics of the Skin’s Immune System. Int J Mol Sci. 2019; 20:1811. doi: 10.3390/ijms20081811
Rodrigues M, Kosaric N, Bonham CA, Gurtner GC. Wound Healing: A Cellular Perspective. Physiol Rev. 2019; 99:665–706. doi: 10.1152/physrev.00067.2017
Ellis S, Lin EJ, Tartar D. Immunology of Wound Healing. Curr Dermatol Rep. 2018; 7:350–8. doi: 10.1007/s13671-018-0234-9
Cañedo-Dorantes L, Cañedo-Ayala M. Skin Acute Wound Healing: A Comprehensive Review. Int J Inflammation. 2019:1–15. doi: 10.1155/2019/3706315
MacLeod AS, Mansbridge JN. The Innate Immune System in Acute and Chronic Wounds. Adv Wound Care. 2016; 5:65–78. doi: 10.1089/wound.2014.0608
Lazarus GS. Definitions and Guidelines for Assessment of Wounds and Evaluation of Healing. Arch Dermatol.1994; 130:489. doi: 10.1001/archderm.1994.01690040093015
Wysocki AB, Staiano-Coico L, Grinnell F. Wound Fluid from Chronic Leg Ulcers Contains Elevated Levels of Metalloproteinases MMP-2 and MMP-9. J Invest Dermatol. 1993;101:64–8. doi: 10.1111/1523-1747.ep12359590
Diegelmann RF. Excessive neutrophils characterize chronic pressure ulcers. Wound Rep Regen. 2003;11:490–5. doi: 10.1046/j.1524-475X.2003.11617.x
Ellis S, Lin EJ, Tartar D. Immunology of Wound Healing. Curr Dermatol Rep. 2018;7:350–8. doi: 10.1007/s13671-018-0234-9
Mast BA, Schultz GS. Interactions of cytokines, growth factors, and proteases in acute and chronic wounds. Wound Rep Regen. 1996;4:411–20. doi: 10.1046/j.1524-475X.1996.40404.x
Herrick S, Ashcroft G, Ireland G, Horan M, McCollum C, Ferguson M. Up-regulation of elastase in acute wounds of healthy aged humans and chronic venous leg ulcers are associated with matrix degradation. Lab Invest. 1997; 77:281–8.
Wlaschek M, Scharffetter-Kochanek K. Oxidative stress in chronic venous leg ulcers. Wound Rep Regen. 2005; 13:452–61. doi: 10.1111/j.1067-1927.2005.00065.x
Schafer M, Werner S. Oxidative stress in normal and impaired wound repair. Pharmacol Res. 2008; 58:165–71. doi: 10.1016/j.phrs.2008.06.004
Sen CK. Wound healing essentials: Let there be oxygen. Wound Rep Regen. 2009; 17:1–18. doi: 10.1111/j.1524-475X.2008.00436.x
Wong SL, Demers M, Martinod K, Gallant M, Wang Y, Goldfine AB, et al. Diabetes primes neutrophils to undergo NETosis, which impairs wound healing. Nat Med. 2015;21:815–9. doi: 10.1038/nm.3887
Dunnill C, Patton T, Brennan J, Barrett J, Dryden M, Cooke J, et al. Reactive oxygen species (ROS) and wound healing: the functional role of ROS and emerging ROS-modulating technologies for augmentation of the healing process. Int Wound J. 2017;14:89–96. doi: 10.1111/iwj.12557
Zamboni P, Izzo M, Tognazzo S, et al. The overlapping of local iron overload and HFE mutation in venous leg ulcer pathogenesis. Free Radical Biol Med. 2006;40:1869–73. doi: 10.1016/j.freeradbiomed.2006.01.026
Sindrilaru A, Peters T, Wieschalka S, Baican C, Baican A, Peter H, et al. An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice. J Clin Invest. 2011;121:985–97. doi: 10.1172/JCI44490
Khanna S, Biswas S, Shang Y, Collard E, Azad A, Kauh C, et al. Macrophage Dysfunction Impairs Resolution of Inflammation in the Wounds of Diabetic Mice. PloS One. 2010;5:e9539. doi: 10.1371/journal.pone.0009539
Klinkert K, Whelan D, Clover AJP, Leblond A-L, Kumar AHS, Caplice NM. Selective M2 Macrophage Depletion Leads to Prolonged Inflammation in Surgical Wounds. Eur Surg Res. 2017;58:109–20. doi: 10.1159/000451078
Versey Z, da Cruz Nizer WS, Russell E, et al. Biofilm-Innate Immune Interface: Contribution to Chronic Wound Formation. Front Immunol. 2021;12:648554. doi: 10.3389/fimmu.2021.648554.
Percival SL, Malone M, Mayer D, et al. Role of anaerobes in polymicrobial communities and biofilms complicating diabetic foot ulcers. Int Wound J. 2018;15(5):776–82. https://doi.org/10.1111/iwj.12926.
Diggle SP, Winzer K,Lazdunski A, Williams P, Cámara M.Advancing the quorum in Pseudomonas aeruginosa: MvaT and the regulation of N-acylhomoserine lactone production and virulence gene expression. J Bacteriol. 2002;184: pp. 25762586, 10.1128/jb.184.10.2576-2586.2002
Antunes LCM, Ferreira RB.Intercellular communication in bacteria. Crit. Rev. Microbiol., 35 (2009), pp. 69-80, doi: 10.1080/10408410902733946
Kleerebezem M, Quadri LE, Kuipers OP, De Vos WM.Quorum sensing by peptide pheromones and two-component signal-transduction systems in Gram-positive bacteria. Mol Microbiol. 1997;24:, pp. 895-904, doi:10.1046/j.1365-2958.1997.4251782.x
Goswami AG, Basu S, Banerjee T. et al. Biofilm and wound healing: from bench to bedside. Eur J Med Res. 2013; 28:157. https://doi.org/10.1186/s40001-023-01121-7
Dowd SE, Wolcott RD, Sun Y, McKeehan T, Smith E, Rhoads D. Polymicrobial nature of chronic diabetic foot ulcer biofilm infections determined using bacterial tag encoded FLX amplicon pyrosequencing (bTEFAP). PLoS ONE. 2008; 3(10): e3326. https://doi.org/10.1371/journal.pone.0003326.
Redel H, Gao Z, Li H, et al. Quantitation and composition of cutaneous microbiota in diabetic and nondiabetic men. J Infect Dis. 2013;207(7):1105–14. https://doi.org/10.1093/infdis/jit005.
Oates A, Bowling FL, Boulton AJ, McBain AJ. Molecular and culture-based assessment of the microbial diversity of diabetic chronic foot wounds and contralateral skin sites. J Clin Microbiol. 2012;50(7):2263–71.
Banerjee T, Das A, Singh A, Bansal R, Basu S. The microflora of chronic diabetic foot ulcers based on culture and molecular examination: a descriptive study. Wound Manag Prev. 2019;65(5):16–23. https://doi.org/10.25270/wmp.2019.5.1623.
Malone M, Johani K, Jensen SO, et al. Next generation DNA sequencing of tissues from infected diabetic foot ulcers. EBioMedicine. 2017;21:142–9.
Johani K, Malone M, Jensen S, et al. Microscopy visualisation confirms multi-species biofilms are ubiquitous in diabetic foot ulcers. Int Wound J. 2017;14(6):1160–9.
Charles PG, Uçkay I, Kressmann B, Emonet S, Lipsky BA. The role of anaerobes in diabetic foot infections. Anaerobe. 2015;34:8-13.
Burmølle M, Ren D, Bjarnsholt T, Sørensen SJ. Interactions in multispecies biofilms: do they actually matter? Trends Microbiol. 2014;22(2):84–91.
Whiteley M, Bangera MG, Bumgarner RE, Parsek MR, Teitzel GM, Lory S et al. Gene expression in Pseudomonas aeruginosa biofilms. Nature. 2001;413:860–4.
Boles BR, Thoendel M, Singh PK. Self-generated diversity produces ‘insurance effects’. Proc Natl Acad Sci USA. 2004;101:16630–5.
Liao C, Huang X, Wang Q, Yao D, Lu W. Virulence factors of Pseudomonas aeruginosaand antivirulence strategies to combat its drug resistance. Front Cell Infect Microbiol. 2022;12:926758. https://doi.org/10.3389/fcimb.2022.926758.
Graf AC, Leonard A, Schäuble M, Rieckmann LM, Hoyer J, Maass S et al. Virulence Factors Produced by Staphylococcus aureus biofilms have a moonlighting function contributing to biofilm integrity. Mol Cell Proteomics. 2019;18(6):1036–53. https://doi.org/10.1074/mcp.RA118.001120.
Sinha M, Ghosh N, Wijesinghe DS, Mathew-Steiner SS, Das A, Singh K et al.Pseudomonas Aeruginosa theft biofilm require host lipids of cutaneous wound. Ann Surg. 2023;277(3):e634–47.
Li P, Tong X, Wang T, et al. Biofilms in wound healing: A bibliometric and visualised study. Int Wound J. 2023; 20:313–327.
Sankar S, Muthukaliannan GK. Deciphering the crosstalk between inflammation and biofilm in chronic wound healing: Phytocompounds loaded bionanomaterials as therapeutics. Saudi Journal of Biological Sciences. 2024;31(4). https://doi.org/10.1016/j.sjbs.2024.103963
