Effect of Stabilized Hypochlorous Acid on Re-epithelialization and Bacterial Bioburden in Acute Wounds: A Randomized Controlled Trial in Healthy Volunteers
Keywords:antiseptic, wound management, wound healing, clinical trial
The aim of this randomized controlled trial was to evaluate the wound-healing effect and antimicrobial properties of a novel stabilized hypochlorous acid solution on acute wounds, using a suction blister wound model. One suction blister was raised and de-roofed on each forearm in 20 healthy volunteers. Stabilized hypochlorous acid/control (sterile 0.9% NaCl) solutions were assigned to either wound by randomization. Wounds were irrigated and treated on days 0, 2 and 4. Re-epithelialization was assessed blindly by digital planimetry, and bacterial growth was assessed as the number of colony-forming units cultured from surface swabs. Hypochlorous acid solution increased the degree of re-epithelialization on day 4 by 14% compared with the control solution (95% confidence interval (CI) 6.8–20%, p = 0.00051) and was not inferior (p < 0.0001) to the control solution on day 10 (0.3%, 95% CI –1.3–1.9%). Median bacterial counts were lower with stabilized hypochlorous acid compared with control and were further reduced after irrigation and treatment of both groups on day 4, but remained lower in the stabilized hypochlorous acid group compared with the control group. This study demonstrates immediate and durable antimicrobial action and a beneficial effect on acute wound healing after irrigation and treatment with a stabilized hypochlorous acid formulation.
Angerås MH, Brandberg A, Falk A, Seeman T. Comparison between sterile saline and tap water for the cleaning of acute traumatic soft tissue wounds. Eur J Surg 1992; 158: 347-350.
Cruse PJ, Foord R. A five-year prospective study of 23,649 surgical wounds. Arch Surg 1973; 107: 206-210.
https://doi.org/10.1001/archsurg.1973.01350200078018 DOI: https://doi.org/10.1001/archsurg.1973.01350200078018
Nicks BA, Ayello EA, Woo K, Nitzki-George D, Sibbald RG. Acute wound management: revisiting the approach to assessment, irrigation, and closure considerations. Int J Emerg Med 2010; 3: 399-407.
https://doi.org/10.1007/s12245-010-0217-5 DOI: https://doi.org/10.1007/s12245-010-0217-5
Burian EA, Sabah L, Kirketerp-Møller K, Ibstedt E, Fazli MM, Gundersen G. The safety and antimicrobial properties of stabilized hypochlorous acid in acetic acid buffer for the treatment of acute wounds - a human pilot study and in vitro data. Int J Low Extrem Wounds 2021: 15347346211015656.
https://doi.org/10.1177/15347346211015656 DOI: https://doi.org/10.1177/15347346211015656
Ono T, Yamashita K, Murayama T, Sato T. Microbicidal effect of weak acid hypochlorous solution on various microorganisms. Biocontrol Sci 2012; 17: 129-133.
https://doi.org/10.4265/bio.17.129 DOI: https://doi.org/10.4265/bio.17.129
Wang L, Bassiri M, Najafi R, Najafi K, Yang J, Khosrovi B, et al. Hypochlorous acid as a potential wound care agent: part I. Stabilized hypochlorous acid: a component of the inorganic armamentarium of innate immunity. J Burns Wounds 2007; 6: e5.
Sakarya S, Gunay N, Karakulak M, Ozturk B, Ertugrul B. Hypochlorous acid: an ideal wound care agent with powerful microbicidal, antibiofilm, and wound healing potency. Wounds 2014; 26: 342-350.
da Costa MC, Ferreira BA, de Moura FBR, de Lima LG, Araujo FA, Mota FCD. Evaluation of 4% stabilized sodium hypochlorite activity in the repair of cutaneous excisional wounds in mice. Injury 2021; 52: 2075-2083.
https://doi.org/10.1016/j.injury.2021.05.035 DOI: https://doi.org/10.1016/j.injury.2021.05.035
Ågren MS, Chafranska L, Eriksen JO, Forman JL, Bjerrum MJ, Schjerling P, et al. Spatial expression of metallothionein, matrix metalloproteinase-1 and Ki-67 in human epidermal wounds treated with zinc and determined by quantitative immunohistochemistry: a randomised double-blind trial. Eur J Cell Biol 2021; 100: 151147.
https://doi.org/10.1016/j.ejcb.2020.151147 DOI: https://doi.org/10.1016/j.ejcb.2020.151147
Ahlström MG, Gjerdrum LMR, Larsen HF, Fuchs C, Sørensen AL, Forman JL, et al. Suction blister lesions and epithelialization monitored by optical coherence tomography. Skin Res Technol 2018; 24: 65-72.
https://doi.org/10.1111/srt.12391 DOI: https://doi.org/10.1111/srt.12391
Kiistala U. Dermal-epidermal separation. I. The influence of age, sex and body region on suction blister formation in human skin. Ann Clin Res 1972; 4: 10-22.
Kiistala U. Dermal-epidermal separation. II. External factors in suction blister formation with special reference to the effect of temperature. Ann Clin Res 1972; 4: 236-246.
Kiistala U, Mustakallio KK, Rorsman H. Suction blisters in the study of cellular dynamics of inflammation. Acta Derm Venereol 1967; 47: 150-153.
Kjaer M, Frederiksen AKS, Nissen NI, Willumsen N, van Hall G, Jorgensen LN, et al. Multinutrient supplementation increases collagen synthesis during early wound repair in a randomized controlled trial in patients with inguinal hernia. J Nutr 2020; 150: 792-799.
https://doi.org/10.1093/jn/nxz324 DOI: https://doi.org/10.1093/jn/nxz324
Larsen HF, Ahlström MG, Gjerdrum LMR, Mogensen M, Ghathian K, Calum H, et al. Noninvasive measurement of reepithelialization and microvascularity of suction-blister wounds with benchmarking to histology. Wound Repair Regen 2017; 25: 984-993.
https://doi.org/10.1111/wrr.12605 DOI: https://doi.org/10.1111/wrr.12605
Mirastschijski U, Schwab I, Coger V, Zier U, Rianna C, He W, et al. Lung surfactant accelerates skin wound healing: a translational study with a randomized clinical phase I study. Sci Rep 2020; 10: 2581.
https://doi.org/10.1038/s41598-020-59394-5 DOI: https://doi.org/10.1038/s41598-020-59394-5
Hatje LK, Richter C, Blume-Peytavi U, Kottner J. Blistering time as a parameter for the strength of dermoepidermal adhesion: a systematic review and meta-analysis. Br J Dermatol 2015; 172: 323-330.
https://doi.org/10.1111/bjd.13298 DOI: https://doi.org/10.1111/bjd.13298
Ågren MS, Phothong N, Burian EA, Mogensen M, Haedersdal M, Jorgensen LN. Topical zinc oxide assessed in two human wound-healing models. Acta Derm Venereol 2021; 101: adv00465.
https://doi.org/10.2340/00015555-3829 DOI: https://doi.org/10.2340/00015555-3829
Bay L, Kragh KN, Eickhardt SR, Poulsen SS, Gjerdrum LMR, Ghathian K, et al. Bacterial aggregates establish at the edges of acute epidermal wounds. Adv Wound Care (New Rochelle) 2018; 7: 105-113.
https://doi.org/10.1089/wound.2017.0770 DOI: https://doi.org/10.1089/wound.2017.0770
Daeschlein G, Alborova J, Patzelt A, Kramer A, Lademann J. Kinetics of physiological skin flora in a suction blister wound model on healthy subjects after treatment with water-filtered infrared-A radiation. Skin Pharmacol Physiol 2012; 25: 73-77.
https://doi.org/10.1159/000332753 DOI: https://doi.org/10.1159/000332753
Halstead FD, Rauf M, Moiemen NS, Bamford A, Wearn CM, Fraise AP, et al. The antibacterial activity of acetic acid against biofilm-producing pathogens of relevance to burns patients. PLoS One 2015; 10: e0136190.
https://doi.org/10.1371/journal.pone.0136190 DOI: https://doi.org/10.1371/journal.pone.0136190
Robson MC, Payne WG, Ko F, Mentis M, Donati G, Shafii SM, et al. Hypochlorous acid as a potential wound care agent: part II. Stabilized hypochlorous acid: its role in decreasing tissue bacterial bioburden and overcoming the inhibition of infection on wound healing. J Burns Wounds 2007; 6: e6.
Badia JM, Torres JM, Tur C, Sitges-Serra A. Saline wound irrigation reduces the postoperative infection rate in guinea pigs. J Surg Res 1996; 63: 457-459.
https://doi.org/10.1006/jsre.1996.0292 DOI: https://doi.org/10.1006/jsre.1996.0292
Hansson C, Hoborn J, Moller A, Swanbeck G. The microbial flora in venous leg ulcers without clinical signs of infection. Repeated culture using a validated standardised microbiological technique. Acta Derm Venereol 1995; 75: 24-30.
Tomic-Canic M, Burgess JL, O'Neill KE, Strbo N, Pastar I. Skin microbiota and its interplay with wound healing. Am J Clin Dermatol 2020; 21: 36-43.
https://doi.org/10.1007/s40257-020-00536-w DOI: https://doi.org/10.1007/s40257-020-00536-w
Tomic-Canic M, Wong LL, Smola H. The epithelialisation phase in wound healing: options to enhance wound closure. J Wound Care 2018; 27: 646-658.
https://doi.org/10.12968/jowc.2018.27.10.646 DOI: https://doi.org/10.12968/jowc.2018.27.10.646
Ågren MS, Mirastschijski U, Karlsmark T, Saarialho-Kere UK. Topical synthetic inhibitor of matrix metalloproteinases delays epidermal regeneration of human wounds. Exp Dermatol 2001; 10: 337-348.
https://doi.org/10.1034/j.1600-0625.2001.100506.x DOI: https://doi.org/10.1034/j.1600-0625.2001.100506.x
Pilcher BK, Dumin JA, Sudbeck BD, Krane SM, Welgus HG, Parks WC. The activity of collagenase-1 is required for keratinocyte migration on a type I collagen matrix. J Cell Biol 1997; 137: 1445-1457.
https://doi.org/10.1083/jcb.137.6.1445 DOI: https://doi.org/10.1083/jcb.137.6.1445
Michopoulou A, Rousselle P. How do epidermal matrix metalloproteinases support re-epithelialization during skin healing? Eur J Dermatol 2015; 25: 33-42.
https://doi.org/10.1684/ejd.2015.2553 DOI: https://doi.org/10.1684/ejd.2015.2553
Springman EB, Angleton EL, Birkedal-Hansen H, Van Wart HE. Multiple modes of activation of latent human fibroblast collagenase: evidence for the role of a Cys73 active-site zinc complex in latency and a "cysteine switch" mechanism for activation. Proc Natl Acad Sci U S A 1990; 87: 364-368.
https://doi.org/10.1073/pnas.87.1.364 DOI: https://doi.org/10.1073/pnas.87.1.364
Draelos ZD. Antipruritic hydrogel for the treatment of atopic dermatitis: an open-label pilot study. Cutis 2012; 90: 97-102.
Fukuyama T, Martel BC, Linder KE, Ehling S, Ganchingco JR, Baumer W. Hypochlorous acid is antipruritic and anti-inflammatory in a mouse model of atopic dermatitis. Clin Exp Allergy 2018; 48: 78-88.
https://doi.org/10.1111/cea.13045 DOI: https://doi.org/10.1111/cea.13045
Portugal-Cohen M, Kohen R. Non-invasive evaluation of skin cytokines secretion: an innovative complementary method for monitoring skin disorders. Methods 2013; 61: 63-68.
https://doi.org/10.1016/j.ymeth.2012.10.002 DOI: https://doi.org/10.1016/j.ymeth.2012.10.002
Cialfi S, Calabro S, Franchitto M, Zonfrilli A, Screpanti I, Talora C. Hypotonic, acidic oxidizing solution containing hypochlorous acid (HClO) as a potential treatment of Hailey-Hailey disease. Molecules 2019; 24: 4427.
https://doi.org/10.3390/molecules24244427 DOI: https://doi.org/10.3390/molecules24244427
Glaser R, Kiecolt-Glaser JK, Marucha PT, MacCallum RC, Laskowski BF, Malarkey WB. Stress-related changes in proinflammatory cytokine production in wounds. Arch Gen Psychiatry 1999; 56: 450-456.
https://doi.org/10.1001/archpsyc.56.5.450 DOI: https://doi.org/10.1001/archpsyc.56.5.450
Pfeifer AC, Schroeder-Pfeifer P, Schneider E, Schick M, Heinrichs M, Bodenmann G, et al. Oxytocin and positive couple interaction affect the perception of wound pain in everyday life. Mol Pain 2020; 16: 1744806920918692.
https://doi.org/10.1177/1744806920918692 DOI: https://doi.org/10.1177/1744806920918692
Cheng YR, Jiang BY, Chen CC. Acid-sensing ion channels: dual function proteins for chemo-sensing and mechano-sensing. J Biomed Sci 2018; 25: 46.
https://doi.org/10.1186/s12929-018-0448-y DOI: https://doi.org/10.1186/s12929-018-0448-y
Wang K, Luo Y, Asaki T, Graven-Nielsen T, Cairns BE, Arendt-Nielsen T, et al. Acid-induced experimental muscle pain and hyperalgesia with single and repeated infusion in human forearm. Scand J Pain 2017; 17: 260-266.
https://doi.org/10.1016/j.sjpain.2017.07.012 DOI: https://doi.org/10.1016/j.sjpain.2017.07.012
How to Cite
Copyright (c) 2022 Ewa A. Burian, Lubna Sabah, Klaus Kirketerp-Møller, Glenn Gundersen, Magnus S. Ågren
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
All digitalized ActaDV contents is available freely online. The Society for Publication of Acta Dermato-Venereologica owns the copyright for all material published until volume 88 (2008) and as from volume 89 (2009) the journal has been published fully Open Access, meaning the authors retain copyright to their work.
Unless otherwise specified, all Open Access articles are published under CC-BY-NC licences, allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material for non-commercial purposes, provided proper attribution to the original work.