Oxygen Therapy in Wound Healing

  • Marjam J. Barysch
  • Severin LäuchliEmail author
Part of the Updates in Clinical Dermatology book series (UCD)


Background: Oxygen is mandatory for almost all wound healing processes, in particular the processes of cell regeneration and angiogenesis. As it is lacking in chronic and even acute wounds, oxygen substitution seems to be an obvious adjuvant tool. In vitro and in vivo tests showed improvement of microenvironment essential for the onset of appropriate healing processes.

Oxygen substitution can be delivered in the form of hyperbaric oxygen therapy (HBOT) or topical oxygen therapy (TOT). The latter can be applied in the form of continuous or cyclic pressurized oxygen therapy, continuous non-pressurized oxygen, oxygen containing wound dressings, and oxygen transferring sprays/solutions or gels. There are numerous studies, case series, and other publications recommending the application of oxygen therapy. In contrast to HBOT, randomized controlled clinical trials are rare for the majority of TOT.

Conclusions: Oxygen therapy has raised expectations due to known pathophysiology and in vitro tests. Nonetheless, integration into routine practice is lacking either due to complexity for HBOT procedure or due to fragmentary or even contradictory clinical data for some approaches of TOT. However, simplicity of application, safety, cost-effectiveness, impressive case studies, and in vitro tests justify the application of many topical oxygen therapies in clinical routine. Nevertheless, further clinical controlled trials in a randomized setting are warranted.


Wounds Oxygen therapy Wound healing Hypoxia Hyperbaric treatment Topical oxygen therapy Peripheral arterial occlusive disease Chronic venous insufficiency Diabetic ulcer Angiogenesis 



Atmosphere absolute


Adenosine triphosphate


Chronic venous insufficiency


Diabetic foot ulcer


Endothelial progenitor cells


Hyperbaric oxygen therapy


Hypoxia-inducible factor




Moisture balance, Oxygen balance, Infection control, Support, Tissue management


Nitric oxide


NADPH oxidase


NADPH oxidase 2


Peripheral arterial disease


Arterial wounds associated with peripheral arterial occlusive disease


Peripheral vascular disease


Reactive oxidative species


Reactive oxygen species


Transcutaneous oximetry


Tissue removal, Infection control, Moisture balance, Edge advancement


Tumor necrosis factor-alpha


Topical oxygen therapies


Vascular endothelial growth factor


  1. 1.
    Gottrup F. Oxygen in wound healing and infection. World J Surg. 2004;28(3):312–5.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Dissemond J, Kroger K, Storck M, Risse A, Engels P. Topical oxygen wound therapies for chronic wounds: a review. J Wound Care. 2015;24(2):53–4, 6–60, 2–3CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Kranke P, Bennett MH, Martyn-St James M, Schnabel A, Debus SE, Weibel S. Hyperbaric oxygen therapy for chronic wounds. Cochrane Database Syst Rev. 2015;(6):CD004123.Google Scholar
  4. 4.
    Fife CE, Smart DR, Sheffield PJ, Hopf HW, Hawkins G, Clarke D. Transcutaneous oximetry in clinical practice: consensus statements from an expert panel based on evidence. Undersea Hyperb Med. 2009;36(1):43–53.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Sen CK. Wound healing essentials: let there be oxygen. Wound Repair Regen. 2009;17(1):1–18.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Gottrup F, Dissemond J, Baines C, Frykberg R, Jensen PO, Kot J, et al. Use of oxygen therapies in wound healing. J Wound Care. 2017;26(Sup5):S1–S43.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Chiang B, Essick E, Ehringer W, Murphree S, Hauck MA, Li M, et al. Enhancing skin wound healing by direct delivery of intracellular adenosine triphosphate. Am J Surg. 2007;193(2):213–8.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Wang Y, Zeigler MM, Lam GK, Hunter MG, Eubank TD, Khramtsov VV, et al. The role of the NADPH oxidase complex, p38 MAPK, and Akt in regulating human monocyte/macrophage survival. Am J Respir Cell Mol Biol. 2007;36(1):68–77.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Jesaitis AJ, Franklin MJ, Berglund D, Sasaki M, Lord CI, Bleazard JB, et al. Compromised host defense on Pseudomonas aeruginosa biofilms: characterization of neutrophil and biofilm interactions. J Immunol. 2003;171(8):4329–39.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Proctor RA. Endotoxin in vitro interactions with human neutrophils: depression of chemiluminescence, oxygen consumption, superoxide production, and killing. Infect Immun. 1979;25(3):912–21.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Kolpen M, Hansen CR, Bjarnsholt T, Moser C, Christensen LD, van Gennip M, et al. Polymorphonuclear leucocytes consume oxygen in sputum from chronic Pseudomonas aeruginosa pneumonia in cystic fibrosis. Thorax. 2010;65(1):57–62.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Campbell EL, Bruyninckx WJ, Kelly CJ, Glover LE, McNamee EN, Bowers BE, et al. Transmigrating neutrophils shape the mucosal microenvironment through localized oxygen depletion to influence resolution of inflammation. Immunity. 2014;40(1):66–77.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Fazli M, Bjarnsholt T, Kirketerp-Moller K, Jorgensen A, Andersen CB, Givskov M, et al. Quantitative analysis of the cellular inflammatory response against biofilm bacteria in chronic wounds. Wound Repair Regen. 2011;19(3):387–91.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    James GA, Ge Zhao A, Usui M, Underwood RA, Nguyen H, Beyenal H, et al. Microsensor and transcriptomic signatures of oxygen depletion in biofilms associated with chronic wounds. Wound Repair Regen. 2016;24(2):373–83.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Dowd SE, Sun Y, Secor PR, Rhoads DD, Wolcott BM, James GA, et al. Survey of bacterial diversity in chronic wounds using pyrosequencing, DGGE, and full ribosome shotgun sequencing. BMC Microbiol. 2008;8:43.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Oates A, Bowling FL, Boulton AJ, Bowler PG, Metcalf DG, McBain AJ. The visualization of biofilms in chronic diabetic foot wounds using routine diagnostic microscopy methods. J Diabetes Res. 2014;2014:153586.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Cianci P. Adjunctive hyperbaric oxygen therapy in the treatment of the diabetic foot. J Am Podiatr Med Assoc. 1994;84(9):448–55.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Banks M, Bauer J, Graves N, Ash S. Malnutrition and pressure ulcer risk in adults in Australian health care facilities. Nutrition. 2010;26(9):896–901.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Wild T, Rahbarnia A, Kellner M, Sobotka L, Eberlein T. Basics in nutrition and wound healing. Nutrition. 2010;26(9):862–6.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Weingarten MS, Samuels JA, Neidrauer M, Mao X, Diaz D, McGuire J, et al. Diffuse near-infrared spectroscopy prediction of healing in diabetic foot ulcers: a human study and cost analysis. Wound Repair Regen. 2012;20(6):911–7.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Daeschlein G, Rutkowski R, Lutze S, von Podewils S, Sicher C, Wild T, et al. Hyperspectral imaging: innovative diagnostics to visualize hemodynamic effects of cold plasma in wound therapy. Biomed Tech (Berl). 2018;63(5):603–8.CrossRefGoogle Scholar
  22. 22.
    Fife CE, Buyukcakir C, Otto GH, Sheffield PJ, Warriner RA, Love TL, et al. The predictive value of transcutaneous oxygen tension measurement in diabetic lower extremity ulcers treated with hyperbaric oxygen therapy: a retrospective analysis of 1,144 patients. Wound Repair Regen. 2002;10(4):198–207.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Perren S, Gatt A, Papanas N, Formosa C. Hyperbaric oxygen therapy in ischaemic foot ulcers in type 2 diabetes: a clinical trial. Open Cardiovasc Med J. 2018;12:80–5.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Korhonen K. Hyperbaric oxygen therapy in acute necrotizing infections. With a special reference to the effects on tissue gas tensions. Ann Chir Gynaecol. 2000;89 Suppl 214:7–36.Google Scholar
  25. 25.
    Cimsit M, Uzun G, Yildiz S. Hyperbaric oxygen therapy as an anti-infective agent. Expert Rev Anti-Infect Ther. 2009;7(8):1015–26.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Kendall AC, Whatmore JL, Harries LW, Winyard PG, Smerdon GR, Eggleton P. Changes in inflammatory gene expression induced by hyperbaric oxygen treatment in human endothelial cells under chronic wound conditions. Exp Cell Res. 2012;318(3):207–16.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Sanford NE, Wilkinson JE, Nguyen H, Diaz G, Wolcott R. Efficacy of hyperbaric oxygen therapy in bacterial biofilm eradication. J Wound Care. 2018;27(Sup1):S20–S8.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Gallagher KA, Goldstein LJ, Thom SR, Velazquez OC. Hyperbaric oxygen and bone marrow-derived endothelial progenitor cells in diabetic wound healing. Vascular. 2006;14(6):328–37.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Thom SR, Fisher D, Zhang J, Bhopale VM, Ohnishi ST, Kotake Y, et al. Stimulation of perivascular nitric oxide synthesis by oxygen. Am J Physiol Heart Circ Physiol. 2003;284(4):H1230–9.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Sen CK. Redox signaling and the emerging therapeutic potential of thiol antioxidants. Biochem Pharmacol. 1998;55(11):1747–58.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Londahl M, Katzman P, Nilsson A, Hammarlund C. Hyperbaric oxygen therapy facilitates healing of chronic foot ulcers in patients with diabetes. Diabetes Care. 2010;33(5):998–1003.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Duzgun AP, Satir HZ, Ozozan O, Saylam B, Kulah B, Coskun F. Effect of hyperbaric oxygen therapy on healing of diabetic foot ulcers. J Foot Ankle Surg. 2008;47(6):515–9.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Liu R, Li L, Yang M, Boden G, Yang G. Systematic review of the effectiveness of hyperbaric oxygenation therapy in the management of chronic diabetic foot ulcers. Mayo Clin Proc. 2013;88(2):166–75.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Hadanny A, Meir O, Bechor Y, Fishlev G, Bergan J, Efrati S. The safety of hyperbaric oxygen treatment–retrospective analysis in 2,334 patients. Undersea Hyperb Med. 2016;43(2):113–22.PubMedPubMedCentralGoogle Scholar
  35. 35.
    Mathieu D, Marroni A, Kot J. Tenth European consensus conference on hyperbaric medicine: preliminary report. Diving Hyperb Med. 2016;46(2):122–3.PubMedPubMedCentralGoogle Scholar
  36. 36.
    Rancourt RC, Hayes DD, Chess PR, Keng PC, O’Reilly MA. Growth arrest in G1 protects against oxygen-induced DNA damage and cell death. J Cell Physiol. 2002;193(1):26–36.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Edmonds J. Nutrition and wound healing: putting theory into practice. Br J Community Nurs. 2007;12(12):S31–4.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Gordillo GM, Roy S, Khanna S, Schlanger R, Khandelwal S, Phillips G, et al. Topical oxygen therapy induces vascular endothelial growth factor expression and improves closure of clinically presented chronic wounds. Clin Exp Pharmacol Physiol. 2008;35(8):957–64.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Heng MC, Harker J, Csathy G, Marshall C, Brazier J, Sumampong S, et al. Angiogenesis in necrotic ulcers treated with hyperbaric oxygen. Ostomy Wound Manage. 2000;46(9):18–28, 30–2PubMedPubMedCentralGoogle Scholar
  40. 40.
    Leslie CA, Sapico FL, Ginunas VJ, Adkins RH. Randomized controlled trial of topical hyperbaric oxygen for treatment of diabetic foot ulcers. Diabetes Care. 1988;11(2):111–5.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Gordillo GM, Sen CK. Evidence-based recommendations for the use of topical oxygen therapy in the treatment of lower extremity wounds. Int J Low Extrem Wounds. 2009;8(2):105–11.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Tawfick WA, Sultan S. Technical and clinical outcome of topical wound oxygen in comparison to conventional compression dressings in the management of refractory nonhealing venous ulcers. Vasc Endovasc Surg. 2013;47(1):30–7.CrossRefGoogle Scholar
  43. 43.
    Tawfick W, Sultan S. Does topical wound oxygen (TWO2) offer an improved outcome over conventional compression dressings (CCD) in the management of refractory venous ulcers (RVU)? A parallel observational comparative study. Eur J Vasc Endovasc Surg. 2009;38(1):125–32.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Niederauer MQ, Michalek JE, Armstrong DG. A prospective, randomized, double-blind multicenter study comparing continuous diffusion of oxygen therapy to sham therapy in the treatment of diabetic foot ulcers. J Diabetes Sci Technol. 2017;11(5):883–91.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Niederauer MQ, Michalek JE, Liu Q, Papas KK, Lavery LA, Armstrong DG. Continuous diffusion of oxygen improves diabetic foot ulcer healing when compared with a placebo control: a randomised, double-blind, multicentre study. J Wound Care. 2018;27(Sup9):S30–45.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Yu J, Lu S, McLaren AM, Perry JA, Cross KM. Topical oxygen therapy results in complete wound healing in diabetic foot ulcers. Wound Repair Regen. 2016;24(6):1066–72.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Davis P, Wood L, Wood Z, Eaton A, Wilkins J. Clinical experience with a glucose oxidase-containing dressing on recalcitrant wounds. J Wound Care. 2009;18(3):114. 6-21Google Scholar
  48. 48.
    Lo JF, Brennan M, Merchant Z, Chen L, Guo S, Eddington DT, et al. Microfluidic wound bandage: localized oxygen modulation of collagen maturation. Wound Repair Regen. 2013;21(2):226–34.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Wood L, Wood Z, Davis P, Wilkins J. Clinical experience with an antimicrobial hydrogel dressing on recalcitrant wounds. J Wound Care. 2010;19(7):287–8, 90–3CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Chandra PK, Ross CL, Smith LC, Jeong SS, Kim J, Yoo JJ, et al. Peroxide-based oxygen generating topical wound dressing for enhancing healing of dermal wounds. Wound Repair Regen. 2015;23(6):830–41.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Scholander PF. Oxygen transport through hemoglobin solutions. Science. 1960;131(3400):585–90.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Petri M, Stoffels I, Jose J, Leyh J, Schulz A, Dissemond J, et al. Photoacoustic imaging of real-time oxygen changes in chronic leg ulcers after topical application of a haemoglobin spray: a pilot study. J Wound Care. 2016;25(2):87, 9–91CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Arenbergerova M, Engels P, Gkalpakiotis S, Dubska Z, Arenberger P. Topical hemoglobin promotes wound healing of patients with venous leg ulcers. Hautarzt. 2013;64(3):180–6.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Hunt S, Elg F. The clinical effectiveness of haemoglobin spray as adjunctive therapy in the treatment of chronic wounds. J Wound Care. 2017;26(9):558–68.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Tickle J. A topical haemoglobin spray for oxygenating pressure ulcers: a pilot study. Br J Community Nurs. 2015;Suppl Wound Care:S12, S4–8.Google Scholar
  56. 56.
    Tickle J, Bateman SD. Use of a topical haemoglobin spray for oxygenating pressure ulcers: healing outcomes. Br J Community Nurs. 2015;20(Suppl 12):S14–21.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Eftekharizadeh F, Dehnavieh R, Noori Hekmat S, Mehrolhassani MH. Health technology assessment on super oxidized water for treatment of chronic wounds. Med J Islam Repub Iran. 2016;30:384.PubMedPubMedCentralGoogle Scholar
  58. 58.
    Kammerlander G, Assadian O, Eberlein T, Zweitmuller P, Luchsinger S, Andriessen A. A clinical evaluation of the efficacy and safety of singlet oxygen in cleansing and disinfecting stagnating wounds. J Wound Care. 2011;20(4):149–50, 52, 54 passim.Google Scholar
  59. 59.
    Kellar RS, Audet RG, Roe DF, Rheins LA, Draelos ZD. Topically delivered dissolved oxygen reduces inflammation and positively influences structural proteins in healthy intact human skin. J Cosmet Dermatol. 2013;12(2):86–95.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Posnett J, Gottrup F, Lundgren H, Saal G. The resource impact of wounds on health-care providers in Europe. J Wound Care. 2009;18(4):154–61.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Dale JJ, Callam MJ, Ruckley CV, Harper DR, Berrey PN. Chronic ulcers of the leg: a study of prevalence in a Scottish community. Health Bull (Edinb). 1983;41(6):310–4.Google Scholar
  62. 62.
    Hjort A, Gottrup F. Cost of wound treatment to increase significantly in Denmark over the next decade. J Wound Care. 2010;19(5):173. –4, 6, 8, 80, 82, 84Google Scholar
  63. 63.
    Dissemond J, Assenheimer B, Engels P, Gerber V, Kroger K, Kurz P, et al. M.O.I.S.T. – a concept for the topical treatment of chronic wounds. J Dtsch Dermatol Ges. 2017;15(4):443–5.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Department of Dermatology, University Hospital ZurichZurichSwitzerland
  2. 2.Dermatologic Centre ZurichZurichSwitzerland

Personalised recommendations