Oxygen has long been recognized as an essential component in the wound healing process. Among other functions, it is essential for collagen production, redox signaling for intracellular synthesis of growth factors, angiogenesis, the “respiratory burst” leading to production of antimicrobial compounds such as Reactive Oxygen Species (ROS) and H2O2, and for cellular ATP synthesis. In fact, wound healing cannot occur without Oxygen at sufficient levels to drive these processes.

Accordingly, Oxygen therapies have been used in clinical practice for more than fifty years to manage acute and chronic wounds such as diabetic foot ulcers (DFU), venous leg ulcers, and pressure ulcers. While most are familiar with the use of systemic Hyperbaric Oxygen Therapy (HBOT), clinicians have been utilizing Topical Oxygen Therapies (TOT) for many years as well. While a number of hypothetical, clinical, and animal studies have supported the positive effects of both systemic and topical oxygen therapy on wound healing, there has heretofore been a paucity of supportive evidence based on formal controlled clinical trials.

The deficiencies in the body of evidence advocating TOT for the healing of chronic wounds necessitated further 1A level scientific investigation. We therefore conducted a state-of-the-art RCT to explore the efficacy of cyclical pressurized Topical Wound Oxygen (TWO2) homecare therapy in healing recalcitrant DFU that had been proven failures to heal with the best Standard of Care (SOC) alone.

The device investigated in this trial was the Cyclical Topical Wound Oxygen therapy (TWO2) system manufactured by AOTI Ltd. The TWO2 System operates by applying cyclical oxygen pressure directly to the wound site within a sealed and humidified environment. Achieving Oxygen partial pressure tensions up to 800mmHg, this provides a greater tissue oxygen diffusion gradient and increased tissue oxygenation at the wound surface. Studies have demonstrated that this form of delivery, in a sealed and humidified environment, allows for oxygen to penetrate 3-4 mm into the granulation bed. This enhances antimicrobial actions, stimulates angiogenesis and maximizes collagen production. The cyclical nature of the pressure (from 5 mb to 50 mb) also creates a sequential non-contact compression effect which helps reduce peripheral edema and stimulates wound site perfusion. (Figure 1)

Figure 1. The single use TWO2 homecare device used in the trial

This rigorous RCT utilized a Group Sequential Design with two apriori interim analyses, requiring a significance of p<0.022 at each. All subjects meeting the inclusion/exclusion criteria were enrolled into a two week run-in of SOC that included gold-standard offloading and sharp debridement. Only DFUs not on a proven healing trajectory with SOC alone (<30% wound area reduction) were randomized into the active phase of the study, where they were assigned (double blind) to either active, or sham (placebo) treatment arms. The primary endpoint of the study was ulcers healed at 12 weeks.

Results: At the first interim analysis point of 73 subjects, the active TWO2 arm was shown to have a significantly superior healing rate compared to the sham arm at 12 weeks (41.7% vs 13.5%, Pearson Chi2 = 7.2707, p = 0.007). Multivariable analysis using logistic regression and Cox proportional hazards modelling of the secondary outcome measure of time to heal showed no other covariates achieved significance. The active TWO2 arm showed nearly 4 times the likelihood to heal DFUs in 12 weeks compared to the sham arm HR 3.88 (95%CI 1.40 to 10.71), p = 0.009. With these very significant interim results, the trial was mandated to be terminated early. (See Figure 2)

Figure 2. Proportion of ulcers healed in active and sham treatment groups over time. Note the separation of healing curves as early as week 1.

Figure 3 (below) shows several of the wounds treated successfully during the active treatment phase of the trial.

In conclusion, this landmark study unequivocally demonstrates at the highest scientific level the efficacy of Cyclical Pressure Topical Wound Oxygen Therapy in healing chronic Diabetic Foot Ulcers. We can now reliably advocate TWO2 therapy as a proven treatment adjunctive to excellent standard of care for the expedited healing of these potentially limb threatening wounds.

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“In conclusion, this landmark study unequivocally demonstrates at the highest scientific level the efficacy of Cyclical Pressure Topical Wound Oxygen Therapy in healing chronic Diabetic Foot Ulcers.”

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Regards,

Robert G Frykberg, DPM, MPH