**4. Discussion**

Twenty‐four patients (36%) in the TWO2 group and 19 patients (28%) in the CCD group were MRSA positive. Following treatment, MRSA was eliminated in 11 patients (46%), while zero

The proportion of ulcers completely healed by 12 weeks was 76% (*n* = 51/67) in patients managed with TWO2 compared to 46% (*n* = 30/65) in patients managed with CCD (*P* < 0.0001). The mean reduction in ulcer surface area at 12 weeks was 96% in the TWO2 therapy group (**Figure 2**) compared to 61% in patients managed with CCD. The median time to full ulcer healing was 57 days in the TWO2 group in contrast to 107 days in patients managed with CCD (*P* < 0.0001). Healing time for patients managed with TWO2 was not affected by the extent of time of the ulcer and its size. In fact, ulcers managed with TWO2 had a considerably shorter healing time, when compared to CCD ulcers, regardless of duration (*P* < 0.0001) or ulcer size (*P* < 0.0001). TWO2 patients had a significantly improved Q‐TWiST compared to CCD patients,

cases of MRSA were eliminated in the CCD group.

314 Wound Healing - New insights into Ancient Challenges

denoting an improved outcome (*p* < 0.0001).

**Figure 2.** Significant healing and decrease in ulcer surface area post 9 weeks of TWO2 therapy.

periphery. This might be the reason for the absence of scarring and recurrence.

In all, three of the patients managed with TWO2 were referred to our facility for primary amputation following the failure of other treatment modalities, including skin grafting. These three ulcers fully healed with no need for amputation in any case. After 36 months of follow‐ up, 14 of the 30 healed CCD ulcers showed recurrence compared to three of the 51 TWO2‐ healed ulcers. Two CCD‐managed ulcers that had not completely healed showed signs of deterioration and increase in surface area (*P* < 0.0001). All the cases that healed with TWO2 showed reversed gradient healing phenomena where the ulcer healed from the centre to the The socio‐economic consequences of management of RVU, merged with high recurrence rates, have encouraged the development of a disruptive technology innovative therapy, such as TWO2 therapy. Compression therapy within the setup of a leg ulcer clinic is widely recognised as the main modality for managing venous leg ulcers [17, 18, 51, 52]. A previous study mentioned that contemporary dressing materials do not stimulate healing, and expenses are not clinically justified as they have no proven efficacy [19]. After 30 years of research, there is no data to defend using anything other than a simple, inexpensive, low‐adherence dressing under multilayer compression [19].

The first publication on the use of TWO2 was by Fischer in 1969 [20]. Fischer noted that lesions became aseptic and enhanced granulation was witnessed two days after TWO2. In a prospec‐ tive randomised study by Heng et al. red granulation tissue was present one week after TWO2 [27]. Heng noted an absence of clinical scarring and most ulcers healed within 2–16 weeks. Gordillo et al. conducted a study on full‐body hyperbaric oxygen (HBO) therapy versus TWO2. Topical oxygen treatment showed a significant reduction in wound size and was associated with higher vascular endothelial growth factor (VEGF)165 expression in healing wounds [53].

Blackman et al. explored the efficacy of topical oxygen therapy as an adjunctive modality in repairing diabetic ulcers that failed to heal by best practice standard wound care. The healing rate after 12 weeks of topical wound oxygen therapy was 82.4%, and the mean time to complete healing was reduced. Patients also showed very low recurrence rates after 18 months [54].

Results from the Venous ULcer Cost‐effectiveness of Antimicrobial dressings (VULCAN) trial showed that it took 101 days to heal 3‐cm ulcers, while there was a 1‐year recurrence rate of 14% in 86% of small ulcers [55], using silver dressings. These types of dressings are now rarely seen in a standard tertiary vein unit. In our unit, we have abandoned the use of silver dressing in any form as it showed a higher incidence of contacting eczema and an increase in the chronicity of the wounds.

Oxygen plays a major role in the promotion of vascular endothelial cell proliferation, collagen synthesis [56, 57] and infection control [58] by providing a direct microbial growth inhibitory effect [59] and also by activating neutrophils [60]. TWO2 therapy evades the consequences of a full‐body hyperbaric chamber [61], such as grand mal seizures and pulmonary oxygen toxicity [61, 62]. There is also the high associated cost of acquiring and maintaining a chamber to consider.

Utilising diffused oxygen raises the capillary partial pressure of oxygen (Po2) levels at the wound site, stimulating epithelialisation and granulation of new healthy tissue [29, 32]. Oxygen generates reactive oxygen species at the wound site, acting as signalling substances, which increase the production of VEGF [63, 64]. Repeated treatment therefore accelerates wound closure.

TWO2 therapy enhances both polymorph nuclear function and bacterial clearance and is fatal to anaerobic bacteria [35–37]. It reduces neutrophil adherence based on hindering the β‐2 integrin function [38]. Eleven patients (46%) with MRSA were negative at the end of treatment with TWO2. This informs us of its effectiveness against MRSA infection in comparison to CCD. TWO2 therapy supports and strengthens antibiotic distribution for aminoglycosides, cephalosporins, quinilones and amphotericin [39, 40].

While TWO2 therapy has been available for many years, there is paucity in clinical evidence for its safety and efficacy. Experience from our clinic shows that TWO2 therapy is effective and valuable in managing RVU. Our course of therapy accomplished enhanced wound healing time, without complications, in a relatively large number of patients. TWO2 therapy drastically reduced the time required for RVU healing and recurrence rates when compared to CCD. Quality of time spent without symptoms or toxicity of the disease was significantly improved in TWO2 managed patients compared to CCD patients (*p* < 0.0001).
