## 1 Introduction  
It has been estimated that 4% annually, and up to 30% in the entire lifetime, of patients with diabetes may experience a foot ulcer [1, 2]. The data suggest a surge in global incidence of diabetes, with which there is a concomitant increase in the global burden of diabetic foot ulcers [3]. A number of factors including bacterial infection, tissue ischemia, ongoing trauma and poor management are major aspects precluding the physiological ulcer healing, often resulting in a chronic, non-healing ulcer formation [4]. The chronic, non-healing foot ulcers are associated with several complication including infections and gangrenees. Furthermore, the diabetic patients with foot ulcers are at a higher risk of amputation [1, 2], as well as a higher risk of requiring re-amputation [5]. Besides, diabetic patients developing foot ulcers are at a much higher risk of death, experiencing an increase in three-yearmortality risk from 13% to 28% [6]. Furthermore, such higher morbidity and mortality burden is associated with a significant psychological and physical stress to the patient, resulting in a poor quality of life [7], as well as with a significant increase in healthcare utilization. The diabetic foot ulcer is thus a major health care concern, incurring significant health care costs [8; 9; 10].  
The risk for foot ulceration is increased in patients with diabetes and chronic kidney disease (CKD) [11]. In this regard, it has been reported that foot ulceration, as well as amputation increased in diabetic patients undergoing dialysis [12]. In addition, the occurrence of foot ulcers in patients with diabetes and CKD receiving dialysis is five times higher compared to pre-dialysis diabetic patients [13]. Hemodialysis has also been linked to a higher risk for peripheral arterial disease (PAD); indeed, hemodialysis causes a reduction in skin microcirculation and tissue oxygenation, leading to ulceration [14]. Interestingly, an improvement in peripheral blood flow in PAD patients in response to CO2 treatment has been reported [15; 16; 17; 18; 19; 20].  
Impairment of microcirculation and the resulting ischemia is at the core of the occurrence of diabetic foot ulcers. Similarly, in patients with PAD, vasoconstriction leads to ischemia and is considered to play a key role in the pathogenesis of foot ulceration [21]. These foot ulcers, secondary to PAD affecting tibial and peroneal arteries, are found in about 50% of cases. The management approach for foot ulcers in patient with diabetes and PAD is to relieve ischemic pain, heal the ulcers and to prevent amputation [22; 23]. CO2 is known to causes vasodilation and therefore bathing limbs in CO2-enriched water will increase blood flow in the skin, given that CO2 can permeate through the skin [20]. The efficacy of CO2-enriched water in healing of diabetic foot ulcers has also been evaluated [24; 25]; however, there are limitations in case studies. Thus, there is a need for an appropriately designed clinical study to determine the efficacy of CO2-enriched water for the treatment of foot ulcers. Furthermore, while several different approaches have been undertaken to examine wound healing [26], only 24-50% of all ulcers are reported to heal after 12 weeks to 6 months of standard treatment [27; 28]. Therefore, there is a need for evaluating novel approaches that may exhibit higher efficacy for the treatment of foot ulcers.  
Accordingly, the present study was undertaken to assess the potential of CO2-enriched water in the treatment of foot ulcers. The study tested the hypothesis that bathing of foot ulcers in CO2-enriched water bath will reduce the size of the foot ulcer. The objectives of the study following treatment with CO2-enriched water were to (1) determine wound area reduction; (2) measure peripheral blood flow; (3) measure oxygen saturation level in the wound and (4) measure blood levels of vascular endothelial growth factor and tumor necrosis factor-\(\alpha\), as well as blood lipid profile, fasting blood glucose and HbA1c.