## 4 Discussion  
We report the creation of HOGP that continuously produces H\({}^{+}\) and O\({}_{2}\), which can effectively penetrate the skin. Due to the controllable chemical reactions within the H\({}^{+}\) and O\({}_{2}\)-generating granules in a moist environment, the gases produced can be absorbed into and permeate the skin tissue, which may further improve H\({}^{+}\) and O\({}_{2}\) penetration to stimulate aerobic metabolism and angiogenesis within hypoxic tissues [38]. Figure 6: Normalized hematological ratios and electrolyte parameters post-application of the HOGP. Normalized Hb and HCT ratio (**A**), and the levels of Na\({}^{+}\), K\({}^{+}\) and Ca\({}^{++}\) (**B**). The normalized ratios (\(y\)-axis) were determined after normalization to the control group. Significant differences were identified using \(t\)-tests (* \(p\) < 0.05). Figure 7: Concentrations of serum cortisol and IL-6 in mice (\(n\) = 6) at different time-points post-application of the HOGP. Significant differences were identified using \(t\)-tests (\(p\) < 0.05). The H\({}^{+}\) and O\({}_{2}\)\({}^{-}\) generating film contain H\({}^{+}\) and O\({}_{2}\)\({}^{-}\) generating granules with a diameter of 18-38 \(\upmu\)m; the granules consume calcium peroxide (CaO\({}_{2}\)) to produce H\({}_{2}\)) and O\({}_{2}\) in response to the moisture in sweat. A polypropylene (PP) membrane with 2-3 \(\upmu\)m apertures is used as the lining of the patch, to ensure bidirectional permeation of clean gases. When the HOGP is affixed to the skin, the impermeable polyurethane film (PE) creates a sealed system and microenvironment between the H\({}^{+}\) and O\({}_{2}\)\({}^{-}\) generating film and the skin (Figure 1B,C). We assume that the levels of H\({}^{+}\) and O\({}_{2}\) in the circulation can be sufficiently raised by the HOGP. Both topical dissolved oxygen (TDO) and topical gaseous oxygen (TGO) can penetrate hydrophilic polytetrafluoroethylene (PTFE) or polypropylene (PP) membranes, which are widely used in medicine, while dissolved H\({}^{+}\) and O\({}_{2}\) from a microalgae-gel patch promoted chronic wound healing [37]. Interestingly, after application of the HOGP, the sweat and moisture-activated H\({}^{+}\) and O\({}_{2}\)\({}^{-}\) generating granules released gas, which resulted in continued, significant increases in the circulating H\({}^{+}\) and O\({}_{2}\) levels for up to 6 h post-administration in vivo compared to control mice. These results indicate the H\({}^{+}\) and O\({}_{2}\) produced by the HOGP were transdermally delivered into blood vessels. Moreover, the application of the HOGP did not alter the levels of hemoglobin (Hb), hematocrit (HCT), sodium (Na\({}^{+}\)), potassium (K\({}^{+}\)), or calcium (Ca\({}^{++}\)). Although the HOGP was sewn to an odorless stretch fabric and applied to the animals, increased levels of stress or stress-induced inflammation markers were not observed in the experimental animals, suggesting the materials or methods employed for the in vivo evaluation were safe and acceptable to the animals. These results imply the potential clinical utility of the HOGP. The depth of transdermal delivery of the gases--not only to the skin tissues but also to the blood circulation--implies the HOGP could possibly be employed for H\({}^{+}\) and O\({}_{2}\) treatment, i.e., an easy-to-handle, long-lasting, moisture-activated face mask could be used to increase blood oxygen levels when wearing face masks for a long time. [PERSON] et al. (2015) designed a wound dressing that produces oxygen in situ, using particulate oxygen generators that consist of a heterogeneous mixture of sodium percarbonate (SPO) and calcium peroxide (CPO). The efficacy of this dressing was tested in a porcine full-thickness surgical wound model and led to better wound closure and faster re-epithelialization [39]. [PERSON] et al. (2020) demonstrated a novel oxygen-producing patch made of a hydrogel of living microalgae, which can produce dissolved oxygen.