July 2023
Valerie Hanft, MD
Zvi Yaniv PhD.

The importance of oxygen:

Oxygen is the fuel required for the proper operation of all body systems. Only 10% of our energy comes from food and water; 90% of our energy comes from oxygen. Oxygen detoxifies free radicals, neutralizes environmental toxins, and destroys anaerobic bacteria, viruses, fungi, and parasites. Without oxygen, cells deteriorate quickly and die. Oxygen helps to reverse the physical and physiological effects of oxygen deprivation from poor health, multiple pollution sources (air, food, water), and aging. Maintaining proper oxygen levels in all body systems is a vital ingredient to health and endurance.

The skin is one of the most important organs, and oxygen benefits to the skin mirror many of its attributes for all body systems. On an epidermal level, oxygen loss affects cellular nourishment and cell division leading to extremely low cell turnover. At the level of the dermis, lack of oxygen impairs fibroblast function which is responsible for collagen and elastin production.

The challenge of oxygen delivery to the skin:

A large amount of oxygen passes into the skin from the atmosphere. This fact allows for the possibility of topical oxygen delivery. Although a small amount is used by the upper layers of the epidermis, the basal layer (deepest layer of the epidermis) consumes most of the epidermal oxygen. P.T. Pugliese, MD emphasizes that without the ability to get the oxygen into the skin first and then down to the basal layer, it will not make any sense for oxygen to be used as a therapeutic modality (published in Skin Inc by P.T. Pugliese, MD, “The Practical Use of Topical Oxygen,” 2008).  Proper topically applied oxygen achieves this task (M. Stucker et al, “The cutaneous uptake of atmospheric oxygen contributes significantly to the oxygen supply of human dermis and epidermis” J.Physiol.538 Pt 3; 984-95, 2008). 

The majority of scientists and dermatologists agree that topical oxygen delivery revitalizes the epidermis and maintains proper cell turnover. Oxygen assists with many metabolic processes and is critical for many enzyme reactions occurring in the skin cells. Oxygen kills anaerobic skin bacteria and promotes the healing of skin wounds and irritation. In the dermis, it promotes collagen and elastin production and helps restructure the extracellular matrix. Dr. Pugliese states that acne, rosacea, and aging skin would all likely respond to topical oxygen therapy. 

Once the properties of topical oxygen delivery for skin care were recognized, an explosion of cosmetic products claiming to deliver oxygen to the skin inundated the market. These include oxygen facials and numerous other products containing buzzwords such as stable oxygen, liquid oxygen, and oxygenating serums. Very few of these products specify the oxygen source and how they actually work to deliver oxygen effectively to the skin. Some of these products propose that hydrogen peroxide is converted to oxygen and water thereby delivering oxygen to the skin. However, this reaction requires a catalyst to produce oxygen at a useful rate, and no such catalysts are included in the ingredients of these products. Furthermore, hydrogen peroxide is an oxidizing agent that dries the skin and may deliver harmful free radicals. 

In 2013 given the abundance of oxygen-based products, researchers in the Dermatology Department of the Mount Sinai School of Medicine posed the question: how can topical oxygen delivery work if there is no evidence that oxygen can penetrate the skin or that it can stay in the product? (A.Strauss, “Oxygen in facial products” New York Times, June 9, 2013 ). Now ten years later in 2023, there are ample demonstrations and scientific papers that prove oxygen can penetrate the epidermal and dermal layers of the skin. However, none of the currently available oxygen products can prove that oxygen is present and stable in an amount that can be useful for the skin. As Dr. Pugliese stated in his paper: “If a company tries to sell you an oxygen treatment without adequate education or instructions, steer clear of it.” 

AO2 Clear—a novel therapeutic option:

AO2 Clear contains only oxygen and distilled water. The product delivers oxygen directly to the skin in the form of dissolved oxygen and oxygen nanobubbles at a concentration of one billion oxygen nanobubbles/mL.

Nanobubble technology is widely used in numerous industries including medicine, water purification, marine farming, wastewater management, and fracking. AO2 Clear is the first product using oxygen nanobubble technology to improve skin health. The size of the nanobubbles (100 nanometers or 10 to the power -7) creates a large surface area that amplifies the oxygen effects. The nanobubbles are negatively charged and so repel each other making them unable to coalesce into larger less effective microbubbles. Because of their nanoscopic volume, they have almost no buoyancy allowing them to be stable in the product for at least one year. (The stability was documented in our laboratory, and results were verified by two independent laboratories.) The unique combined properties of oxygen nanobubbles facilitate their diffusion into the skin and follicles, and this diffusion is driven by the dramatic oxygen gradient between the product and the skin. The stability and the high concentration of pure oxygen in AO2 Clear make it a unique and effective formulation for topical oxygen delivery. 

From the cosmetic point of view, users have reported improvement in hydration and skin texture. User photos have also shown significant clinical improvement in acne (both superficial papules and deep nodules). Because of the known effects of oxygen on the skin, there are also theoretical benefits for reduced signs of aging via increased production of collagen and elastin. 

AO2 Clear is innovative in its oxygen delivery in that it is free of artificial chemicals. It contains only distilled water, oxygen nanobubbles, and dissolved oxygen. Laboratory measurements verify that the oxygen gas in the product is stable and present at a high concentration.

The science behind AO2 Clear’s effectiveness in topical oxygen delivery for skin health:

All cells require a continuous supply of oxygen which is especially true for skin cells. Higher organisms, such as humans, employ an extensive infrastructure to achieve this. The challenge is to avoid local oxygen starvation.

It is now recognized by the medical and scientific communities that a protein called Hypoxia Inducible Factor (HIF)-1 alpha operates in all mammalian cell types and is centrally involved in many aspects of homeostasis. At the heart of HIF-1 alpha factor is the fact that it reacts to molecular oxygen in such a way that it becomes the sensor of the cell’s oxygenation status. It functions to secure the well-being of the cell in hypoxic conditions. HIF-1 alpha factor is a key regulator of a broad range of cellular and systemic responses to hypoxia. More specifically, HIF-1 alpha factor plays a regulatory function in response to molecular signals of infection and inflammation occurring in hypoxic environments.

The skin is, in general, in a state of hypoxia, and the situation is most pronounced in skin pores/hair follicles. Sebum, the oil that lubricates the skin, is produced by specialized cells called sebocytes in sebaceous glands located near follicles. Excessive sebum is considered one of the primary causes of acne. The overproduction of sebum is a direct result of the hypoxic environment of the follicle (Choi K et al, “Increased Lipid Accumulation under Hypoxia,” Dermatology 237: 131-141, 2021).

HIF-1 alpha plays a critical role in the signaling process that triggers excess sebum. In a normal oxygen environment, HIF-1 alpha value is low, but HIF-1 alpha increases significantly in conditions of hypoxia such as the skin follicle. Increased HIF-1 alpha upregulates leptin, a hormonal mediator of the inflammatory response. Leptin activates increased sebum production by sebocytes and an overproliferation of keratinocytes. This creates a keratin plug in the duct of the sebaceous gland connected to the follicle. The follicular plugging further aggravates the hypoxia. The plug increases in size until the follicle ruptures provoking an innate immune response and localized inflammation (B.C.Melnik, “Is sebocyte derived leptin the missing link between hyperseborrhea, ductal hypoxia, inflammation and comedogenesis in acne vulgaris?” Experimental Dermatology, Vol. 25, Issue 3, p. 181, 2015).

Through direct oxygen delivery to the skin, AO2 Clear maintains HIF-1 alpha at a low value compatible with optimal homeostasis. By preventing and reversing hypoxia, HIF-1 alpha does not increase, leptin is not activated, and sebum production and keratinocyte proliferation do not occur. Thus, AO2 Clear prevents the entire inflammatory cascade set in motion by hypoxia-induced follicular plugging.

Oxygen also inhibits the growth of the anaerobic bacteria (Cutibacteria acnes) that plays a role in inflammatory acne thus providing a separate mechanism of action for oxygen in the treatment of acne.

AO2 Clear is the only commercially available product that delivers oxygen to the skin via oxygen nanobubbles and dissolved oxygen. It can be easily incorporated into a daily routine at the user’s home as it requires no clinical equipment or professional application.

Well-accepted science has shown that the lack of oxygen plays a critical role in the development of acne. The following are peer-reviewed articles that validate the mechanism of action of AO2 Clear.

Ductal hypoxia in acne: Is it the missing link between comedogenesis and inflammation

“Hypoxia has two acnegenic effects. First, it induces the failure of both terminal differentiation and desquamation (thus inducing the noninflammatory form of acne). Second, it stimulates the production of HIF-1, and the HIF-1 stimulates inflammatory cytokines (thus inducing the inflammatory form of acne).”

Potential applications of topical oxygen therapy in dermatology

“The combination of oxygen therapy with clindamycin, in our opinion, enhances the effect of topical antibiotic therapy and favors its penetration. Sessions performed 3 times per week also considerably reduced the quantity of drugs that would otherwise be applied daily for months, risking drug resistance of Propionibacterium.”

Topically delivered dissolved oxygen reduces inflammation and positively influences structural proteins in healthy intact human skin.

“The blinded clinical investigator’s grading of desquamation, roughness, and skin texture show significant decreases from baseline to the 8-week time point (P < 0.05).”

Is sebocyte-derived leptin the missing link between hyperseborrhea, ductal hypoxia, inflammation and comedogenesis in acne vulgaris?

“There is compelling evidence that the sebocyte– in analogy to the adipocyte – is an active endocrine cell that promotes pro-inflammatory leptin signalling. Leptin expression depends on mTORC1 activity and HIF-1a expression and is thus related to overnutrition and local hypoxia, respectively. Common mTORC1-driven diseases of civilization such as obesity and acne vulgaris thus share increased pro-inflammatory leptin signalling.”

Increased Lipid Accumulation under Hypoxia in SZ95 Human Sebocytes

“A hypoxic microenvironment can increase lipogenesis and provides a link between seborrhea and inflammation.”