Nitric Oxide and Foam: The Breakthrough for Wound Healing
Nitric oxide (NO) is a natural molecule that is endogenously produced in the human body, and plays a key role in various physiological processes, foremost being wound healing. In the wound healing process, NO has multiple beneficial effects, including reducing inflammation by regulating the inflammatory response; stimulating tissue growth through cell proliferation and collagen formation; improving blood flow through angiogenesis; and killing bacteria through its natural mode of action as an antimicrobial agent. However, the natural endogenous production of NO may be impaired by common factors such as hypoxia, infection, oxidative stress, or reduced expression of NO synthase enzymes, which can result in a wound entering a chronic state. To remedy this and avoid or even reverse the chronic condition, local exogenous NO is a promising strategy for enhancing wound healing.
In this post, we review the leading advances in the development and application of NO-releasing products and therapies for wound healing. We also discuss some of the challenges and limitations of current NO delivery systems and how a novel NO-releasing foam technology developed by NOxy Health Products (“NOxy”) can overcome those challenges to offer a potential breakthrough solution for chronic wound healing.
Advancements in Nitric Oxide
The role of NO in wound healing has been extensively studied in both animal and human models. Several preclinical studies have shown NO’s efficacy in accelerating wound healing by modulating various cellular and molecular processes involved in inflammation, angiogenesis, collagen synthesis, and tissue remodeling.[2,3,4] In clinical studies NO has shown promise for chronic wound healing. For instance:
A double-blind placebo-controlled study showed more rapid and improved quality of healing in non-healing diabetic ulcers, vascular compromised non-healing wounds, surgical incisions, split-thickness grafts, full-thickness grafts, and regional and free flaps that were treated with NO, compared to the control.
A multicenter, randomized controlled, observer-blinded study of NO for diabetic foot ulcers reported a median percentage area reduction of 88.6%, compared to 46.9% for the control group (p=0.016) at 12 weeks in the intention-to-treat population.
Ormerod et al. and Weller et al. both found that NO was effective in treating infected, non-healing wounds in humans.
As a result of the promising effects of NO, several new NO delivery systems are being developed or in testing for chronic wound healing. These NO-delivery options include dressings, gels, sprays, and patches that use various chemical NO donors or carriers to deliver gaseous NO to the wound site.
The Challenges of Nitric Oxide Therapies in Wound Healing
Despite the increased interest in testing the many physiological benefits of NO, its widespread adoption for clinical and commercial applications remains challenging for several reasons. These reasons include the following:
1. Difficulty presenting NO at the point of care:
The high reactivity of NO gas with other molecules when exposed to air or biological fluids makes it difficult to produce, capture, transport, and deliver NO at the point of care in an inexpensive and convenient way.[7,8] To circumvent these limitations, current products or therapies require:
i) specific storage or handling conditions, such as refrigeration, pressurization, or sterilization, to maintain the purity of the NO;
ii) specialized equipment or personnel, such as hyperbaric chambers or trained operators to entrap the gas therapy; or
iii) frequent application or removal of dressings, gels, or sprays, to deliver pharmaceutically effective amounts of NO to a wound.
These conditions are not always feasible for bedside wound treatment.
2. Controlling the release of NO:
For sources of NO gas that do not depend on a state of equilibrium, such as a hyperbaric chamber, controlling the even distribution of NO is challenging.[7,8] Thus, even among clinically tested products, it is difficult to assess the continuity or uniformity of the NO distribution to the unique contours of a wound site. This can result in the release of NO being too quick, too slow, uneven, or intermittent. An ideal NO-delivery product would conform to and deliver NO evenly to all geometries of a wound.
3. Controlling the directional flow of the NO gas for absorption into the tissue:
NO has a density similar to air and a small molecular size, allowing it to easily diffuse through air and other materials.[7,8] While this allows it to penetrate the body’s tissue, it also implies that NO is easily lost through films or coverings intended to hold it in place. Without the ability to control the direction of NO release, delivery methods may require more NO production or longer application time and rely on serendipitous absorption to deliver a therapeutically meaningful dose. For example, patches, dressings, and sprays are unable to direct the flow of NO into the tissue and rely on chance absorption. Consequently, a large amount of the NO from these products escapes into the air and away from the wound site requiring longer treatment cycles to achieve effective NO exposure. Gels and creams have the opposite problem. They keep NO gas trapped within their thick, viscous mediums. Very little NO is released, and what little is released cannot be directionally controlled, requiring more frequent application. An innovative solution is needed that can generate sufficient NO, hold the NO against the wound bed, allowing the NO to perfuse into the body’s tissue, and prevent NO from escaping into the atmosphere.
4. NO therapies are often burdensome to integrate into existing clinical protocols:
Chronic wounds are pervasive and present a heavy medical, economic, and logistical toll on patients and healthcare providers. It is unreasonable to expect the adoption of NO products that require additional time or resources. To overcome this challenge, NO products must not only be effective in delivering NO to the wound bed, but they must be able to accommodate different wound types and sizes, integrate seamlessly with prescribed or preferred dressings, and not encumber the timing, logistics, or flow of care. Very few products or therapies meet these criteria, as many of them require additional steps or procedures, interfere with other treatments or assessments, cause discomfort to patients, or present an inconvenience for patients or caregivers.[7,8] The design and application of a NO delivery product should allow easy and effective implementation into existing clinical protocols for wound care.[8,10]
There is a clear need for a novel NO delivery system that effectively, affordably, and safely provides personalized and user-friendly wound healing solutions for patients with chronic wounds.
The Solution: Nitric Oxide-Releasing Foam Technology
NOxy Health Products is a biotechnology company that is developing and studying a novel NO-releasing foam technology to address the challenges and limitations found in NO delivery, offering a potential breakthrough solution for chronic wound care.
NOxy’s technology generates NO in situ as a foam. When applied to a wound site, the foam technology, still in development, can potentially provide the patient several advantages and wound healing benefits over other NO delivery systems. NOxy’s NO foam technology, currently under study for clinical approval, is designed to do the following:
Generate and transport a therapeutically sufficient dose of NO.
Prevent the contact of NO gas with ambient air.
Hold and press the NO against the skin, which enhances the penetration and absorption of NO gas into the wound tissue.
Apply a NO dose over a 5-minute treatment time, which allows it to fit into the flow of care without disrupting other treatments or assessments.
Adapt to a variety of wound sizes and types, as it can be applied in amounts sufficient to fully cover any wound surface.
Does not require a specific bandage or dressing and can be used as an adjunct to standard of care and with any wound cover.
Be priced congruently with other wound care products.
Be safe and biocompatible for short- and long-term use, as it does not contain any toxic or allergenic substances or residues.
Be practical and convenient to use in clinical settings or home care, not require any special storage or handling conditions, be easily applied and removed, and not require any specialized equipment or personnel.
NOxy has recruited some of the top researchers and advisors in the wound care space to help continue its topical NO foam development and has obtained several patents for its technology. The company has also secured a strong base of investors from skilled nursing facilities, which further bridges its commercialization strategy. The company will soon begin its first-in-human trial in Israel to evaluate the safety and efficacy of its NO-releasing foam technology for chronic wound healing. The company is also in the final stages of completing its battery of non-clinical work ahead of its IND application in the US.
Nitric oxide is a natural molecule that has multiple beneficial effects on wound healing. However, current NO delivery approaches have many challenges that limit their application and effectiveness and prevent adoption. NOxy is developing a novel NO-releasing foam technology that can overcome these challenges and limitations and can offer a potential breakthrough solution for chronic wound care. The foam technology is being designed to produce, maintain, control, and ensure delivery of NO to the wound site in a safe, practical, and convenient manner.
If you are a wound care physician, patient, or market participant who is interested in learning more about NOxy and its investigational NO-releasing foam technology, please check out the resources on our site or contact us at firstname.lastname@example.org.
We believe that NOxy’s nitric oxide foam technology holds the long-awaited answer to wound healing.
1. Kandhwal, Mimansa et al. “Understanding the Potential Role and Delivery Approaches of Nitric Oxide in Chronic Wound Healing Management.” Current pharmaceutical design vol. 27,17 (2021): 1999-2014. doi:10.2174/1381612826666201026152209
6. Edmonds, Michael E. et al. “Multicenter, randomized controlled, observer‐blinded study of a nitric oxide generating treatment in foot ulcers of patients with diabetes—ProNOx1 study.” Wound Repair and Regeneration 26 (2018): n. pag.
8. Poh, Wee Han, and Scott A Rice. “Recent Developments in Nitric Oxide Donors and Delivery for Antimicrobial and Anti-Biofilm Applications.” Molecules (Basel, Switzerland) vol. 27,3 674. 20 Jan. 2022, doi:10.3390/molecules27030674
9. Miller CM, et al, 2018, US Patents: 10,052,348 and 10,751,364