Abstract
Chronic, nonhealing wounds inflict significant patient morbidity and mortality and impose considerable economic burdens to health care systems. This has prompted investigations of the potential wound healing therapies, and exogenous delivery of nitric oxide (NO) is one avenue that has been explored. NO is crucial for normal wound repair: it mediates many vital processes that take place after cutaneous injury and helps to ward off invading pathogens due to its inherent antimicrobial and cytostatic properties. Because of its dual wound repair and antimicrobial features, exogenous NO delivery for the acceleration of wound healing is an attractive therapeutic strategy. Several exogenous NO delivery methods have been studied, but limitations preclude their widespread clinical use. Nanotechnology can be exploited for therapeutic delivery of a variety of active ingredients including NO. A hybrid hydrogel/glass composite NO-releasing nanoparticles platform has demonstrated wound healing efficacy both in vitro and in vivo, and circumvents many of the limitations associated with other NO delivery methods. This is a promising new technology that has potential for broad clinical application owing to several advantageous features. Here, we review normal wound healing and NO’s role in this process, examine the efficacy and limitations of several NO delivery methods and highlight the therapeutic potential of NO nanoparticles.
Financial & competing interests disclosure
A Friedman is co-inventor of the hybrid/hydrogel glass composite NO-releasing nanoparticles. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Key issues
• Wound healing is a highly orchestrated series of events that is coordinated by numerous biological factors including nitric oxide (NO).
• NO-deficient states have been associated with delayed wound repair, because NO is critical to proper wound healing.
• Because of its dual wound repair and antimicrobial properties, exogenous NO delivery is an attractive therapy to accelerate wound healing. However, harnessing NO’s therapeutic potential is challenging because of its high reactivity and short half-life.
• Several sources of NO have been evaluated for exogenous NO delivery, these include gaseous NO, acidified nitrites, diazeniumdiolates and molsidomine. Yet, limitations including toxicity, inability to control the NO release profile and difficult and expensive administration have largely precluded their translation to the bedside.
• NO nanoparticles (NO-nps) are an innovative therapeutic strategy to deliver NO to the wound bed. They possess unique characteristics and circumvent many of the limitations encountered by gaseous NO and synthetic NO donors. A key feature of this platform is the ability to deliver NO in a sustained and predictable manner over time.
• NO-nps are advantageous over other NO delivery methods because they are easily synthesized and stored, NO release is sustained over time and modifiable, they are minimally toxic and they do not require bioactivation by an external agent.
• NO-nps accelerate wound healing by facilitating fibroblast migration and collagen deposition in vitro. In vivo, NO-nps significantly accelerated wound closure in a variety of murine wound models. These included uninfected excisional wounds in normal and immunocompromised hosts, infected excisional and burn wounds and subcutaneous and intramuscular abscesses. NO-nps also decreased bacterial or fungal burden in infected wounds and abscesses and increased wound NO levels.
• Given the preponderance and economic burden of chronic, nonhealing wounds in the USA, a technology that successfully delivers NO is needed. NO-nps are a promising platform for exogenous NO delivery and have potential for broad clinical application.