Wound healing essentials: let there be oxygen

Abstract

The state of wound oxygenation is a key determinant of healing outcomes. From a diagnostic standpoint, measurements of wound oxygenation are commonly used to guide treatment planning such as amputation decision. In preventive applications, optimizing wound perfusion and providing supplemental O(2) in the perioperative period reduces the incidence of postoperative infections. Correction of wound pO(2) may, by itself, trigger some healing responses. Importantly, approaches to correct wound pO(2) favorably influence outcomes of other therapies such as responsiveness to growth factors and acceptance of grafts. Chronic ischemic wounds are essentially hypoxic. Primarily based on the tumor literature, hypoxia is generally viewed as being angiogenic. This is true with the condition that hypoxia be acute and mild to modest in magnitude. Extreme near-anoxic hypoxia, as commonly noted in problem wounds, is not compatible with tissue repair. Adequate wound tissue oxygenation is required but may not be sufficient to favorably influence healing outcomes. Success in wound care may be improved by a personalized health care approach. The key lies in our ability to specifically identify the key limitations of a given wound and in developing a multifaceted strategy to specifically address those limitations. In considering approaches to oxygenate the wound tissue it is important to recognize that both too little as well as too much may impede the healing process. Oxygen dosing based on the specific need of a wound therefore seems prudent. Therapeutic approaches targeting the oxygen sensing and redox signaling pathways are promising.

Figures

Figure 1. Significance of molecular oxygen and its derivatives in wound healing

In its molecular form, oxygen is required for oxidative metabolism derived energy synthesis, protein synthesis and the maturation (hydroxylation) of extracellular matrices such as collagen. Molecular oxygen is also required for NO synthesis which in turn plays a key role in the regulation of vascular tone as well as in angiogenesis. In a wound setting, large amounts of molecular oxygen are partially reduced to form reactive oxygen species (ROS). ROS includes oxygen free radicals such as superoxide anion as well its non-radical derivative hydrogen peroxide (H2O2). Superoxide anion radical is the one-electron reduction product of oxygen. NADPH oxidases represent one major source of superoxide anion radicals at the wound-site. NADPH oxidases in phagocytic cells help fight infection. Superoxide anion also drives endothelial cell signaling such as required during angiogenesis. In biological tissues, superoxide anion radical rapidly dismutates to hydrogen peroxide-either spontaneously or facilitated by enzymes called superoxide dismutases. Endogenous hydrogen peroxide drives redox signaling, a molecular network of signal propagation that supports key aspects of wound healing such as cell migration, proliferation and angiogenesis. Neutrophil-derived hydrogen peroxide may be utilized by myeloperoxidase to mediate peroxidation of chloride ions resulting in the formation of hypochlorous acid (HOCl), a potent disinfectant.

Figure 2. Heterogeneous distribution of oxygen in the wound tissue: hypothetical pockets of graded levels of hypoxia

Structures outside the illustrated magnifying glass represent the macro tissue structures. Objects under the glass represent a higher resolution. Shade of black (anoxia) or blue represents graded hypoxia. Shade of red or pink represents oxygenated tissue. Tissue around each blood vessel is dark pink in shade representing regions that are well oxygenated (oxygen-rich pockets). Bacteria and bacterial infection are presented by shades of green on the surface of the open wound.