Molecular Biomarkers of Oxygen Therapy in Patients with Diabetic Foot Ulcers

Abstract

Hyperbaric oxygen therapy (HBOT) and topical oxygen therapy (TOT) including continuous diffuse oxygen therapy (CDOT) are often utilized to enhance wound healing in patients with diabetic foot ulcerations. High pressure pure oxygen assists in the oxygenation of hypoxic wounds to increase perfusion. Although oxygen therapy provides wound healing benefits to some patients with diabetic foot ulcers, it is currently performed from clinical examination and imaging. Data suggest that oxygen therapy promotes wound healing via angiogenesis, the creation of new blood vessels. Molecular biomarkers relating to tissue inflammation, repair, and healing have been identified. Predictive biomarkers can be used to identify patients who will most likely benefit from this specialized treatment. In diabetic foot ulcerations, specifically, certain biomarkers have been linked to factors involving angiogenesis and inflammation, two crucial aspects of wound healing. In this review, the mechanism of how oxygen works in wound healing on a physiological basis, such as cell metabolism and growth factor signaling transduction is detailed. Additionally, observable clinical outcomes such as collagen formation, angiogenesis, respiratory burst and cell proliferation are described. The scientific evidence for the impact of oxygen on biomolecular pathways and its relationship to the outcomes in clinical research is discussed in this narrative review.

Topical Wound Oxygen Therapy in the Treatment of Chronic Diabetic Foot Ulcers

“…The benefit of this approach is that the higher pressure gradient (pO 2 ) results in oxygen molecules diffusing deeper into the hypoxic wound tissue to enhance multiple molecular and enzymatic functions [ 20 , 23 ]. Within the extremity chamber containing pure O 2 at sea level (760 mmHg), the pO 2 can be cyclically pressurized up to nearly 800 mmHg that optimizes enzymatic activity as previously discussed [ 8 ]. The cyclical pressure applied with TWO 2 of between 8 mmHg and 38 mmHg creates sequential non-contact compression of the limb that also helps to reduce peripheral edema, and thereby, stimulate wound site perfusion further [ 24 , 25 ].…”

“…Recognizing that Oxygen (O 2 ) is required for almost every step of the response to the injury and wound healing cascade, several recent reviews have focused not only on the role of molecular oxygen in this regard but also on cellular and biochemical mechanisms for O 2 generation [ 3 , 7 , 8 , 9 , 10 ]. Chronic wounds are typically characterized as being hypoxic in that the partial pressure of oxygen (pO 2 ) in the center of the wound is often below a critical threshold necessary to fully support those enzymatic processes necessary to regenerate tissue [ 10 ].…”

“…Molecular oxygen is, of course, also necessary for the synthesis of nitric oxide (NO) that regulates vasodilatation. Oxygen-dependent processes, so relevant in wound healing, include mitochondrial-driven adenosine triphosphate (ATP) production for chemical/cellular energy and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase for the production of ROS (“respiratory burst”) involved in signal transduction of growth factors, cellular recruitment, and bacterial killing [ 8 , 9 , 10 , 11 ]. The two most prevalent ROS, superoxide and hydrogen peroxide (H 2 O 2 ), both serve to upregulate the release of vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) that stimulate endothelial cell division and migration to initiate angiogenesis, lymphocyte/leukocyte migration, and fibroblast division and migration to synthesize new extracellular matrix (ECM).…”

“…Collagen synthesis, deposition, and polymerization can only take place provided there is the necessary molecular oxygen present for the hydroxylation of proline and lysine. Prolyl hydroxylase and lysyl hydroxylase are oxygen dependent and very sensitive to local pO 2 levels, with maximal activity at oxygen levels approaching 250 mmHg [ 8 , 10 ]. Since the pO 2 in the center of a chronic wound can be as low as 10 mmHg, maximal enzymatic activity and collagen production can only be achieved by increasing oxygen concentrations above normal physiologic levels.…”

“…Since the pO 2 in the center of a chronic wound can be as low as 10 mmHg, maximal enzymatic activity and collagen production can only be achieved by increasing oxygen concentrations above normal physiologic levels. In fact, this is also true for NADPH oxidase where maximal ROS production occurs at oxygen levels approaching 300 mmHg [ 8 , 12 ]. Supplemental oxygen should therefore augment all of the biological processes necessary for healing by raising the pO 2 above those levels found not only in chronic wounds but also above normal tissue levels of 100 mmHg.…”