Background: Oxygen is vital for healing wounds. It is intricately involved in numerous biological processes including cell proliferation, angiogenesis, and protein synthesis, which are required for restoration of tissue function and integrity. Adequate wound tissue oxygenation can trigger healing responses and favorably influence the outcomes of other treatment modalities. The Problem: Chronic ischemic wounds fail to heal appropriately secondary to extreme hypoxia that leads to cellular demise. Wound tissue hypoxia is typically greater at the center of the wound. Accordingly, oxygen requirements of the regenerating tissue will vary. Basic/Clinical Science Advances: As oxygen levels decrease within the wound, cell response mechanisms (hypoxia inducible factor [HIF]) trigger the transcription of genes that promote cell survival and angiogenesis. HIF stabilizers are currently being tested to determine wound healing potential. Clinically, topical oxygen therapy (TOT) has been proved as an effective therapeutic modality for chronic wounds. TOT is reputed to have several advantages over hyperbaric oxygen therapy. Namely, TOT has a lower risk of oxygen toxicity, it is less expensive and is relatively easy to apply to target areas. Clinical Care Relevance: Wound tissue oxygen is necessary for appropriate wound healing; however, the relative complexity of the healing process requires a multifaceted approach for successful healing outcomes. A key component of this multifaceted approach should be specific oxygen dosing as a function of tissue hypoxia. Conclusion: New treatment approaches that exploit cell hypoxia sensing and response mechanisms and that enable the precise application of oxygen therapy to hypoxic areas of regenerating tissue are very promising.

Diabetic foot disease is a major health problem, which affects 15% of the 200 million patients with diabetes worldwide. Diminished peripheral blood flow and decreased local neovascularization are critical factors that contribute to the delayed or nonhealing wounds in these patients. The correction of impaired local angiogenesis may be a key component in developing therapeutic protocols for treating chronic wounds of the lower extremity and diabetic foot ulcers. Endothelial progenitor cells (EPCs) are the key cellular effectors of postnatal neovascularization and play a central role in wound healing, but their circulating and wound-level numbers are decreased in diabetes, implicating an abnormality in EPC mobilization and homing mechanisms. The deficiency in EPC mobilization is presumably due to impairment of eNOS-NO cascade in bone marrow (BM). Hyperoxia, induced by a clinically relevant hyperbaric oxygen therapy (HBO) protocol, can significantly enhance the mobilization of EPCs from the BM into peripheral blood. However, increased circulating EPCs failed to reach to wound tissues. This is partly a result of downregulated production of SDF-1α in local wound lesions with diabetes. Administration of exogenous SDF-1α into wounds reversed the EPC homing impairment and, with hyperoxia, synergistically enhanced EPC mobilization, homing, neovascularization, and wound healing. Antioxid. Redox Signal . 10, 1869–1882.

Fibroblasts are stromal cells ubiquitously distributed in the body of nearly every organ tissue. These cells were previously considered to be “passive cells”, solely responsible for ensuring the turnover of the extracellular matrix (ECM). However, their versatility, including their ability to switch phenotypes in response to tissue injury and dynamic activity in the maintenance of tissue specific homeostasis and integrity have been recently revealed by the innovation of technological tools such as genetically modified mouse models and single cell analysis. These highly plastic and heterogeneous cells equipped with multifaceted functions including the regulation of angiogenesis, inflammation as well as their innate stemness characteristics, play a central role in the delicately regulated process of wound healing. Fibroblast dysregulation underlies many chronic conditions, including cardiovascular diseases, cancer, inflammatory diseases, and diabetes mellitus (DM), which represent the current major causes of morbidity and mortality worldwide. Diabetic foot ulcer (DFU), one of the most severe complications of DM affects 40 to 60 million people. Chronic non-healing DFU wounds expose patients to substantial sequelae including infections, gangrene, amputation, and death. A complete understanding of the pathophysiology of DFU and targeting pathways involved in the dysregulation of fibroblasts are required for the development of innovative new therapeutic treatments, critically needed for these patients.