Reoxygenation Modulates the Adverse Effects of Hypoxia on Wound Repair

Abstract

Hypoxia is a major stressor and a prominent feature of pathological conditions, such as bacterial infections, inflammation, wounds, and cardiovascular defects. In this study, we investigated whether reoxygenation has a protective effect against hypoxia-induced acute injury and burn using the C57BL/6 mouse model. C57BL/6 mice were exposed to hypoxia and treated with both acute and burn injuries and were in hypoxia until wound healing. Next, C57BL/6 mice were exposed to hypoxia for three days and then transferred to normoxic conditions for reoxygenation until wound healing. Finally, skin wound tissue was collected to analyze healing-related markers, such as inflammation, vascularization, and collagen. Hypoxia significantly increased inflammatory cell infiltration and decreased vascular and collagen production, and reoxygenation notably attenuated hypoxia-induced infiltration of inflammatory cells, upregulation of pro-inflammatory cytokine levels (IL-6 and TNF-α) in the wound, and remission of inflammation in the wound. Immunofluorescence analysis showed that reoxygenation increased the expression of the angiogenic factor α-SMA and decreased ROS expression in burn tissues compared to hypoxia-treated animals. Moreover, further analysis by qPCR showed that reoxygenation could alleviate the expression of hypoxic-induced inflammatory markers (IL-6 and TNF), increase angiogenesis (SMA) and collagen synthesis (Col I), and thus promote wound healing. It is suggested that oxygen can be further evaluated in combination with oxygen-releasing materials as a supplementary therapy for patients with chronic hypoxic wounds.

Oxygen Therapy to Enhance Wound Healing After Revascularization

“…Oxygen is a vital component in all phases of wound healing, alleviating the process of eradicating microorganisms for infection prevention and breakage of biofilm. [18][19][20][21][22][48][49][50] The revascularization procedure's purpose is to optimize the flow of blood perfusion to provide an adequate amount of oxygen for normal cell function. Some patients may not achieve a successful outcome from the increased flow operation and remaining hypoxia.…”

“…19 A low level of oxygen environment increases angiogenesis in the acute period but lowers the production of new formation of cells and vessels in the long term. [20][21][22] Collagen production and hydroxylation were disturbed in the hypoxic wound base. 21 Delayed epithelization and poor quality of wound granulation are the outcomes of retard of the proliferative phase.…”

“…In terms of scar, hypoxic conditions lead to higher collagen type I and lower collagen type III production. 22 Worse scars present as a complete wound healing in case of achieved healing. Hypoxia can cause abnormalities in all phases of wound healing as seen in Table 1.…”

Advanced Bioadhesive Hydrogels for Skin Care and Therapy

“…Hypoxic tissue conditions often form within burn wounds, which severely hinders tissue regeneration and thus reoxygenation is required to reconstruct an adequate environment for wound healing. [ 126 ] Research conducted by Bai et al. approached this problem by using a gallic acid‐conjugated chitosan and oxidized HA‐based hydrogel that could deliver oxygen‐releasing microspheres (Figure 3E).…”

“…Hypoxic tissue conditions often form within burn wounds, which severely hinders tissue regeneration and thus reoxygenation is required to reconstruct an adequate environment for wound healing. [126] Research conducted by Bai et al approached this problem by using a gallic acid-conjugated chitosan and oxidized HA-based hydrogel that could deliver oxygen-releasing microspheres (Figure 3E). [127] More precisely, oxygen-releasing microspheres fabricated from CaO 2 -incorporating gelatin were encapsulated within the gallic acid-conjugated hydrogel which may undergo spontaneous self-oxidative tissue adhesion and gelation.…”