Flap graft wound healing microenvironment HBO

The acquired experience and the detection that oxygen is a pivotal nutrient component of healing procedure has implicated the importance of insufficient oxygen supply in all the phases of wound repair.

Traditionally wound healing involves an inflammatory, a proliferative, and a remodeling phase. As oxygen participates in all phases, the demand for sufficient oxygen tension levels is the rational for HBO treatment in compromised tissues.

The role of HBO in compromised grafts or flaps concerning the stage of healing is usually referred as the same in both categories, although their pathophysiology is different.

Graft is especially susceptible to hypoxic insult, as initially it is completely dependent upon oxygen diffused from the base and wound margins, until the vascular net is re-established. Flap has its own vasculature and in order to survive an adequate nutritive process is necessary after the first postoperatively hours until the progressive promotion of angiogenetic response.

Despite the fact that insufficient blood supply is not favoring HBO action in hypoperfused tissues, there are studies in which skin flaps almost totally anoxic have been shown to present reduced necrosis extension after hyperbaric hyperoxia32.

Proliferative phase is the real healing part including fibroblast mediated collagen deposition and the formation of new blood vessels.

Increased hypoxia and lactate levels are considered to be the trigger for the attraction of activated macrophages which release angiogenetic stimulating factors, orchestrating fibroblast and endothelial cells migration and proliferation.

Today a lactate level is acknowledged as the most important factor far more than hypoxia to lead the repairing cascade actions. It is also acknowledged that its levels remain high in the wound area even in the presence of local raised PO2 50.

Lactate stimulates many cells to release cytokines and growth factors e.g.IL1, 6 and 8, trasforming growth factor p, (TGF P) platelet-derived growth factor, (PDGF) or vascular endothelial growth factor, (VEGF) which dominate angiogenesis. Oxygen presence in parallel seems to encourage their production and excite their action, a property not shared by hypoxia51'52.

Passaniti et al53 proposed that fibroblast proliferation - migration and new capillaries development act in unison both demanding adequate oxygen.

Collagen synthesis from fibroblasts and deposition to extracellular space requires adequate oxygen as substrate for the post-translational hydroxylation of pro-collagen. The proper wound PO2 for this extraction was estimated to be close to 100 mmHg, where this oxygen tension influences also the cross-linking of collagen enhancing its tensile strength 51,

In the zone of dividing fibroblasts, the mostly confined to the front capillary line, PO2 is in the range of 30-80 mmHg. Fibroblasts deposit collagen providing a structural matrix crucial for the development of angiogenesis.

The effect of HBO on human skin cells in culture and in human dermal and skin equivalents was studied by Dimitrijevich et al55. Beyond the increase in fibroblast proliferation, (up to 2 ata oxygen) HBO dramatically enhanced keratinocyte differentiation and epidermopoiesis in the complete human skin equivalent (up to 3 ata). The authors suggest utilization of HBO during repair of peripheral human tissue.

Angiogenetic response, the sprouting of new blood vessels from preexisting vessels, takes place through migration of the activated endothelial cells, cell division, tube formation, and neo-capillary net development.

Strong clinical evidence supports HBO inducement of angiogenesis although the mechanism of its biological action is not clear.

Gibson and Hunt52 demonstrated in a Matrigel model angiogenesis to be stimulated paradoxically by both hypoxia and oxygen through released endothelial growth factor, (VEGF) although the long HBO acquired clinical experience has provided indirect evidence supporting this co-existence. This study shows further beneficial effects of HBO upon angiogenesis as seem to influence the interaction of VEGF and its cellular target.

Li et al.56 proposed that although lactate and hypoxia stimulate macrophages to produce VEGF, lack of oxygen up-regulates VEGF receptors and the expressing cells may grow faster when exposed to hyperoxia.

Sheikh et al.57 used a rat wound model to show that HBO induced VEGF production by 40% suggesting that this explains in part the angiogenetic action of HBO.

Recently Lin et al.58 presented an impressive study to further clarify the angiogenetic HBO effect. They have noted that VEGF in order to promote vessel formation must act synergistically with specific angiopoietins, specifically the A2 one. HBO was observed to selectively enhance its action through e-NOS related signaling pathway.

Summarizing, adequate tissular oxygen appears to have a key role in the expression of healing, although the mechanism of angiogenetic stimulation is not clearly defined.

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