Oxygen-loaded nanobubbles counteract hypoxia-deregulated gelatinase/chemokine release from human dermal microvascular endothelium and monocytes: implications in wound healing.

Cutaneous wound healing is orchestrated by several physiological factors leading to reformation of skin integrity and production of functional scar tissue; however, in some pathological conditions (diabetic foot, bedsores) efficient wound healing is hampered by hypoxia, altering the levels of angiogenic/inflammatory molecules released from surrounding cells (endothelium, immune cells). Provided that cellular phenotypes in such environments are better understood, impaired chronic wounds could be targeted by new effective oxygenating drugs, such as O2-Loaded Nanobubbles (OLNs). Here we investigated whether dextran-shelled OLNs (500 nm sized and negatively charged) could counteract hypoxia in modulating secretion of matrix metalloproteinases (MMP-2 and -9) and chemokines (CXCL-8/IL-8 and CCL-5/RANTES) from human dermal microvascular endothelium (HMEC-1 cell line) or peripheral monocytes (primary cultures). In normoxia, HMEC-1 released MMP-2 and CXCL-8/IL-8, but not MMP-9 and CCL-5/RANTES; monocytes secreted MMP-9, CXCL-8/IL-8 and CCL-5/RANTES, but not MMP-2. In both cell types, hypoxia significantly reduced all molecules apart from monocytic CXCL-8/IL-8 and endothelial MMP-2, which were enhanced. OLNs abrogated all hypoxia effects, without displaying toxicity. Notably, neither O2–saturated solution (OSS) nor O2–free nanobubbles (OFNs) did mimic OLN activity, specifically dependent on gradual O2 diffusion from OLN core. Collectively, these data support the hypothesis that topical administration of exogenous O2, properly encapsulated in nanobubble formulations, might promote wound healing in hypoxia-associated pathologies.