Dextran oxygen-loaded nanobubbles restore physiological MMP/TIMP balances in hypoxic human dermal microvascular endothelium.

In chronic wounds, hypoxia seriously undermines tissue repair processes by altering the balances between proangiogenic proteolytic enzymes (matrix metalloproteinases, MMPs) and their inhibitors (tissue inhibitors of metalloproteinases, TIMPs) released from endothelial cells. Provided the phenotype of the cellular environment is better understood, chronic wounds might be targeted by new effective oxygenating drugs such as O2-Loaded Nanobubbles (OLNs). Here, hypoxia effects on MMP/TIMP secretion from human dermal microvascular endothelial cells (HMEC-1) were investigated, and dextran-shelled decafluoropentane-containing OLNs were evaluated as potential therapeutic devices. Normoxic HMEC-1 released MMP-9, TIMP-1 and TIMP-2 protein. Hypoxia enhanced MMP-2 and reduced TIMP-1 secretion, without affecting TIMP-2. Consequently, hypoxic HMEC-1 displayed compromised Matrigel invasion ability. Dextran OLNs (with spherical morphology, diameters of 550 nm and anionic surfaces) were uptaken by HMEC-1, neither displaying cytotoxicity nor affecting cell viability. Interestingly, OLNs abrogated all hypoxia effects, restoring normoxic MMP/TIMP levels and invasion ability. Such abrogation was specifically dependent on time-sustained O2 diffusion from OLN core, as it was not achieved by O2-saturated solution (OSS) or O2-free nanobubbles (OFNs). Collectively, these data show that dextran OLNs can counteract hypoxia dysregulating effects on MMP/TIMP balances in human dermal microvascular endothelium and might be used as effective tools to promote chronic wound healing processes.