Abstract
Chronic wounds (CWs) are typically characterized by persistent hypoxia, exacerbated inflammation, and impaired skin tissue remodeling. Additionally, CWs are often worsened by microbial infections. Oxygen-loaded nanobubbles (OLNBs), displaying a peculiar structure based on oxygen-solving perfluorocarbons such as perfluoropentane in the inner core and polysaccharydes including chitosan in the outer shell, have proven effective in delivering oxygen to hypoxic tissues. Antimicrobial properties have been largely reported for chitosan. In the present work chitosan/perfluoropentane OLNBs were challenged for biocompatibility with human skin cells and ability to promote wound healing processes, as well as for their antimicrobial properties against methicillin-resistant Staphylococcus aureus (MRSA) and Candida albicans. After cellular internalization, OLNBs were not toxic to human keratinocytes (HaCaT), whereas oxygen-free NBs (OFNBs) slightly affected their viability. Hypoxia-dependent inhibition of keratinocyte migratory ability after scratch was fully reversed by OLNBs, but not OFNBs. Both OLNBs and OFNBs exerted chitosan-induced short-term bacteriostatic activity against MRSA (up to 6 h) and long-term fungistatic activity against C. albicans (up to 24 h). Short-term antibacterial activity associated with NB prolonged adhesion to MRSA cell wall (up to 24 h) while long-term antifungal activity followed NB early internalization by C. albicans (already after 3 h of incubation). Taken altogether, these data support chitosan-shelled and perfluoropentane-cored OLNB potential as innovative, promising, non-toxic, and cost-effective antimicrobial devices promoting repair processes to be used for treatment of MRSA- and C. albicans-infected CWs.
Highlights
Oxygen plays a pivotal role in achieving successful wound healing as a consequence of its increased demand for reparative processes
Instruments: ultrapure water was obtained using a 1–800 Millipore system (Molsheim, France); Ultra-Turrax SG215 homogenizer was from IKA (Staufen, Germany); Delsa Nano C analyzer was from Beckman Coulter (Brea, USA); HQ40d model oxymeter was from Hach Lange (Derio, Spain); AE31 optical microscope was from Motic (Xiangan Qu, China); XDS-3FL optical microscope was from Optika (Ponteramica, Italy); CM10 transmission electron microscopy (TEM) was from Philips (Eindhoven, The Netherlands); Synergy HT microplate reader was from Bio-Tek Instruments (Winooski, USA); Olympus Fluoview 200 laser scanning confocal system and inverted IX70 Olympus microscope was from Olympus America Inc. (Center Valley, USA); plan flour fluorescent microscope was from Nikon (Minato, Japan)
Further light scattering analyses revealed NB sizes to be in the nanometer range, with average diameters of ~700 nm for Oxygen-loaded nanobubbles (OLNBs) and ~300 nm for oxygen-free NBs (OFNBs)
Summary
Oxygen plays a pivotal role in achieving successful wound healing as a consequence of its increased demand for reparative processes. A chronic wound (CW) is defined as a break in skin epithelial continuity lasting more than 42 days and characterized by persistent hypoxia, exacerbated inflammation, and impaired skin tissue remodeling [2,3,4]. Their prevalence varies with age, ranging approximately from 1% in the adult population to 3–5% in >65 year-old subjects. In CWs the sudden gain of access to the underlying tissues by microbes becomes persistent, leading to prolonged increase of pro-inflammatory cytokines and elongation of the inflammatory phase [6]. There is an urgent need for innovative and effective therapies for the treatment of infected CWs [6,11]
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