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      Biodegradable and Drug-Eluting Inorganic Composites Based on Mesoporous Zinc Oxide for Urinary Stent Applications

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          Abstract

          Conventional technologies for ureteral stent fabrication suffer from major inconveniences such as the development of encrustations and bacteria biofilm formation. These drawbacks typically lead to the failure of the device, significant patient discomfort and an additional surgery to remove and replace the stent in the worst cases. This work focuses on the preparation of a new nanocomposite material able to show drug elution properties, biodegradation and eventually potential antibacterial activity. Poly(2-hydroxyethyl methacrylate) or the crosslinked poly(2-hydroxyethyl methacrylate)-co-poly(acrylic acid) hydrogels were prepared by the radical polymerization method and combined with a biodegradable and antibacterial filling agent, i.e., flower-like Zinc Oxide (ZnO) micropowders obtained via the hydrothermal route. The physico-chemical analyses revealed the correct incorporation of ZnO within the hydrogel matrix and its highly mesoporous structure and surface area, ideal for drug incorporation. Two different anti-inflammatory drugs (Ibuprofen and Diclofenac) were loaded within each composite and the release profile was monitored up to two weeks in artificial urine (AU) and even at different pH values in AU to simulate pathological conditions. The addition of mesoporous ZnO micropowders to the hydrogel did not negatively affect the drug loading properties of the hydrogel and it was successfully allowed to mitigate undesirable burst-release effects. Furthermore, the sustained release of the drugs over time was observed at neutral pH, with kinetic constants (k) as low as 0.05 h −1. By exploiting the pH-tunable swelling properties of the hydrogel, an even more sustained release was achieved in acidic and alkaline conditions especially at short release times, with a further reduction of burst effects (k ≈ 0.01–0.02 h −1). The nanocomposite system herein proposed represents a new material formulation for preparing innovative drug eluting stents with intrinsic antibacterial properties.

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          Antibacterial activity and mechanism of action of zinc oxide nanoparticles against Campylobacter jejuni.

          The antibacterial effect of zinc oxide (ZnO) nanoparticles on Campylobacter jejuni was investigated for inhibition and inactivation of cell growth. The results showed that C. jejuni was extremely sensitive to treatment with ZnO nanoparticles. The MIC of ZnO nanoparticles for C. jejuni was determined to be 0.05 to 0.025 mg/ml, which is 8- to 16-fold lower than that for Salmonella enterica serovar Enteritidis and Escherichia coli O157:H7 (0.4 mg/ml). The action of ZnO nanoparticles against C. jejuni was determined to be bactericidal, not bacteriostatic. Scanning electron microscopy examination revealed that the majority of the cells transformed from spiral shapes into coccoid forms after exposure to 0.5 mg/ml of ZnO nanoparticles for 16 h, which is consistent with the morphological changes of C. jejuni under other stress conditions. These coccoid cells were found by ethidium monoazide-quantitative PCR (EMA-qPCR) to have a certain level of membrane leakage. To address the molecular basis of ZnO nanoparticle action, a large set of genes involved in cell stress response, motility, pathogenesis, and toxin production were selected for a gene expression study. Reverse transcription-quantitative PCR (RT-qPCR) showed that in response to treatment with ZnO nanoparticles, the expression levels of two oxidative stress genes (katA and ahpC) and a general stress response gene (dnaK) were increased 52-, 7-, and 17-fold, respectively. These results suggest that the antibacterial mechanism of ZnO nanoparticles is most likely due to disruption of the cell membrane and oxidative stress in Campylobacter.
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            Properties of Zinc Oxide Nanoparticles and Their Activity Against Microbes

            Zinc oxide is an essential ingredient of many enzymes, sun screens, and ointments for pain and itch relief. Its microcrystals are very efficient light absorbers in the UVA and UVB region of spectra due to wide bandgap. Impact of zinc oxide on biological functions depends on its morphology, particle size, exposure time, concentration, pH, and biocompatibility. They are more effective against microorganisms such as Bacillus subtilis, Bacillus megaterium, Staphylococcus aureus, Sarcina lutea, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumonia, Pseudomonas vulgaris, Candida albicans, and Aspergillus niger. Mechanism of action has been ascribed to the activation of zinc oxide nanoparticles by light, which penetrate the bacterial cell wall via diffusion. It has been confirmed from SEM and TEM images of the bacterial cells that zinc oxide nanoparticles disintegrate the cell membrane and accumulate in the cytoplasm where they interact with biomolecules causing cell apoptosis leading to cell death.
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              Selective toxicity of zinc oxide nanoparticles to prokaryotic and eukaryotic systems.

              We report on the toxicity of ZnO nanoparticles (NPs) to gram-negative and gram-positive bacterial systems, Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus), and primary human immune cells. ZnO NP (~13 nm) showed complete inhibition of E. coli growth at concentrations 3.4 mM, whereas growth of S. aureus was completely inhibited for 1 mM. Parallel experiments using flow cytometry based assays clearly demonstrated that growth inhibitory properties of ZnO NP were accompanied by a corresponding loss of cell viability. Identical ZnO NP had minimal effects on primary human T cell viability at concentrations toxic to both gram-negative and gram-positive bacteria. Collectively, these experiments demonstrate selectivity in the toxic nature of ZnO NP to different bacterial systems and human T lymphocytes. Developing selective toxicity to biological systems and controlling it by NP design could lead to biomedical and antibacterial applications.
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                Author and article information

                Journal
                Materials (Basel)
                Materials (Basel)
                materials
                Materials
                MDPI
                1996-1944
                29 August 2020
                September 2020
                : 13
                : 17
                : 3821
                Affiliations
                [1 ]Department of Applied Science and Technology, Politecnico di Torino, Corso Duca degli Abruzzi 24, 10129 Torino, Italy; marco.laurenti@ 123456polito.it (M.L.); or elena.dragoni@ 123456gmail.com (E.D.); marco.carofiglio@ 123456polito.it (M.C.); tania.limongi@ 123456polito.it (T.L.)
                [2 ]Department of Polymer Chemistry, Institute of Chemical Sciences, Faculty of Chemistry, Maria Curie Sklodowska University, Gliniana 33, 20-614 Lublin, Poland; mgrochowicz@ 123456poczta.umcs.lublin.pl or
                Author notes
                [* ]Correspondence: valentina.cauda@ 123456polito.it ; Tel.: +39-011-090-7389
                Author information
                https://orcid.org/0000-0003-3844-2106
                https://orcid.org/0000-0002-9225-5232
                https://orcid.org/0000-0002-7589-696X
                https://orcid.org/0000-0001-5510-5561
                https://orcid.org/0000-0003-2382-1533
                Article
                materials-13-03821
                10.3390/ma13173821
                7504493
                32872464
                d93ca345-b4b9-4fb4-9c4a-0c5fa460423b
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 28 July 2020
                : 26 August 2020
                Categories
                Article

                mesoporous zinc oxide,polyhema,hydrogel,drug-eluting stent,ph-triggered drug release

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