Publications by authors named "Gracia Mendoza"

41 Publications

Antimicrobial Wound Dressings against Fluorescent and Methicillin-Sensitive Intracellular Pathogenic Bacteria.

ACS Appl Mater Interfaces 2020 Nov 4;12(46):51302-51313. Epub 2020 Nov 4.

Department of Chemical Engineering, Aragon Institute of Nanoscience (INA), University of Zaragoza, Campus Río Ebro-Edificio I+D, C/Mariano Esquillor S/N, 50018 Zaragoza, Spain.

There is limited evidence indicating that drug-eluting dressings are clinically more effective than simple conventional dressings. To shed light on this concern, we have performed evidence-based research to evaluate the antimicrobial action of thymol (THY)-loaded antimicrobial dressings having antibiofilm forming ability, able to eradicate intracellular and extracellular pathogenic bacteria. We have used four different strains, including the ATCC 25923 strain, the Newman strain (methicillin-sensitive strain, MSSA) expressing the coral green fluorescent protein from the vector pCN47, and two clinical reference strains, Newman-(MSSA) and USA300-(methicillin-resistant strain), as traceable models of pathogenic bacteria commonly infecting skin and soft tissues. Compared to non-loaded dressings, THY-loaded polycaprolactone-based electrospun dressings were also able to eliminate pathogenic bacteria in coculture models based on infected murine macrophages. In addition, by using confocal microscopy and the conventional microdilution plating method, we corroborated the successful ability of THY in preventing also biofilm formation. Herein, we demonstrated that the use of wound dressings loaded with the natural monoterpenoid phenol derivative THY are able to eliminate biofilm formation and intracellular methicillin-sensitive more efficiently than with their corresponding THY-free counterparts.
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http://dx.doi.org/10.1021/acsami.0c17043DOI Listing
November 2020

Isolation of exosomes from whole blood by a new microfluidic device: proof of concept application in the diagnosis and monitoring of pancreatic cancer.

J Nanobiotechnology 2020 Oct 22;18(1):150. Epub 2020 Oct 22.

Department of Chemical Engineering, University of Zaragoza, 50018, Zaragoza, Spain.

Background: Exosomes are endocytic-extracellular vesicles with a diameter around 100 nm that play an essential role on the communication between cells. In fact, they have been proposed as candidates for the diagnosis and the monitoring of different pathologies (such as Parkinson, Alzheimer, diabetes, cardiac damage, infection diseases or cancer).

Results: In this study, magnetic nanoparticles (FeONPs) were successfully functionalized with an exosome-binding antibody (anti-CD9) to mediate the magnetic capture in a microdevice. This was carried out under flow in a 1.6 mm (outer diameter) microchannel whose wall was in contact with a set of NdFeB permanent magnets, giving a high magnetic field across the channel diameter that allowed exosome separation with a high yield. To show the usefulness of the method, the direct capture of exosomes from whole blood of patients with pancreatic cancer (PC) was performed, as a proof of concept. The captured exosomes were then subjected to analysis of CA19-9, a protein often used to monitor PC patients.

Conclusions: Here, we describe a new microfluidic device and the procedure for the isolation of exosomes from whole blood, without any need of previous isolation steps, thereby facilitating translation to the clinic. The results show that, for the cases analyzed, the evaluation of CA19-9 in exosomes was highly sensitive, compared to serum samples.
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http://dx.doi.org/10.1186/s12951-020-00701-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7579907PMC
October 2020

Potential Implantable Nanofibrous Biomaterials Combined with Stem Cells for Subchondral Bone Regeneration.

Materials (Basel) 2020 Jul 10;13(14). Epub 2020 Jul 10.

French National Institute of Health and Medical Research (INSERM), UMR 1260, Regenerative Nanomedicine (RNM), FMTS, 11 rue Humann, 67000 Strasbourg, France.

The treatment of osteochondral defects remains a challenge. Four scaffolds were produced using Food and Drug Administration (FDA)-approved polymers to investigate their therapeutic potential for the regeneration of the osteochondral unit. Polycaprolactone (PCL) and poly(vinyl-pyrrolidone) (PVP) scaffolds were made by electrohydrodynamic techniques. Hydroxyapatite (HAp) and/or sodium hyaluronate (HA) can be then loaded to PCL nanofibers and/or PVP particles. The purpose of adding hydroxyapatite and sodium hyaluronate into PCL/PVP scaffolds is to increase the regenerative ability for subchondral bone and joint cartilage, respectively. Human bone marrow-derived mesenchymal stem cells (hBM-MSCs) were seeded on these biomaterials. The biocompatibility of these biomaterials in vitro and in vivo, as well as their potential to support MSC differentiation under specific chondrogenic or osteogenic conditions, were evaluated. We show here that hBM-MSCs could proliferate and differentiate both in vitro and in vivo on these biomaterials. In addition, the PCL-HAp could effectively increase the mineralization and induce the differentiation of MSCs into osteoblasts in an osteogenic condition. These results indicate that PCL-HAp biomaterials combined with MSCs could be a beneficial candidate for subchondral bone regeneration.
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http://dx.doi.org/10.3390/ma13143087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7412392PMC
July 2020

Drug-eluting wound dressings having sustained release of antimicrobial compounds.

Eur J Pharm Biopharm 2020 Jul 28;152:327-339. Epub 2020 May 28.

Department of Chemical Engineering, Aragon Institute of Nanoscience (INA), University of Zaragoza, Campus Río Ebro-Edificio I+D, C/ Poeta Mariano Esquillor S/N, 50018 Zaragoza, Spain; Networking Research Center on Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN, 28029 Madrid, Spain; Aragon Health Research Institute (IIS Aragon), 50009 Zaragoza, Spain.

Wound healing is a complex and costly public health problem that should be timely addressed to achieve a rapid and adequate tissue repair avoiding or even eliminating potential pathogenic infection. Chronic infected non-healing wounds represent a serious concern for health care systems. Efficient wound dressings with tailored therapy having the best response and highest safety margin for the management of chronic non-healing wounds are still needed. The use of novel wound dressing materials has emerged as a promising tool to fulfil these requirements. In this work, asymmetric electrospun polycaprolactone (PCL)-based nanofibers (NFs) were decorated with electrosprayed poly(lactic-co-glycolic acid) microparticles (PLGA MPs) containing the natural antibacterial compound thymol (THY) in order to obtain drug eluting antimicrobial dressings having sustained release. The synthesized dressings successfully inhibited the in vitro growth of Staphylococcus aureus ATCC 25923, showing also at the same doses cytocompatibility on human dermal fibroblasts and keratinocyte cultures after treatment for 24 h, which was not observed when using free thymol. An in vivo murine excisional wound splinting model, followed by the experimental infection of the wounds with S. aureus and their treatment with the synthesized dressings, pointed to the reduction of the bacterial load in wounds after 7 days, though the total elimination of the infection was not reached. The findings indicated the relevance of the direct contact between the dressings and the bacteria, highlighting the need to tune their design considering the wound surface and the nature of the antimicrobial cargo contained.
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http://dx.doi.org/10.1016/j.ejpb.2020.05.025DOI Listing
July 2020

Novel intracellular antibiotic delivery system against : cloxacillin-loaded poly(d,l-lactide-co-glycolide) acid nanoparticles.

Nanomedicine (Lond) 2020 05 6;15(12):1189-1203. Epub 2020 May 6.

Microbiology Department, Hospital Universitari Germans Trias i Pujol, Fundació Institut d'Investigació en Ciències de la Salut GermansTrias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.

First, to compare minimum inhibitory concentrations (MIC) of free cloxacillin and cloxacillin-containing nanoparticles (NP) against methicillin-susceptible (MSSA) and resistant (MRSA) and second, to assess NP antimicrobial activity against intracellular . Poly(d,l-lactide-co-glycolide) acid (PLGA)-NP were loaded with cloxacillin and physico-chemically characterized. MICs were determined for reference strains Newman-(MSSA) and USA300-(MRSA). Murine alveolar macrophages were infected, and bacterial intracellular survival was assessed after incubating with free-cloxacillin or PLGA-cloxacillin-NP. For both isolates, MICs for antibiotic-loaded-NP were lower than those obtained with free cloxacillin, indicating that the drug encapsulation improves antimicrobial activity. A sustained antibiotic release was demonstrated when using the PLGA-cloxacillin-NP. When considering the lowest concentrations, the use of drug-loaded NP enabled a higher reduction of intracellular bacterial load.
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http://dx.doi.org/10.2217/nnm-2019-0371DOI Listing
May 2020

Antibacterial Effect of Thymol Loaded SBA-15 Nanorods Incorporated in PCL Electrospun Fibers.

Nanomaterials (Basel) 2020 Mar 27;10(4). Epub 2020 Mar 27.

Department of Chemical Engineering. Aragon Institute of Nanoscience (INA), University of Zaragoza, Campus Río Ebro-Edificio I+D, C/Poeta Mariano Esquillor S/N, 50018 Zaragoza, Spain.

For the effective management of infected chronic wounds, the incorporation of antimicrobial drugs into wound dressings can increase their local availability at the infection site. Mesoporous silicon dioxide SBA-15 is an excellent drug carrier with tunable drug release kinetics. In this work, synthesized SBA-15 loaded with the natural antimicrobial compound thymol (THY) was incorporated into polycaprolactone (PCL) electrospun nanofibers to obtain an advanced wound dressing. Rod-shaped particles with internal parallel channels oriented along the longitudinal axis (diameter: 138 ± 30 nm, length: 563 ± 100 nm) were loaded with 70.8 wt.% of THY. Fiber mats were prepared using these particles as nanofillers within polycaprolactone (PCL) electrospun fibers. The resulting mats contained 5.6 wt.% of THY and more than half of this loading was released in the first 7 h. This release would prevent an initial bacterial colonization and also inhibit or eliminate bacterial growth as in vitro shown against ATCC 25923. Minimal inhibitory concentration (MIC: 0.07 mg/mL) and minimal bactericidal concentration (MBC: 0.11 mg/mL) of released THY were lower than the amount of free THY required, demonstrating the benefit of drug encapsulation for a more efficient bactericidal capacity due to the direct contact between mats and bacteria.
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http://dx.doi.org/10.3390/nano10040616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221837PMC
March 2020

Customized hybrid and NIR-light triggered thermoresponsive drug delivery microparticles synthetized by photopolymerization in a one-step flow focusing continuous microreactor.

Colloids Surf B Biointerfaces 2020 Jun 25;190:110904. Epub 2020 Feb 25.

Department of Chemical Engineering. Aragon Institute of Nanoscience (INA) and Instituto de Ciencia de Materiales de Aragón (ICMA), Universidad de Zaragoza-CSIC, University of Zaragoza, Campus Río Ebro-Edificio I+D, C/ Poeta Mariano Esquillor S/N, 50018, Zaragoza, Spain; Aragon Health Research Institute (IIS Aragón), 50009, Zaragoza, Spain; Networking Research Center on Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN, 28029, Madrid, Spain.

Photopolymerization is a selective technique that takes advantage of light-sensitive molecules to initiate and propagate monomeric structures to render covalently bonded macromolecular materials structures known as polymers. Herein, we present a novel one-step microfluidic synthesis of customized hybrid-thermoresponsive Poly(N-isopropylacrylamide) (PNIPAm) based microparticles (MPs) containing plasmonic hollow gold nanoparticles (HGNPs) and bupivacaine (BVP) used as a model drug. Those hybrid microparticles were prepared using a flow-focusing microreactor coupled to a UV LED device built with a simple outer PTFE tubing and an inner flexible capillary. Different tubing characteristics and flow rate ratios were altered in order to control the size of the resulting microparticles. In addition, components such as monomer, crosslinker and photoinitiator concentrations, as well as LED intensity and irradiation time were tuned to obtain different MPs and their characteristics and polymerization rates were compared by Gel Permeation Chromatography (GPC). Thermoresponsive properties were analyzed and the presence of HGNPs was confirmed in light-activated triggered drug release applications. Bupivacaine loading and release studies were evaluated with the resulting hollow and solid microparticles (which were obtained depending on the polymerization rate used) and their temperature responsiveness was assessed using a NIR laser when HGNPs were present in the constructs. Finally, cytotoxicity studies, cell-cycle arrest and apoptotic induction were carried out to certify their suitability for further biomedical applications to be used as triggerable drug depots.
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http://dx.doi.org/10.1016/j.colsurfb.2020.110904DOI Listing
June 2020

Metallocenyl 7-ACA Conjugates: Antibacterial Activity Studies and Atomic-Resolution X-ray Crystal Structure with CTX-M β-Lactamase.

Chembiochem 2020 08 16;21(15):2187-2195. Epub 2020 Apr 16.

Department of Organic Chemistry, Faculty of Chemistry, University of Łódź, Tamka 12, 91-403, Łódź, Poland.

The conjugation of organometallic groups to current β-lactam antibiotics is a field of increasing study due to the ability of certain organometallic groups to enhance the antibiotic potency of these drugs. Herein, we report the antibacterial properties of two metallocenyl (ferrocenyl and ruthenocenyl) 7-aminocephalosporanic acid (7-ACA) antibiotic conjugates. Continuing a trend we found in our previous studies, the ruthenocenyl conjugate showed greater antibacterial activity than its ferrocenyl counterpart. Compared with the previously published 7-aminodesacetoxycephalosporanic acid (7-ADCA) conjugates, the 3-acetyloxymethyl group significantly improved the compounds' activity. Furthermore, the Rc-7-ACA compound was more active against clinical Staphylococcus aureus isolates than the ampicillin reference. Noticeably, neither of the two new compounds showed an undesirable toxic effect in HeLa and L929 cells at the concentrations at which they displayed strong antibacterial effects. The antibacterial activity of the two metallocenyl 7-ACA derivatives was further confirmed by scanning electron microscopy (SEM). SEM micrographs showed that bacteria treated with metallocenyl 7-ACA derivatives feature cell wall damage and morphology changes. Using a CTX-M-14 β-lactamase competition assay based on nitrocefin hydrolysis, we showed that the Rc-7-ACA bound more favorably to CTX-M-14 than its ferrocenyl counterpart, again confirming the superiority of the ruthenocenyl moiety over the ferrocenyl one in interacting with proteins. We also report a 1.47 Å resolution crystal structure of Rc-7-ACA in complex with the CTX-M-14 E166A mutant, an enzyme sharing a similar active site configuration with penicillin-binding proteins, the molecular target of β-lactam antibiotics. These results strengthen the case for the antibacterial utility of the Rc and Fc groups.
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http://dx.doi.org/10.1002/cbic.202000054DOI Listing
August 2020

Light-triggered nanoparticles for pain management.

Expert Opin Drug Deliv 2020 05 5;17(5):627-633. Epub 2020 Mar 5.

Department of Chemical Engineering and Environmental Technologies, Aragon Nanoscience Institute, University of Zaragoza, Zaragoza, Spain.

: Recent technological progress in pain management includes patient´s stratification depending on their disease subtype, prognosis, risk, or treatment response using data analysis and genetic testing in order to select the most appropriate drug for each group. A spatiotemporal control on the release of the selected anesthetic drug is also desirable in order to minimize side effects and to provide the patient with the appropriate dose above the therapeutic threshold and below the maximum desirable concentration. Light can be used non-invasively as an exogenous trigger to allow multiple drug administrations with precise spatiotemporal control. By controlling light fluence/irradiance, pulse structure, and duration of the irradiation drug release kinetics can be controlled in a pulsatile manner to release totally or partially the drug loaded into particulate carriers.: Recent advances in the field of light-triggered nanoparticles used in pain management specially those studies which include preclinical models are reviewed.: Two decades later after the first light-sensitive drug delivery systems reported still several limitations hinder their clinical translation. Additional efforts should be undertaken to understand the nanoparticles biological fate, to satisfy their large-scale production, and to facilitate the technology to apply this therapeutic approach at a low cost.
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http://dx.doi.org/10.1080/17425247.2020.1737670DOI Listing
May 2020

Electrospun anti-inflammatory patch loaded with essential oils for wound healing.

Int J Pharm 2020 Mar 22;577:119067. Epub 2020 Jan 22.

Regenerative Medicine Program, Houston Methodist Research Institute, Houston, TX, USA; Orthopedics & Sports Medicine, Houston Methodist Hospital, Houston, TX, USA.

Wound healing is a complex process that consists of three overlapping phases: inflammation, proliferation, and remodeling. A bacterial infection can increase inflammation and delay this process. Microorganisms are closely related to the innate immune system, such as macrophages and neutrophils, as they can start an inflammatory cascade. Essential oils play an important role in the inhibition and prevention of bacterial growth due to their ability to reduce antimicrobial resistance. The possibility to find a strategy that combines antimicrobial and anti-inflammatory properties is particularly appealing for wound healing. In this work, we showcase a variety of patches based on electrospun polycaprolactone (PCL) nanofibers loaded with natural compounds derived from essential oils, such as thymol (THY) and tyrosol (TYR), to achieve reduced inflammation. In addition, we compared the effect these essential oils have on activated macrophages when incorporated into the PCL patch. Specifically, we demonstrate that PCL-THY resulted in more efficient down-regulation of pro-inflammatory genes related to the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κb) pathway when compared to PCL-TYR and the combination patch containing TYR and THY (i.e., PCL-TYR-THY). Furthermore, PCL-THY displayed low affinity for cell attachment, which may hinder wound adherence and integration. Overall, our results indicate that THY-loaded patches could serve as promising candidates for the fabrication of dressings that incorporate bactericidal and anti-inflammatory properties while simultaneously avoiding the limitations of traditional antibiotic-loaded devices.
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http://dx.doi.org/10.1016/j.ijpharm.2020.119067DOI Listing
March 2020

Organometallic ciprofloxacin conjugates with dual action: synthesis, characterization, and antimicrobial and cytotoxicity studies.

Dalton Trans 2020 Feb 18;49(5):1403-1415. Epub 2019 Dec 18.

Faculty of Chemistry, Department of Organic Chemistry, University of Łódź, Tamka 12, 91-403 Łódź, Poland.

The synthesis, characterization and biological activity of six bioorganometallic conjugates of ciprofloxacin with ferrocenyl, ruthenocenyl and cymantrenyl entities are described. Their antimicrobial activities were investigated against Gram-positive bacteria, Gram-negative bacteria and bloodstream forms of Trypanosoma brucei. Furthermore, the morphological changes of bacterial cells upon treatment with the conjugates were examined by scanning electron microscopy. In addition, the cytotoxicity of the conjugates against tumor and normal mammalian cells was also investigated. The results showed that conjugation of an organometallic moiety can significantly enhance the antimicrobial activity of the antibiotic ciprofloxacin drug. It was found that N-alkyl cymantrenyl and ruthenocenyl ciprofloxacin conjugates were the most effective derivatives although other conjugates also showed significant antimicrobial activity. The increase in the antimicrobial activity was most likely due to two independent mechanisms of action. The first mechanism is due to the bacterial topoisomerase inhibitory activity of ciprofloxacin while the second mechanism can be attributed to the generation of reactive oxygen species caused by the organometallic moiety. The presence of two modes of action enables the conjugates to kill bacteria in their stationary growth phase and to overcome the drug resistance of S. aureus strains. In addition, the conjugates showed promising selectivity toward bacterial and parasitic cells over mammalian cells.
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http://dx.doi.org/10.1039/c9dt03948aDOI Listing
February 2020

Triggered drug release from hybrid thermoresponsive nanoparticles using near infrared light.

Nanomedicine (Lond) 2020 02 27;15(3):219-234. Epub 2019 Nov 27.

Department of Chemical Engineering, Aragon Institute of Nanoscience (INA), University of Zaragoza, Campus Río Ebro-Edificio I+D, C/ Poeta Mariano Esquillor S/N, 50018-Zaragoza, Spain.

Developing hybrid poly(N-isopropylacrylamide)-based nanogels decorated with plasmonic hollow gold nanoparticles for on-demand drug delivery and their physico-chemical characterization, bupivacaine loading and release ability upon light irradiation, and cell viability. Hollow gold nanoparticles were prepared by galvanic replacement reaction; poly(N-isopropylacrylamide)-based nanogels were synthesized via precipitation polymerization and their electrostatic coupling was accomplished using poly(allylamine hydrochloride) as cationic polyelectrolyte linker. Colloidal stability of the resulted hybrid nanovectors was demonstrated under physiological conditions together with their fast response and excellent heating efficiency after light stimulation, indicating their potential use as triggered drug-delivery vectors. Moreover, their influence on cell metabolism and cell cycle under subcytotoxic doses were studied showing excellent cytocompatibility.
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http://dx.doi.org/10.2217/nnm-2019-0270DOI Listing
February 2020

Antimicrobial Electrospun Polycaprolactone-Based Wound Dressings: An Study About the Importance of the Direct Contact to Elicit Bactericidal Activity.

Adv Wound Care (New Rochelle) 2019 Sep 9;8(9):438-451. Epub 2019 Aug 9.

Department of Chemical Engineering, Aragon Institute of Nanoscience (INA), University of Zaragoza, Zaragoza, Spain.

To prepare efficient antibacterial carvacrol (CAR) and thymol (THY)-loaded electrospun polycaprolactone (PCL)-based wound dressings. Using electrospinning we were able to prepare wound dressings with antimicrobial action thanks to their large surface per volume ratio, which allows their loading with therapeutic amounts of active principles. By nuclear magnetic resonance we demonstrated that the antimicrobial compounds are donors of hydrogen bonds to the ester functional group in PCL, which acts as acceptor and that intermolecular interaction is responsible for the high drug loading achieved. Those mats loaded with CAR and THY without the use of solubilizing agents were able to completely eradicate both Gram-positive ( ATCC 25923) and Gram-negative ( S17 strain) bacteria at doses inferior to the ones needed when using the free nonsupported compounds. A superior antimicrobial action was observed for THY and CAR against Gram-negative bacteria than against Gram-positive bacteria, despite the higher hydrophilicity of the outer layer of Gram-negative bacteria. We demonstrate that a direct contact between the bacteria and the dressing is required to elicit antimicrobial action. We also evaluated drug loadings by gas chromatography coupled with mass spectrometry and nuclear magnetic resonance validating a new analytical approach. Finally we were able to visualize the pathogenic bacteria on the dressings by confocal microscopy. The interaction between the PCL-based mat and the pathogenic bacteria is a key issue to achieve complete pathogen eradication. Under no-contact conditions, released CAR or THY from the electrospun mats did not exert any antimicrobial action at the doses tested.
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http://dx.doi.org/10.1089/wound.2018.0893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6855275PMC
September 2019

Targeted Release of Probiotics from Enteric Microparticulated Formulations.

Polymers (Basel) 2019 Oct 13;11(10). Epub 2019 Oct 13.

Department of Chemical Engineering. Aragón Institute of Nanoscience (INA), University of Zaragoza, Campus Río Ebro-Edificio I+D, C/ Poeta Mariano Esquillor S/N, 50018-Zaragoza, Spain.

The development of advanced probiotic delivery systems, which preserve bacteria from degradation of the gastrointestinal tract and achieve a targeted release mediated by pH-independent swelling, is of great interest to improve the efficient delivery of probiotic bacteria to the target tissue. Gram-positive and Gram-negative bacteria models ( (Moro) Hansen and Mocquot (ATCC® 4356™) and S17, respectively) have been successfully encapsulated for the first time in pH-independent microparticulate polymethacrylates (i.e., Eudraguard biotic) used for the targeted delivery of nutraceuticals to the colon. These bacteria have also been encapsulated within the mucoadhesive polymethacrylate Eudragit RS 100 widely used as targeted release formulation for active pharmaceutical ingredients. The enteric microparticles remained unaltered under simulated gastric conditions and released the contained viable microbial cargo under simulated intestinal conditions. Buoyancies of 90.2% and 57.3% for Eudragit and Eudraguard microparticles, respectively, and long-term stability (5 months) for the encapsulated microorganisms were found. Cytotoxicity of the microparticles formulated with both polymers was evaluated (0.5-20 mg/mL) on Caco-2 cells, showing high cytocompatibility. These results underline the suitability of the synthesized materials for the successful delivery of probiotic formulations to the target organ, highlighting for the first time the potential use of Eudraguard biotic as an effective enteric coating for the targeted delivery of probiotics.
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http://dx.doi.org/10.3390/polym11101668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6835770PMC
October 2019

Electrospun asymmetric membranes for wound dressing applications.

Mater Sci Eng C Mater Biol Appl 2019 Oct 29;103:109822. Epub 2019 May 29.

Department of Chemical Engineering, Aragon Institute of Nanoscience (INA), University of Zaragoza, Campus Rio Ebro-Edificio I+D, C/Mariano Esquillor S/N, 50018 Zaragoza, Spain; Aragon Health Research Institute (IIS Aragon), 50009 Zaragoza, Spain; Networking Research Center on Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN, 28029 Madrid, Spain. Electronic address:

To accomplish a rapid wound healing it is necessary to develop an asymmetric membrane with interconnected pores consisting of a top layer that prevents rapid dehydration of the wound and bacteria penetration and a sub-layer with high absorption capacity and bactericidal properties. Polycaprolactone (PCL)/polyvinyl acetate (PVAc) asymmetric membranes loaded with the bactericidal monoterpene carvacrol (CRV) were synthesized and characterized by scanning electron microscopy and Fourier transform infrared spectroscopy. Mechanical properties in dry and wet conditions and fluid handling behavior were also assessed. In addition, biological studies regarding their bactericidal effects, cytocompatibility and wound closure properties were also developed. Loading efficiencies of 40-50% were achieved in the prepared samples and 85-100% of the loaded CRV was released in simulated wound pH evolution medium. The significant inhibition of Gram negative (Escherichia coli S17) and Gram positive (Staphylococcus aureus ATCC 25923) bacteria growth clearly showed the suitability of the fabricated membranes for wound healing applications. Furthermore, cytocompatibility of the loaded membranes was demonstrated both in 2D and 3D human dermal fibroblast cultures, as well as cell migration was not impaired by released carvacrol from the membranes. These results highlight the potential of these polymeric electrospun membranes for wound healing.
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http://dx.doi.org/10.1016/j.msec.2019.109822DOI Listing
October 2019

Matryoshka-type gastro-resistant microparticles for the oral treatment of Mycobacterium tuberculosis.

Nanomedicine (Lond) 2019 Mar 8;14(6):707-726. Epub 2019 Feb 8.

Department of Chemical Engineering. Aragon Institute of Nanoscience (INA), University of Zaragoza, Campus Río Ebro-Edificio I+D, C/Poeta Mariano Esquillor S/N, Zaragoza 50018, Spain.

Aim: Production of Matryoshka-type gastroresistant microparticles containing antibiotic-loaded poly lactic-co-glycolic acid (PLGA) nanoparticles (NP) against Mycobacterium tuberculosis.

Materials & Methods: The emulsification and evaporation methods were followed for the synthesis of PLGA-NPs and methacrylic acid-ethyl acrylate-based coatings to protect rifampicin from degradation under simulated gastric conditions.

Results & Conclusion: The inner antibiotic-loaded NPs here reported can be released under simulated intestinal conditions whereas their coating protects them from degradation under simulated gastric conditions. The encapsulation does not hinder the antituberculosis action of the encapsulated antibiotic rifampicin. A sustained antibiotic release could be obtained when using the drug-loaded encapsulated NPs. Compared with the administration of the free drug, a more effective elimination of M. tuberculosis was observed when applying the NPs against infected macrophages. The antibiotic-loaded PLGA-NPs were also able to cross an in vitro model of intestinal barrier.
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http://dx.doi.org/10.2217/nnm-2018-0258DOI Listing
March 2019

Exosome origin determines cell targeting and the transfer of therapeutic nanoparticles towards target cells.

J Nanobiotechnology 2019 Jan 25;17(1):16. Epub 2019 Jan 25.

Department of Chemical Engineering, Aragon Institute of Nanoscience (INA), University of Zaragoza, Campus Río Ebro-Edificio I+D, C/ Mariano Esquillor S/N, 50018, Zaragoza, Spain.

Background: Exosomes are considered key elements for communication between cells, but very little is known about the mechanisms and selectivity of the transference processes involving exosomes released from different cells.

Results: In this study we have investigated the transfer of hollow gold nanoparticles (HGNs) between different cells when these HGNs were loaded within exosomes secreted by human placental mesenchymal stem cells (MSCs). These HGNs were successfully incorporated in the MSCs exosome biogenesis pathway and released as HGNs-loaded exosomes. Time-lapse microscopy and atomic emission spectroscopy allowed us to demonstrate the selective transfer of the secreted exosomes only to the cell type of origin when studying different cell types including cancer, metastatic, stem or immunological cells.

Conclusions: In this study we demonstrate the selectivity of in vitro exosomal transfer between certain cell types and how this phenomenon can be exploited to develop new specific vectors for advanced therapies. Specifically, we show how this preferential uptake can be leveraged to selectively induce cell death by light-induced hyperthermia only in cells of the same type as those producing the corresponding loaded exosomes. We describe how the exosomes are preferentially transferred to some cell types but not to others, thus providing a better understanding to design selective therapies for different diseases.
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http://dx.doi.org/10.1186/s12951-018-0437-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6346572PMC
January 2019

Composite scaffold obtained by electro-hydrodynamic technique for infection prevention and treatment in bone repair.

Int J Pharm 2019 Feb 11;557:162-169. Epub 2018 Dec 11.

Department of Chemical Engineering, Aragon Institute of Nanoscience (INA), University of Zaragoza, Campus Rio Ebro-Edificio I+D, C/Mariano Esquillor S/N, 50018 Zaragoza, Spain; Aragon Health Research Institute (IIS Aragon), 50009 Zaragoza, Spain. Electronic address:

Bone infection is a devastating condition resulting from implant or orthopaedic surgery. Therapeutic strategies are extremely complicated and may result in serious side effects or disabilities. The development of enhanced 3D scaffolds, able to promote efficient bone regeneration, combined with targeted antibiotic release to prevent bacterial colonization, is a promising tool for the successful repair of bone defects. Herein, polymeric electrospun scaffolds composed of polycaprolactone (PCL) nanofibres decorated with poly(lactic-co-glycolic acid) (PLGA) particles loaded with rifampicin were fabricated to achieve local and sustained drug release for more efficient prevention and treatment of infection. The release profile showed an initial burst of rifampicin in the first six hours, enabling complete elimination of bacteria. Sustained and long-term release was observed until the end of the experiments (28 days), facilitating a prolonged effect on the inhibition of bacterial growth, which is in agreement with the common knowledge concerning the acidic degradation of the microparticles. In addition, bactericidal effects against gram negative (Escherichia coli) and gram positive (Staphylococcus aureus) bacteria were demonstrated at concentrations of released rifampicin up to 58 ppm after 24 h, with greater efficacy against S. aureus (13 ppm vs 58 ppm for E. coli). Cell morphology and cytocompatibility studies highlighted the suitability of the fabricated scaffolds to support cell growth, as well as their promising clinical application for bone regeneration combined with prevention or treatment of bacterial infection.
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http://dx.doi.org/10.1016/j.ijpharm.2018.12.002DOI Listing
February 2019

Cleavable and thermo-responsive hybrid nanoparticles for on-demand drug delivery.

J Colloid Interface Sci 2019 Jan 23;533:171-181. Epub 2018 Aug 23.

Department of Chemical Engineering, Aragon Institute of Nanoscience (INA), University of Zaragoza, Campus Río Ebro-Edificio I+D, C/ Poeta Mariano Esquillor S/N, 50018 Zaragoza, Spain; Aragon Health Research Institute (IIS Aragón), 50009 Zaragoza, Spain; Networking Research Center on Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN, 28029 Madrid, Spain.

By combining the photothermal ability of copper sulphide nanoparticles (NPs) upon excitation with Near Infrared (NIR) Light and the thermo-responsive properties of the homemade oligo (ethylene glycol) methyl ether methacrylate copolymer we have obtained fragmentable nanocomposites able to release a carried drug on-demand after NIR-light triggering. A complete physico-chemical characterization of the resulting nanoparticles has been carried out and their degradation assessed at different temperatures. Herein, we have also evaluated the drug loading capacity of those nanoparticles and the temperature dependence in their drug release kinetics using bupivacaine hydrochloride as a model drug. For those hybrid nanoparticles, subcytotoxic doses on four different cell lines and their potential interference in cell metabolism, induction of apoptosis, and cell cycle have been evaluated by Alamar Blue fluorometry and flow cytometry.
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http://dx.doi.org/10.1016/j.jcis.2018.08.069DOI Listing
January 2019

Enzyme structure and function protection from gastrointestinal degradation using enteric coatings.

Int J Biol Macromol 2018 Nov 23;119:413-422. Epub 2018 Jul 23.

Department of Chemical Engineering, Aragon Institute of Nanoscience (INA), University of Zaragoza, Campus Río Ebro-Edificio I + D, C/ Poeta Mariano Esquillor S/N, 50018 Zaragoza, Spain; Networking Research Center on Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN, 28029 Madrid, Spain; Aragon Institute for Health Research (IIS Aragon), Zaragoza 50009, Spain.

Bovine Serum Albumin (BSA) and Horseradish Peroxidase (HRP) have been encapsulated within microparticulated matrices composed of Eudragit RS100 by the water-in-oil-in-water double emulsion solvent evaporation method. Good encapsulation efficiencies were achieved for BSA and HRP, 88.4 and 95.8%, respectively. The stability of the loaded proteins was confirmed by using circular dichroism and fluorescence. The gastroresistance of the protein-loaded microparticles was evaluated under simulated gastric conditions demonstrating the preservation of the structural integrity of the proteins loaded inside the particles. The enzymatic activity of HRP after being released from the enteric microparticles was evaluated by using the peroxidase substrate, revealing that the released enzyme preserved its 100% function. The high drug loadings achieved, reduced cytotoxicity and efficient gastric protection point out towards the potential use of those carriers as oral delivery vectors of therapeutic proteins offering a more controlled targeted release in specific sites of the intestine and an enhanced gastrointestinal absorption.
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http://dx.doi.org/10.1016/j.ijbiomac.2018.07.143DOI Listing
November 2018

Polymeric electrospun scaffolds for bone morphogenetic protein 2 delivery in bone tissue engineering.

J Colloid Interface Sci 2018 Dec 18;531:126-137. Epub 2018 Jul 18.

Department of Chemical Engineering, Aragon Institute of Nanoscience (INA), University of Zaragoza, Campus Rio Ebro-Edificio I+D, C/Mariano Esquillor S/N, 50018 Zaragoza, Spain; Aragon Health Research Institute (IIS Aragon), 50009 Zaragoza, Spain. Electronic address:

Hypothesis: The development of novel scaffolds based on biocompatible polymers is of great interest in the field of bone repair for fabrication of biodegradable scaffolds that mimic the extracellular matrix and have osteoconductive and osteoinductive properties for enhanced bone regeneration.

Experiments: Polycaprolactone (PCL) and polycaprolactone/polyvinyl acetate (PCL/PVAc) core-shell fibers were synthesised and decorated with poly(lactic-co-glycolic acid) [PLGA] particles loaded with bone morphogenetic protein 2 (BMP2) by simultaneous electrospinning and electrospraying. Hydroxyapatite nanorods (HAn) were loaded into the core of fibers. The obtained scaffolds were characterised by scanning and transmission electron microscopy, Fourier-transform infrared spectroscopy, and thermogravimetric analysis. The in vitro potential of these materials for bone regeneration was assessed in biodegradation assays, osteoblast viability assays, and analyses of expression of specific bone markers, such as alkaline phosphatase (ALP), osteocalcin (OCN), and osteopontin (OPN).

Findings: PLGA particles were homogeneously distributed in the entire fibre mat. The growth factor load was 1.2-1.7 μg/g of the scaffold whereas the HAn load was in the 8.8-12.6 wt% range. These scaffolds were able to support and enhance cell growth and proliferation facilitating the expression of osteogenic and osteoconductive markers (OCN and OPN). These observations underline the great importance of the presence of BMP2 in scaffolds for bone remodelling as well as the good potential of the newly developed scaffolds for clinical use in tissue engineering.
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http://dx.doi.org/10.1016/j.jcis.2018.07.029DOI Listing
December 2018

Evaluation of the Antimicrobial Activity and Cytotoxicity of Different Components of Natural Origin Present in Essential Oils.

Molecules 2018 06 8;23(6). Epub 2018 Jun 8.

Department of Chemical and Environmental Engineering, Aragon Institute of Nanoscience (INA), University of Zaragoza, Campus Río Ebro-Edificio I+D, C/Poeta Mariano Esquillor S/N, 50018 Zaragoza, Spain.

Even though essential oils (EOs) have been used for therapeutic purposes, there is now a renewed interest in the antimicrobial properties of phytochemicals and EOs in particular. Their demonstrated low levels of induction of antimicrobial resistance make them interesting for bactericidal applications, though their complex composition makes it necessary to focus on the study of their main components to identify the most effective ones. Herein, the evaluation of the antimicrobial action of different molecules present in EOs against planktonic and biofilm-forming Gram-positive () and Gram-negative () bacteria was assessed. The bactericidal mechanisms of the different molecules, as well as their cytocompatibility, were also studied. Carvacrol, cinnamaldehyde, and thymol exhibit the highest in vitro antimicrobial activities against and , with membrane disruption the bactericidal mechanism identified. The addition of those compounds (≥0.5 mg/mL) hampers biofilm formation and partially eliminates preformed biofilms. The subcytotoxic values of the tested EO molecules (0.015⁻0.090 mg/mL) are lower than the minimum inhibitory and bactericidal concentrations obtained for bacteria (0.2⁻0.5 mg/mL) but are higher than that obtained for chlorhexidine (0.004 mg/mL), indicating the reduced cytotoxicity of EOs. Therefore, carvacrol, cinnamaldehyde, and thymol are molecules contained in EOs that could be used against ⁻ and ⁻mediated infections without a potential induction of bactericidal resistance and with lower cell toxicity than the conventional widely used chlorhexidine.
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http://dx.doi.org/10.3390/molecules23061399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6100501PMC
June 2018

Rapid on-Chip Assembly of Niosomes: Batch versus Continuous Flow Reactors.

ACS Appl Mater Interfaces 2018 Jun 24;10(22):19197-19207. Epub 2018 May 24.

Department of Chemical Engineering and Environmental Technology and Institute of Nanoscience of Aragon (INA) , University of Zaragoza , Zaragoza 50009 Spain.

The large-scale continuous production of niosomes remains challenging. The inherent drawbacks of batch processes such as large particle polydispersity and reduced batch-to-batch reproducibility are here overcome by using commercially available microfluidic reactors. Compared to the traditional batch-based film hydration method, herein, we demonstrate that it is possible to carry out the homogeneous, large-scale (up to 120 mg/min) production of niosomes using two different synthesis techniques (the thin film hydration method and the emulsification technique). Niosomes particle size can be controlled depending on the need by varying the synthesis temperature. The high cytocompatibility of the resulting niosomes was also demonstrated in this work on three different somatic cell lines. For the first time, the structure of the niosome multilamellar shell was also elucidated using high-resolution transmission electron microscopy (HR-STEM) as well as their colloidal stability over time (6 weeks) under different storage conditions. The morphology of cryo-protected or as-made niosomes was also evaluated by HR-STEM after freeze-drying. Finally, the dual ability of those synthetic, nonionic, surfactant-based vesicles to carry both hydrophilic and hydrophobic molecules was also here demonstrated by using laser scanning confocal microscopy.
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http://dx.doi.org/10.1021/acsami.8b02994DOI Listing
June 2018

Controlled release of bupivacaine using hybrid thermoresponsive nanoparticles activated via photothermal heating.

J Colloid Interface Sci 2018 Aug 30;523:234-244. Epub 2018 Mar 30.

Department of Chemical Engineering, Aragon Institute of Nanoscience (INA), University of Zaragoza, Campus Río Ebro - Edificio I+D, C/ Poeta Mariano Esquillor S/N, 50018 Zaragoza, Spain; Aragon Health Research Institute (IIS Aragón), 50009 Zaragoza, Spain; Networking Research Center on Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN, 28029 Madrid, Spain.

Near-infrared (NIR) responsive nanoparticles are of great interest in the biomedical field as antennas for photothermal therapy and also as triggers for on-demand drug delivery. The present work reports the preparation of hollow gold nanoparticles (HGNPs) with plasmonic absorption in the NIR region covalently bound to a thermoresponsive polymeric shell that can be used as an on-demand drug delivery system for the release of analgesic drugs. The photothermal heating induced by the nanoparticles is able to produce the collapse of the polymeric shell thus generating the release of the local anesthetic bupivacaine in a spatiotemporally controlled way. Those HGNPs contain a 10 wt.% of polymer and present excellent reversible heating under NIR light excitation. Bupivacaine released at physiological temperature (37 °C) showed a pseudo-zero order release that could be spatiotemporally modified on-demand after applying several pulses of light/temperature above and below the lower critical solution temperature (LCST) of the polymeric shell. Furthermore, the nanomaterials obtained did not displayed detrimental effects on four mammalian cell lines at doses up to 0.2 mg/mL. From the results obtained it can be concluded than this type of hybrid thermoresponsive nanoparticle can be used as an externally activated on-demand drug delivery system.
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http://dx.doi.org/10.1016/j.jcis.2018.03.107DOI Listing
August 2018

Near infrared dye-labelled polymeric micro- and nanomaterials: in vivo imaging and evaluation of their local persistence.

Nanoscale 2018 Feb;10(6):2970-2982

Department of Chemical Engineering. Aragon Institute of Nanoscience (INA), University of Zaragoza, Campus Río Ebro-Edificio I+D, C/Poeta Mariano Esquillor S/N, 50018-Zaragoza, Spain.

The use of micro- and nanomaterials as carriers of therapeutic molecules can enhance the efficiency of treatments while avoiding side effects thanks to the development of controlled drug delivery systems. The binding of a dye to a drug or to a drug carrier has opened up a wide range of possibilities for an effective in vivo optical tracing of drug biodistribution by using non-invasive real-time technologies prior to their potential use as therapeutic vectors. Here, we describe the fluorescent tagging of polymeric micro- and nanomaterials based on poly(lactic-co-glycolic) acid and on the thermoresponsive poly(N-isopropylacrylamide) with the fluorescent probe IR-820 which was chemically modified for its covalent coupling to the materials. The chemical modification of the dye and the polymers yielded micro- and nanoparticulated labelled materials to be potentially used as drug depots of different therapeutic molecules. In vitro biological studies revealed their reduced cytotoxicity. A spatiotemporal in vivo micro- and nanoparticle tracking allowed the evaluation of the biodistribution of materials showing their local persistence and high biocompatibility after pathological studies. These results underline the suitability of these materials for the local, sustained, not harmful and/or on-demand drug delivery and the remarkable importance of evaluating the biodistribution of materials and tissue persistence for their use as local drug depots.
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http://dx.doi.org/10.1039/c7nr07345cDOI Listing
February 2018

Cymantrenyl-Nucleobases: Synthesis, Anticancer, Antitrypanosomal and Antimicrobial Activity Studies.

Molecules 2017 Dec 14;22(12). Epub 2017 Dec 14.

Department of Organic Chemistry, Faculty of Chemistry, University of Łódź, Tamka 12, 91-403 Łódź, Poland.

The synthesis of four cymantrene-5-fluorouracil derivatives (-) and two cymantrene-adenine derivatives ( and ) is reported. All of the compounds were characterized by spectroscopic methods and the crystal structure of two derivatives ( and ), together with the previously described cymantrene-adenine compound was determined by X-ray crystallography. While the compounds and crystallized in the triclinic P-1 space group, compound crystallized in the monoclinic 2₁/ space group. The newly synthesized compounds - were tested together with the two previously described cymantrene derivatives and for their in vitro antiproliferative activity against seven cancer cell lines (MCF-7, MCF-7/DX, MDA-MB-231, SKOV-3, A549, HepG2m and U-87-MG), five bacterial strains (methicillin-sensitive, methicillin-resistant and vancomycin-intermediate strains), , and , including clinical isolates of and , as well as against the protozoan parasite . The most cytotoxic compounds were derivatives and for A549 and SKOV-3 cancer cell lines, respectively, with 50% growth inhibition (IC) values of about 7 µM. The anticancer activity of the cymantrene compounds was determined to be due to their ability to induce oxidative stress and to trigger apoptosis and autophagy in cancer cells. Three derivatives (, and ) displayed promising antitrypanosomal activity, with GI values in the low micromolar range (3-4 µM). The introduction of the 5-fluorouracil moiety in enhanced the trypanocidal activity when compared to the activity previously reported for the corresponding uracil derivative. The antibacterial activity of cymantrene compounds and was within the range of 8-64 µg/mL and seemed to be the result of induced cell shrinking.
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http://dx.doi.org/10.3390/molecules22122220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6149849PMC
December 2017

Light-Emitting Photon-Upconversion Nanoparticles in the Generation of Transdermal Reactive-Oxygen Species.

ACS Appl Mater Interfaces 2017 Dec 21;9(48):41737-41747. Epub 2017 Nov 21.

Department of Chemical Engineering, Aragon Institute of Nanoscience (INA), University of Zaragoza, Campus Río Ebro , Edificio I+D, C/Poeta Mariano Esquillor S/N, 50018 Zaragoza, Spain.

Common photosensitizers used in photodynamic therapy do not penetrate the skin effectively. In addition, the visible blue and red lights used to excite such photosensitizers have shallow penetration depths through tissue. To overcome these limitations, we have synthesized ultraviolet- and visible-light-emitting, energy-transfer-based upconversion nanoparticles and coencapsulated them inside PLGA-PEG (methoxy poly(ethylene glycol)-b-poly(lactic-co-glycolic acid)) nanoparticles with the photosensitizer protoporphyrin IX. Nd has been introduced as a sensitizer in the upconversion nanostructure to allow its excitation at 808 nm. The subcytotoxic doses of the hybrid nanoparticles have been evaluated on different cell lines (i.e., fibroblasts, HaCaT, THP-1 monocytic cell line, U251MG (glioblastoma cell line), and mMSCs (murine mesenchymal stem cells). Upon NIR (near infrared)-light excitation, the upconversion nanoparticles emitted UV and VIS light, which consequently activated the generation of reactive-oxygen species (ROS). In addition, after irradiating at 808 nm, the resulting hybrid nanoparticles containing both upconversion nanoparticles and protoporphyrin IX generated 3.4 times more ROS than PLGA-PEG nanoparticles containing just the same dose of protoporphyrin IX. Their photodynamic effect was also assayed on different cell cultures, demonstrating their efficacy in selectively killing treated and irradiated cells. Compared to the topical application of the free photosensitizer, enhanced skin permeation and penetration were observed for the nanoparticulate formulation, using an ex vivo human-skin-permeation experiment. Whereas free protoporphyrin IX remained located at the outer layer of the skin, nanoparticle-encapsulated protoporphyrin IX was able to penetrate through the epidermal layer slightly into the dermis.
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http://dx.doi.org/10.1021/acsami.7b14812DOI Listing
December 2017

Chitosan-based coatings in the prevention of intravascular catheter-associated infections.

J Biomater Appl 2018 01 7;32(6):725-737. Epub 2017 Nov 7.

1 Department of Chemical Engineering, Aragon Institute of Nanoscience (INA), 88201 University of Zaragoza , Campus Río Ebro-Edificio I+D, C/ Mariano Esquillor S/N, Zaragoza, Spain; Networking Research Center on Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN, Madrid, Spain; Aragon Health Research Institute (IIS Aragón), Zaragoza, Spain.

Central venous access devices play an important role in patients with prolonged intravenous administration requirements. In the last years, the coating of these devices with bactericidal compounds has emerged as a potential tool to prevent bacterial colonization. Our study describes the modification of 3D-printed reservoirs and silicone-based catheters, mimicking central venous access devices, through different approaches including their coating with the well known biocompatible and bactericidal polymer chitosan, with the anionic polysaccharide alginate; also, plasma treated surfaces were included in the study to promote polymer adhesion. The evaluation of the antimicrobial action of those surface modifications compared to that exerted by a model antibiotic (ciprofloxacin) adsorbed on the surface of the devices was carried out. Surface characterization was developed by different methodologies and the bactericidal effects of the different coatings were assayed in an in vitro model of Staphylococcus aureus infection. Our results showed a significant reduction in the reservoir roughness (≤73%) after coating though no changes were observed for coated catheters which was also confirmed by scanning electron microscopy, pointing to the importance of the surface device topography for the successful attachment of the coating and for the subsequent development of bactericidal effects. Furthermore, the single presence of chitosan on the reservoirs was enough to fully inhibit bacterial growth exerting the same efficiency as that showed by the model antibiotic. Importantly, chitosan coating showed low cytotoxicity against human keratinocytes, human lung adenocarcinoma epithelial cells, and murine colon carcinoma cells displaying viability percentages in the range of the control samples (>95%). Chitosan-based coatings are proposed as an effective and promising solution in the prevention of microbial infections associated to medical devices.
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http://dx.doi.org/10.1177/0885328217739199DOI Listing
January 2018

Antibiotic-eluting orthopedic device to prevent early implant associated infections: Efficacy, biocompatibility and biodistribution studies in an ovine model.

J Biomed Mater Res B Appl Biomater 2018 07 4;106(5):1976-1986. Epub 2017 Oct 4.

Department of Animal Pathology, University of Zaragoza, Zaragoza, Spain.

Infection of orthopedic devices is a major complication in the postsurgical period generating important health issues and economic consequences. Prevention strategies could be based on local release of antibiotics from the orthopedic device itself to avoid adhesion and growth of bacteria. The purpose of this work is to demonstrate the efficiency to prevent these infections by a cefazolin-eluting, perforated stainless steel implant in an in vivo ovine model. The device was placed in the tibia of sheep, one group receiving cefazolin-loaded implants whereas the control group received empty implants. All implants were experimentally infected by direct inoculation of Staphylococcus aureus ATCC 6538. In vitro cytotoxicological studies were also performed to check the effect of antibiotic on cell viability, integrity, and cycle. Results showed that sheep receiving cefazolin-loaded devices were able to avoid implant-associated infections, with normal tissue healing process. The antibiotic release followed a local concentric pattern as demonstrated by high-performance liquid chromatography detection in tissues. The in vitro results indicate the lack of relevant cytotoxic effects for the maximum antibiotic concentration released by the device. These results demonstrate the efficiency and safety of cefazolin-eluting implants in an ovine model to prevent early postsurgical infections of orthopedic devices. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1976-1986, 2018.
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http://dx.doi.org/10.1002/jbm.b.34009DOI Listing
July 2018

Laser-treated electrospun fibers loaded with nano-hydroxyapatite for bone tissue engineering.

Int J Pharm 2017 Jun 13;525(1):112-122. Epub 2017 Apr 13.

Department of Chemical Engineering, Nanoscience Institute of Aragon (INA), University of Zaragoza, 50018, Zaragoza, Spain; Networking Research Center on Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN, 28029, Madrid, Spain. Electronic address:

Core-shell polycaprolactone/polycaprolactone (PCL/PCL) and polycaprolactone/polyvinyl acetate (PCL/PVAc) electrospun fibers loaded with synthesized nanohydroxyapatite (HAn) were lased treated to create microporosity. The prepared materials were characterized by XRD, FTIR, TEM and SEM. Uniform and randomly oriented beadless fibrous structures were obtained in all cases. Fibers diameters were in the 150-300nm range. Needle-like HAn nanoparticles with mean diameters of 20nm and length of approximately 150nm were mostly encase inside the fibers. Laser treated materials present micropores with diameters in the range 70-120μm for PCL-HAn/PCL fibers and in the 50-90μm range for PCL-HAn/PVAC material. Only samples containing HAn presented bioactivity after incubation during 30days in simulated body fluid. All scaffolds presented high viability, very low mortality, and human osteoblast proliferation. Biocompatibility was increased by laser treatment due to the surface and porosity modification.
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http://dx.doi.org/10.1016/j.ijpharm.2017.04.022DOI Listing
June 2017