Polycaprolactone nanofiber mats decorated with photoresponsive nanogels and silver nanoparticles: Slow release for antibacterial control

Journal Pre-proof Polycaprolactone nanofiber mats decorated with photoresponsive nanogels and silver nanoparticles: Slow release for antibacterial control Camilo A.S. Ballesteros, Daniel S. Correa, Valtencir Zucolotto PII:

S0928-4931(19)32896-6

DOI:

https://doi.org/10.1016/j.msec.2019.110334

Reference:

MSC 110334

To appear in:

Materials Science & Engineering C

Received Date: 6 August 2019 Revised Date:

25 September 2019

Accepted Date: 14 October 2019

Please cite this article as: C.A.S. Ballesteros, D.S. Correa, V. Zucolotto, Polycaprolactone nanofiber mats decorated with photoresponsive nanogels and silver nanoparticles: Slow release for antibacterial control, Materials Science & Engineering C (2019), doi: https://doi.org/10.1016/j.msec.2019.110334. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier B.V.

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Polycaprolactone nanofiber mats decorated with

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photoresponsive nanogels and silver nanoparticles: slow

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release for antibacterial control

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Camilo A. S. Ballesteros1,2, Daniel S. Correa2*, Valtencir Zucolotto1.

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1 Nanomedicine and Nanotoxicology Group (GNano), IFSC, USP, P.O. Box 369, 13566-590 São Carlos, São Paulo, Brazil 2 Nanotechnology National Laboratory for Agriculture (LNNA), Embrapa Instrumentação, P.O. Box 741, 13560-970, São Carlos, São Paulo, Brazil.

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*Corresponding author: [email protected]

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Abstract

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Smart nanomaterials activated by light is one of the most exciting strategies to

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control the release of substances in varied environments. Here we developed a smart

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nanomaterial formed by a photoresponsive nanogel containing silver nanoparticles

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(AgNPs) immobilized on the surface of biodegradable polycaprolactone (PCL) nanofibers

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mats produced by electrospinning. The silver nanoparticles (AgNps) are released from the

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nanogel and dispersed inside the nanofiber mats when this system is irradiated by light at

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405 nm. This light excites the plasmonic band of the silver nanoparticles, which breaks the

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nanogel and, as a consequence, releases the AgNps in the nanofibers. Consequently, this

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AgNps release mechanism controls the propagation of silver ions by the application of

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light. Different configurations of antibacterial nanofibers mats, including neat PCL

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nanofibers and PCL nanofibers modified with AgNps-Nanogels and AgNps excited by

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laser light at 405nm were investigated regarding antibacterial properties. The best result

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was achieved using PCL nanofiber mats functionalized with AgNps and AgNps-Nanogels

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after light exposure, which generated inhibition diameter of 2.6 ± 0.3 mm and 1.8 ± 0.5 mm

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for S. aureus and E. coli, respectively. The smart nanomaterial developed here is a

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promising material for clinical application as wound dressing activated by light.

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Keywords: Photoactivated release; smart nanomaterials; bactericide material; silver nanoparticles; electrospinning.

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1. Introduction

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In recent years, researchers have made efforts to design smart nanomaterials with

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antibacterial properties activated by light irradiation [1–7], which mechanism of action may vary

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from heat production, pH variation, or reactive oxygen species generations (ROS) such as in the

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case of photocatalysis, photodynamic therapy, photoexcitation and/or photoinduced acidification.

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[8–13] Smart nanomaterials with antibacterial properties have been mainly applied in water

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treatment [14,15], textile modification [14,16,17],

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treatment [14,16,17] and coatings for medical devices [14,16,17]. Among the different types of

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nanomaterials available, nanofibers produced by electrospinning have shown interesting

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properties when functionalized with other nanomaterials or substances [6,16–19]. Such

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nanofibers display a similar structure to the extracellular matrix of biological tissues, viz., large

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specific surface area, high and interconnected porosity which enhances cell adhesion and

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proliferation and mass transfer properties. Nanofibers fabrication also allows the selection of

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distinct raw materials for the nanofibers to be spun [20–22].

food protection [7,14], bacterial infections

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Recently, considerable progress has been made on the generation of smart nanofibers that

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are responsive to stimuli and undergo chemical and/or physical changes. Such stimuli on smart

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nanofibers can generate changes in pH, temperature, light, ionic strength, electric or magnetic

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fields, or combinations of them for a variety of applications [23]. For instance,

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polymethylmethacrylate (PMMA) electrospun nanofibers with silver nanoparticles and meso-

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tetraphenylporphyrin (TPP) upon light irradiation have been reported to increase antibacterial

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activity due to release of AgNps from the polymer matrix [7]. Smart nanofibers based on poly(N-

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isopropylacrylamide) (PNIPAAm), polycaprolactone (PCL) and nattokinase (NK) were

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developed and demonstrated to switch hydrophobicity to hydrophilicity properties with the

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temperature change, displaying capability to capture and release blood cells from the blood [24].

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Biosensing for analysis of agricultural and food products [25] and human breath [26] using

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modified electrospun nanofibers is another example where smart nanosystems can be employed.

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Additionally, conductive electrospun nanofibers are potential materials for neural tissue

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engineering, once they improve the hydrophilicity and biodegradation of the materials while the

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cells are regenerated [27]. Specifically, in the field of skin tissue repair, electrospun biopolymers

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can maximize the treatment efficiency by avoiding tissue damage while maintaining the water

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vapor permeability within the wound [28]. For instance, it has been reported that therapies based

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on visible light irradiation of a hydrogel embedded with nanostructures promote wound healing

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and mitigate bacterial infections with controllable release of Ag+, Zn+ and photosensitizers

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generating singlet oxygen (1O2) [29–32].

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The functionalization and/or immobilization of other nanomaterials (nanocapsules,

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liposomes, injectable hydrogels, nanogels) on the nanofibers can yield a smart nanomaterial with

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antibacterial, photocatalytic and self-cleaning properties that can be activated by an external

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stimuli, including light absorption [33,34]. Here we report the development of PCL nanofibers

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mats decorated with photoresponsive nanogels containing silver nanoparticles. Such system can

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be activated by light to regulate or release active substances to control bacterial growth. The

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nanogel-containing silver nanoparticles (AgNps) used here was developed in a previous

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investigation of our group recently reported [35], in which the physical-chemical activation of

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the AgNps-nanogel occurs mainly by the excitation of the surface plasmon resonance (SPR) of

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AgNps inside of the nanogel. Here we advance the potential use of this AgNps-nanogels by

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immobilizing them onto the surface of biodegradable PCL nanofibers mats and investigated their

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release and antibacterial properties by the laser irradiation at 405 nm. PCL was chosen for being

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a biodegradable, biocompatible and FDA-approved polymer widely used in biomedical

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applications [36–40]. The PCL nanofibers were produced by electrospinning technique [39,41–

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43] which is a cost-effective techniques that allows the production of nanofibers with size range

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and scaffold structure optimal for biomedical applications [41,44–46]. The smart nanomaterial

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developed here present a great potential to be used as wound dressing activated by light, with

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possibilities to control dermal bacterial infections including Gram-negative Escherichia coli and

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Gram-positive Staphylococcus aureus [47].

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2. Materials and methods

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2.1 Materials

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Chitosan (CS, medium molecular weight), aniline hydrochloride ≥ 99.0% (mw = 129.59

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g/mol), silver nitrate (AgNO3) (mw = 169.87 g/mol), N,N-dimethylformamide (DMF),

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dichloromethane (DCM), and polycaprolactone (PCL) (Mn= 80.000) and sodium borohydride

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granular, 99.99% (mw = 33.83 g/mol) were purchased from Sigma-Aldrich. Glacial acetic acid

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(CH3COOH) was purchased from Synth (Brazilian Industry, São Paulo, Brazil). All aqueous

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solutions were prepared with double-distilled water and the chemicals were used without further

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purification.

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2.2 Synthesis of AgNps-nanogels using a complexation-reduction method

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The synthesis of the AgNps-nanogels followed a complexation-reduction method. Full

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details is given in a recent work published by our group [35]. Such methodology was adapted

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from Mi et al. [48]. Specifically, chitosan (CS) (16.5 % w/v, 50 mL) was dissolved in acetic acid

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(1 % v/v, 50 mL). Aniline (A) hydrochloride (10 mM) was mixed with the CS solution and left

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under magnetic stirring for 1 h, to produce cross-linking between aniline and chitosan [35]. Next,

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AgNO3 (0.5 mM) was added to the chitosan-aniline solution and mixed (1 h) under magnetic

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stirring, until the resulting mixture acquired a milky greenish opalescence. The full

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characterization of AgNps-nanogels is described in [35]. FTIR spectra revealed stretching and

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deformation modes occurring during the formation of chitosan-aniline nanogel, as revealed by

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the bans at 3349, 2810, 2599 and 2025 cm-1, which suggests that chitosan and aniline are able to

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cross-link through multiamine cross-linkers via multiple H-bonds. Specifically, the band at 3349

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cm-1 shows the interaction mechanism between amino groups and hydroxyl groups, suggesting

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that the hydrogen bonds were formed between aniline and chitosan by H-bonds cross-

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linking[50–53]. Additionally, the protonated amine group (−NH3+) in CS (solubilized in acetic

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acid) originates electrostatic repulsion and behaves as a chelating agent that forces the silver ions

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to chelate and form AgNps inside of the nanogel [35],[54].

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The synthesized material was washed by centrifugation to eliminate residues of the

125

synthesis. The AgNps-Nanogel characterization was fully described in a recently published work

126

of our group [35]. Specifically, the UV-vis spectroscopy was used to characterize the surface

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plasmon resonance band of AgNps at 405 nm, in order to reveal the presence of AgNps inside of

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the nanogels [35]. Dynamic light scattering (DLS) was used to determine the nanogel size

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distribution.

130

important to the evaluate the interaction with the electrospun fibers [35]. The stability of the

potential was employed to evaluate the nanomaterial surface charge, which is

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AgNps-Nanogels was studied for 10 days via DLS measurements [35]. FT-IR spectra were

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collected to elucidate the interactions between the functional groups of the AgNps-nanogels

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components [35].

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2.3 Kinetics of AgNps release

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The study of photoactivated release of AgNps from the AgNps-Nanogels was carried out

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using a diode laser (Thorlabs diode laser, L405P150) at 405 nm with an intensity of 32 mW/cm2,

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as illustrated in figure 1. For the measurements, 500 µL of nanogels dispersion (0.9 µg/mL)

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contained in a glass cuvette were irradiated at intervals of 30 s, during 600 s, changing the

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irradiated sample for every measurement, which were monitored by UV-Vis absorption

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spectroscopy (405 nm) at room temperature.

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Figure 1. Schematic representation of LASER source at 405 nm used to study the release of AgNps and data collection.

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2.4 Fabrication AgNPs-containing PCL electrospun nanofibers

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To improve the antibacterial properties of the smart nanomaterial AgNps-containing PCL

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electrospun nanofibers were fabricated. For the nanofibers fabrication, PCL (8% wt/v) was

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mixed with dichloromethane (DCM) and N,N-dimethylformamide, (3:7 v/v) and left under

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magnetic stirring for 5 h, until total dissolution was achieved, yielding a solution viscosity of

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80.7 cP. For the fabrication of AgNps embedded in the bulk of PCL electrospun nanofibers,

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N,N-dimethylformamide (DMF) was used as a slowly reducing agent for silver ions. Initially, 20

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mM of AgNO3 were dissolved in DMF and the formation of the silver nanoparticles was

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manifested by the yellowish coloration attained in the dispersion. AgNps-DMF was mixed with

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dichloromethane (DCM), in the same proportion of PCL nanofibers (3:7, dichloromethane :

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AgNps-DMF) to which 8% wt/v of PCL pellets was added and left under magnetic stirring for 5

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h, until total dissolution was achieved, yielding a solution a viscosity of 100,2 cP. All stages

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were carried out at room temperature.

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The electrospun nanofibers were fabricated using an electrospinning apparatus, using a

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feed rate of 0.5 mL/h and electric voltage of 17 kV. A working distance of 12 cm was kept

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between syringe (inner diameter of the steel needle was 0.7 mm) and the metallic collector. The

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experiments were performed at the relative humidity and temperature of 35% ± 5% and 25 °C ±

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2 °C, respectively. Nanofibers were directly deposited onto the aluminum foil wrapped around

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the rotating collector (Length =15.0 cm and diameter = 7.3 cm), using a rotation speed of 150

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rpm and a collection time of 1h. Control of the experimental conditions was important to ensure

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reproducibility, once the diameter and morphology of nanofibers depend on all parameters

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associated to electrospinning.

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2.5 Immobilization of AgNps-nanogels onto the surface of PCL Nanofibers

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Initially, the PCL nanofibers surface was modified by means of O2 plasma treatment. The

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plasma was applied during 2 min (5 W, 250 torr) on the nanofiber mats, breaking the ester bonds

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and producing carboxylate functional groups [55,56]. The latter process brings advantageous

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features for wound dressing application, including the possibility of immobilizing the

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photoresponsive nanogels, the enhancement of antibacterial capacity and the ability to increase

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cell adhesion.

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We determined the best concentration for the immobilization of AgNps-nanogels by

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combining MIC studies (which results are presented in our previous work [35]), and FESEM

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microscopy image analysis, in order to guarantee a homogeneous distribution of AgNPs-

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nanogels onto the surface of PCL nanofibers. Therefore, the modified nanofiber mats were

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immersed in a dispersion of AgNps-nanogels (57.6µg/mL), rinsed with distillated water and

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dried under ambient conditions. AgNps-nanogels were immobilized onto the nanofibers surface

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by H-bonds and electrostatic interactions between the negative charge of nanofibers and amine

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functional groups of nanogels.

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To determine the immobilization time of AgNps-nanogels onto the PCL nanofiber mats,

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three immersion times (3, 7 and 10 min) were tested. The samples were visually inspected by

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field emission scanning electron microscopy (FE-SEM) (JEOL 6510) and the time selected was

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10 min, once it allowed a higher number of nanogels to be deposited onto the nanofiber surface

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compared to 3 and 7 min.

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2.6 Characterization of the smart nanomaterial

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The morphology of the nanofibers, AgNps-Nanogels and AgNps were analyzed using a

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FE-SEM. Energy dispersive X ray spectroscopy (EDS) coupled to the microscope was employed

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to evaluate the presence of silver nanoparticles in the nanofibers mats. The nanofibers were

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covered with carbon layer using a sputterer Leica model SCD 050. In order to determine the

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average diameter and their distribution, 100 random nanofibers were analyzed using the software

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of image, Image J of National Institutes of Health, USA. UV–vis absorption spectra were used to

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determine the plasmonic band of the silver nanoparticles and the release kinetics study of silver

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nanoparticles from AgNps-nanogels on a Hitachi U–2900 spectrometer. Dynamic light-scattering

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(DLS) measurements were performed using a Malvern Nano-ZS spectrometer (Malvern

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Instruments, UK) at 25 °C to determine the size and ζ potential of the AgNps and AgNps-

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Nanogels. The surface of PCL nanofibers was modified by means of O2 plasma treatment. The

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nanofibers mats were submitted to this treatment during 2 min (5 W, 250 torr) by using a plasma

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Etch PE50 system. Contact angles of water droplets on the surface of the nanofibers were

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measured using a contact angle measuring system (CAM 101 model KSV Instruments) equipped

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with a CCD camera (KGV-5000). From these images, contact angle values were calculated using

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dedicated software (KSV CAM 2008).

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2.7 Agar diffusion method

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The antimicrobial activity of the developed system was evaluated against Gram-positive

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Staphylococcus aureus (ATCC 25923) and Gram-negative Escherichia coli (ATCC 25922)

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bacteria. The microorganism concentrations were adjusted to 1-5×106 cells/mL using 0.5

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McFarland scale. The antimicrobial activity of the nanofiber mats was determined by the Agar

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diffusion technique according to the CLSI standard protocols 2009 [57]. Agar was prepared in a

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solution of Mueller Hinton Broth and 30 mL was placed in each petri dish (150 mm of diameter).

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The nanofiber mats were cut into a disk shape having diameter of 2 cm. 100 µl (1×106 cells/mL)

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of each microorganism S. aureus and E. coli were cultured on the agar and each disk were

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placed on it.

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The laser source was placed 5 cm distant from the sample, which was irradiated for 150 s,

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according to the kinetics experiments for silver nanoparticles release, figure 1. After light

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exposure, agar dishes (triplicate) were incubated in an oven at 37 ˚C by 24 h.

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3. Results and discussion

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3.1 Characterization of the AgNps-Nanogels

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The morphology of AgNps-nanogels is shown by the FESEM image in Figure 2. The

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nanogels particles have an average size of 78 ± 19 nm, which value is in agreement to that

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determined by dynamic light scattering (DLS) technique (average diameter of 79 ± 9 nm, with a

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polydispersity index (PdI) of 0.281 ± 0.073) [35]. By the FE-SEM images, AgNps can be

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observed inside the nanogel due to their greater electron density, figure S1. The ζ potential

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value was determined as +39 ± 2 mV, and the AgNp size contained inside the nanogels was

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evaluated in our previous work and determined as 18±3 nm. Size differences given by DLS and

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FE-SEM techniques are within experimental error and indicate the AgNps-Nanogels are not

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aggregates. The UV-Vis absorption spectrum of the AgNps-nanogels shows a surface plasmon

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resonance (SPR) at 405 nm, typical of AgNPs [35].

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Figure 2. FESEM images of AgNps-nanogels with average size of 78 ± 19 nm.

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3.2 AgNps-nanogels photoactivated by a laser source at 405 nm

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AgNps-nanogels were irradiated with a laser source at 405 nm (Thorlabs diode laser,

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L405P150) to excite the SPR band of AgNps (in a way similar to the experiments described in

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ref. [35], which breaks the cross-linking of the nanogels and induce the AgNPs release. The

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intensity of this absorption band when the AgNps is inside the nanogel is low, as can be seen in

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Fig. 3a for t = 0 s. When the AgNps-nanogels are shined by the laser light for longer times

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(Figure 3a), the AgNps are released from the nanogel, and consequently the absorption intensity

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at 405 nm is increased [58] as displayed in the release kinetics study shown in Fig. 3 b. This

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increase occurs until nearly 150s, from which the absorbance band reaches a plateau, indicating

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the AgNps release reached its maximum. After release of AgNps from the nanogel, the size of

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the nanoparticles was determined by DLS and yielded with an average size of 18.2 ± 4.6 nm and

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PdI of 0.48 ± 0.11, as illustrated in Figure 3c and figure S1b. According to recent studies from

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our group [35], the AgNps released from the nanogel could be covered with chitosan, which

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could help making the AgNps more stable (avoiding aggregation).

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0.15 0s 30 s 60 s

0.2

540 s 570 s 600 s

405 nm

0.1

(b)

150 s

0.13 0.12 0.11 0.10 0.09 0.08

250

300

350

400

450

500

550

600

650

0.07

700

-100

0

100

200

λ(nm)

300

400

500

600

700

t(s)

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(c)

30 25

Number (%)

Absorbance

0.14

. . .

Absorbance at 405 nm

(a)

20 15 10 5 0 -5 100

1000

t(s)

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Figure 3. Photoactivation of AgNps-nanogels: (a) UV-Vis absorption spectra regarding the

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release of AgNps from the nanogels as a function of time (b) the release kinetics study indicates

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a stabilization in the release of AgNps at 150 s. (c) Size distribution of AgNps after irradiation:

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diameter = 18 ± 5 nm and PdI = 0.48 ± 0.11.

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3.3 PCL Nanofibers Characterization

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PCL nanofibers fabricated by electrospinning are displayed in FESEM image in figure

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4a. The nanofibers presented diameters of 240 ± 70 nm with homogeneous morphology without

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surface porosity, discontinuities neither beads. The homogeneous morphology of the nanofibers

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was achieved by the correct choice of the experimental parameters during electrospinning, which

272

were evaluated in a set of subsidiary experiments (results not shown). These results demonstrate

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that continuous biocompatible and biodegradable PCL nanofibers suitable for wound dressing

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applications [28,59]could be produced by electrospinning.

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The PCL nanofibers containing AgNps were produced using the same conditions

276

employed for the fabrication of neat PCL nanofibers, where the silver ions were reduced to

277

metallic

278

dichloromethane and AgNps stabilized in dimethylformamide (DCM:AgNpsDMF) was

279

employed. According to FESEM images displayed in figure 4b, AgNps can be observed along

280

the bulk of PCL nanofibers, which show homogenous morphology, without porosity and beads.

281

The AgNps appear brighter than the nanofibers due to their higher electronic density. An

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increase in the diameter of PCL nanofibers containing AgNps (417 ± 14) nm is observed as a

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result of the increase of solution conductivity caused by the AgNps [60]. This morphological

silver

by N,N-dimethylformamide

(DMF).

A

proportion

of

3:7

between

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characteristic is also dependent on the physical-chemical interactions between polymer/solvent

285

and solvent rate evaporation [54,61].

286

The formation of AgNps into the nanofiber bulk is proposed as a strategy to improve the

287

antibacterial properties of the AgNps-Nanogels immobilized on the nanofibers surface as shown

288

in section 3.5 and figure S4, is interesting because it avoids the direct contact of AgNps with the

289

surrounding environment or host and can decrease possible toxic effects of AgNPs to the host,

290

while the mechanism of action is based on the release of silver ions from the nanofibers [62].

291

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Figure 4. (a) FESEM image of PCL electrospun nanofiber, which presented homogeneous

293

morphology. (b) FESEM backscattering electron image of PCL nanofibers containing AgNps in

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the bulk.

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The surface of PCL nanofiber mats containing AgNps was modified by means of O2

297

plasma treatment (details in experimental section) to increase their hydrophilicity, breaking the

298

ester bonds and producing carboxylate functional groups which improve biological performance

299

to clinical applications [55]. Figure 5 shows the image of contact angle measurements regarding

15

300

the deposition of water drop on the PCL nanofibers and plasma-modified PCL nanofibers to

301

determine the effect of treatment on the nanofiber surface, which yielded contact angles of 90.4

302

± 3.8 ̊ and 57.7± 3.8 ̊, respectively. These measurements confirm that the O2 plasma treatment

303

changes the chemical feature of nanofibers surface, which favors the anchoring with the

304

functional groups of the AgNps-Nanogels and the wettability of the system. These measurements

305

are crucial because it represents the behavior of the smart nanomaterial when it is in contact with

306

a biological surface such as a skin wound.

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308 309 310

Figure 5. Images of contact angle of PCL nanofibers mats before (left side) and after (right side) surface modification by O2 plasma during 2 min at 5 W and 250 torr.

311 312

3.4 Smart nanomaterials activated by laser irradiation

313 314

AgNps-nanogels were immobilized onto the surface of nanofiber mats through their

315

immersion onto the nanogels dispersion during 10 min, as mentioned in the experimental section.

316

The immobilization of AgNps-Nanogels on the modified surface of the PCL nanofibers occurred

317

by H-bonds and electrostatic interactions between amine functional groups and carboxylate

318

functional groups, respectively. Figure 6 shows the FESEM images of AgNps-nanogels

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319

immobilized onto PCL nanofibers mats, collected using secondary electrons (Figure 6a) and

320

backscattered electrons (Figure 6b), which shows the different electronic density of AgNps-

321

nanogels on PCL nanofibers. The nanoparticles can be found on the surface and in the bulk of

322

the PCL nanofibers,as a strategy to improve the antibacterial properties of the nanomaterial.

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324 325

Figure 6. FESEM image of PCL nanofibers mats with AgNps-nanogels immobilized onto

326

their surface. (a) secondary and (b) backscattering electrons show the difference between

327

electronic density of AgNps-nanogels and PCL nanofiber.

328 329

The laser source at 405 nm was used to shine the nanofibers mats/AgNps-nanogels mat

330

during 150 s to release the AgNps as illustrated in figure 7a. FESEM images of nanofiber mats

331

before and after irradiation are displayed in figure 7 b and c, respectively. EDS spectroscopy was

332

employed to confirm the presence of the silver nanoparticles on the nanofibers mats, as displayed

333

in figure S3. The smooth surface of nanofibers mats in Figure 7c indicates that the majority of

334

AgNps were released on the mat when light was applied. Such result is interesting for

335

antibacterial applications, once it makes possible the control the silver ions release by adjusting

17

336

the laser excitation wavelength (405 nm), density power, doses and time. Such innovative silver

337

ions delivery systems can be applied in wound dressing activated by light and, therefore, can

338

help keeping skin wounds free of bacterial infections with a simple procedure.

339

Figure 7. (a) Laser irradiation on PCL nanofibers functionalized with AgNps-nanogels.

340

FESEM images of nanofibers mats (b) before and (c) after laser irradiation (at 405 nm) during

341

150 s. The insets in (b) and (c) show magnified regions of the nanofibers mats.

342 343

3.5 Antibacterial Applications

344 345

The antibacterial properties of the AgNps-nanogels and PCL nanofibers mats were

346

investigated by Agar diffusion test through the evaluation of the inhibition zone around the disk

18

347

after incubation at 37 ˚C. Eight different samples were prepared to investigate their antibacterial

348

properties, named samples A-H, which full description is displayed in table 1 and in Fig. S4.

349 350

Table 1. Description of samples A-H employed in the antibacterial tests. Sample Description of samples compositions A

S. aureus and E. coli bacteria (control sample)

B

Control sample irradiated by laser at 405 nm

C

PCL nanofibers (neat)

D

PCL nanofiber functionalized with AgNps and AgNps-nanogels

E

PCL nanofiber functionalized with AgNps and AgNps-nanogels under laser irradiation

F

PCL nanofiber functionalized with nanogels (without AgNps) under laser irradiation

G

PCL nanofiber functionalized with AgNps

H

PCL nanofiber functionalized with AgNps-nanogels under laser irradiation

351 352

Samples D, E, G and H presented bacterial inhibition due to the AgNps and the Ag+ ions

353

on the nanofibers. However, sample E (PCL nanofiber functionalized with AgNps and AgNps-

354

nanogels under laser irradiation) showed the best antibacterial performance with inhibition

355

diameter of 2.6 ± 0.3 mm and 1.8 ± 0.5 mm for S. aureus and E. coli, respectively, as displayed

356

in figure 8. The antibacterial activity may arise from oxidative stress induced by reactive oxygen

357

species (ROS) and silver ions released under irradiation [63]. ROS generations on AgNps can

358

occur due to surface plasmon resonance which produces superoxide and hydroxyl radicals

359

[63,64]. Additionally, bacterial membranes can uptake the free Ag+ ions, which disrupts ATP

19

360

production and DNA replication, generating reactive oxygen species (ROS) that are capable to

361

damage cell membranes leading the bacteria to death [17,65,66].

362 363

364 365

Figure 8. Evaluation of antibacterial activity after exposition to laser excitation at 405 nm.

366

(a) and (c) are control samples (sample A) for S. aureus and E. coli , respectively. PCL nanofiber

367

functionalized with AgNps and AgNps-nanogels under laser irradiation (sample E) against (b) S.

368

aureus (diameter of inhibition was 2.6 ± 0.3 mm), and (d) E. coli (diameter of inhibition = 1.8 ±

369

0.5 mm). The scale bar is 5 mm.

370 371

Although some recent works have reported antibacterial mats containing silver

372

nanoparticles with larger inhibition zone [10,67], this is due to the higher AgNps concentration

20

373

and exposition time employed in those works [11]. The strategy of using the controlled release of

374

silver ions by irradiation yielded a not large inhibition zone (which values are similarly to other

375

results reported in the literature for silver [68,69], but this might be desirable for the treatment of

376

skin wounds, avoiding possible toxic effects that might be caused by an excess of silver release

377

[38,59,70]. Additionally, the biodegradable and biocompatible properties of PCL nanofibers are

378

also beneficial for wound healing, avoiding toxic effects from the polymer matrix

379 380

4. Conclusions

381 382

We developed and characterized a smart nanomaterial based on biodegradable PCL

383

nanofibers mats decorated with photoresponsive nanogels and silver nanoparticles, which

384

displayed antibacterial activity against Gram-positive S. aureus and Gram-negative E. coli.

385

Although our system does not have a high concentration of AgNps, it exhibited the ability to

386

release them in a controlled manner after laser irradiation, which AgNps are dispersed in the

387

nanofiber mats, avoiding the bacterial growth of both types of bacteria. Based on the bactericide

388

properties of our nanosystem associated with the AgNps, AgNps-nanogels and biodegradable

389

and biocompatible polymer matrix, this smart nanomaterial can be considered highly suitable for

390

biomedical applications, combined to the capability to reduce AgNps dose-related toxicity and

391

increase the local antibacterial activity. Specifically, the bacterial growth inhibition zone

392

obtained with this smart nanomaterial activated by light proved its applicability as a wound

393

dressing, which can be used to control dermal bacterial infections against Gram-positive S.

394

aureus and Gram-negative E. coli by the release of the silver ions from the nanofiber mats, but

395

decreasing the time of interaction of the nanoparticles with the cells and tissues.

21

396 397

Acknowledgments

398

The authors thank the financial support from Fundação de Amparo à Pesquisa do Estado

399

de São Paulo (FAPESP) (grant number: 2017/12174-4), Conselho Nacional de Desenvolvimento

400

Científico e Tecnológico (CNPq), MCTI-SisNano (CNPq/402.287/2013-4), Coordenação de

401

Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Código de Financiamento 001

402

and Rede Agronano-EMBRAPA from Brazil.

403 404

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T. Khampieng, S. Wongkittithavorn, S. Chaiarwut, P. Ekabutr, P. Pavasant, P.

624

Supaphol, Silver nanoparticles-based hydrogel: Characterization of material parameters for

625

pressure ulcer dressing applications, Journal of Drug Delivery Science and Technology. 44

31

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(2018) 91–100. doi:10.1016/j.jddst.2017.12.005. [69]

B. Boonkaew, P. Suwanpreuksa, L. Cuttle, P.M. Barber, P. Supaphol, Hydrogels

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containing silver nanoparticles for burn wounds show antimicrobial activity without cytotoxicity,

629

Journal of Applied Polymer Science. 131 (2014) 1–10. doi:10.1002/app.40215.

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M. Konop, T. Damps, A. Misicka, L. Rudnicka, Certain Aspects of Silver and

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Silver Nanoparticles in Wound Care: A Minireview, Journal of Nanomaterials. 2016 (2016) 1–

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10. doi:10.1155/2016/7614753.

633 634

32

635 636

Graphical Abstract

637

638 639 640 641 642 643 644

33

Highlights

•

Smart nanomaterials activated by light can control the release of substances in varied environments.

•

Photoresponsive nanogel containing silver nanoparticles (AgNPs) can be immobilized on the surface of polycaprolactone (PCL) nanofibers.

•

PCL nanofiber functionalized with AgNps and AgNps-Nanogels inhibited the growth of S. aureus and E. coli.

To the Editor-in-Chief Materials Science and Engineering: C

Dear Prof. Dr. Qunfeng Cheng

The authors declare they have no conflict of interest.

Yours sincerely

Dr. Daniel S. Correa Full Researcher Nanotechnology National Laboratory for Agriculture (LNNA)- Embrapa Instrumentation, São Carlos, SP, Brazil. e-mail: [email protected]