Featured paper: Clay Labyrinth in Hydrogel Matrix for Controlled Drug Release.


[Paper: Highly Controlled Diffusion Drug Release from Ureasil–Poly(ethylene oxide)–Na+–Montmorillonite Hybrid Hydrogel Nanocomposites. ACS Appl. Mater. Interfaces, 2018, 10 (22), pp 19059–19068. DOI: 10.1021/acsami.8b04559]

Clay Labyrinth in Hydrogel Matrix for Controlled Drug Release

By combining a clay and a polymer gel at the nanoscale, a brazilian scientific team with members of the São Paulo State University (UNESP) and the University of Franca (UNIFRAN) developed a new material that can carry drugs and release them in a gradual and controlled manner.

The team tested in vitro – that is, in the laboratory, in containers that simulate the biological conditions – the performance of the material in the release of sodium diclofenac. This drug is an anti-inflammatory, given orally or by injection, widely used to relieve swelling and pain from, for example, arthritis, rheumatism, muscle injuries, surgeries or gout.

The material developed is a nanocomposite that includes polymeric hydrogel, clay and the drug. The hydrogel (gel that absorbs water amounts higher than normal without dissolving) is composed of an organic-inorganic hybrid material known as siloxane-polyether or ureasil. The clay is known as montmorillonite, and is present in the nanocomposite in the form of nanometric lamellae homogeneously dispersed in the hydrogel. The diclofenac sodium, which appears encapsulated within the nanocomposite, is incorporated into the material during its preparation, as if it were another “ingredient”.

The nanocomposite was obtained by the São Paulo team through the sol-gel process. This preparation method is based on a series of chemical reactions with the transformation of a “sol” (liquid with nanometric particles in suspension) into a gel (rigid three-dimensional network with interstices in which the liquid remains immobilized).

In this nanocomposite the main function of the hydrogel, which is hydrophilic, is absorbing water from the external environment and storing it in its interstices. In this aqueous environment, the drug molecules disperse due to the physical diffusion process until they cross the pores of the hydrogel and exit into the external environment, in this case the human body if the material were being used to release drugs into real patients.

clay hydrogelThe main novelty of the material is the use of clay, which is impermeable, to control how the drug is released. In fact, in the material developed by the São Paulo team, the nanometric clay lamellae acted as a physical barrier to the passage of the molecules of water and drug.

As shown in the image below, the lamella set formed a real labyrinth that slowed the movement of these molecules, determining a specific rhythm to water absorption and the release of diclofenac sodium.

“The main contribution of this work was to develop a barrier system based on an organic-inorganic hybrid material containing polymer-clay for the fine control of the diclofenac sodium release,” says Eduardo Ferreira Molina, corresponding author of an article on the subject, recently published in the journal ACS Applied Materials & Interfaces. Molina is currently a professor at the University of Franca (SP).

In the work reported in this journal, the authors prepared a series of samples of the nanocomposite using different proportions of montmorillonite clay, as well as samples of the clayless hydrogel. The scientists used different characterization techniques to analyze the structure of the nanocomposites and their phases (hydrogel and clay) and also to study water absorption and release of the drug in the material. The team was able thus to verify that the presence of the clay was essential to control the way the drug was released. By adjusting the clay percentage used in nanocomposite preparation, the researchers were able to prevent the early release of a large dose of sodium diclofenac (a common problem in drug delivery systems). They also succeeded in releasing it slowly and at a steady and predictable rate.

The results of this work may constitute a first step towards the use of this nanocomposite as a drug release system for prolonged treatments of arthritis, migraine, postoperative pain and etc. With a system like this, medication could be released gradually at the most appropriate doses and rates, keeping the ideal concentration of the drug in the bloodstream.

Celso R. N. Jesus (left), first author of the paper and Eduardo F. Molina, corresponding author.
Celso R. N. Jesus (left), first author of the paper and Eduardo F. Molina, corresponding author.

The work, which received funding from the Brazilian federal agencies CAPES and CNPq and the São Paulo State agency FAPESP, was carried out at the Chemistry Institute of UNESP, in the city of Araraquara, with the exception of small-angle X-ray scattering (SAXS) measurements, performed at the Brazilian Synchrotron Light Laboratory (LNLS), in the city of Campinas.

The research was developed between 2010 and 2014 in the doctorate in Chemistry of Celso Ricardo Nogueira Jesus, under the supervision of Professor Celso Valentim Santilli (UNESP) and Professor Sandra Helena Pulcinelli (UNESP). The idea, previously unpublished, of developing these nanocomposites to function as barriers to controlled drug release arose at the beginning of the doctoral research of Nogueira Jesus. The theme brought together themes developed in two other postgraduate works. On the one hand, Eduardo Molina’s doctoral research, guided by Professor Santilli, on siloxane-polyether for controlled release of drugs. In 2010, this work was in the final phase. And on the other hand, Márcia Hikosaka’s master’s work, guided by Professor Pulcinelli and completed a few years ago, on the preparation of nanocomposites with polymers and montmorillonite clay.

Featured paper. A lot of science and some serendipity to discover the recipe for a multifunctional nanocomposite.


[Paper: One material, multiple functions: graphene/Ni(OH)2 thin films applied in batteries, electrochromism and sensors. Eduardo G. C. Neiva, Marcela M. Oliveira, Márcio F. Bergamini, Luiz H. Marcolino Jr & Aldo J. G. Zarbin. Scientific Reports 6, 33806 (2016). doi:10.1038/srep33806. Link para o artigo: http://www.nature.com/articles/srep33806]

A lot of science and some serendipity to discover the recipe for a multifunctional nanocomposite.

boxnickel_enA recently published paper in the journal Scientific Reports, from the Nature group, reports a study carried out in universities of the state of Paraná (Brazil) on a material based on nickel hydroxide Ni(OH)2 – a composite of great technological interest [See box]. The group of authors developed an innovative method to fabricate a material based on nickel hydroxide graphene and nanoparticles, prepared thin films with this material and demonstrated the efficiency of these films when used as rechargeable battery electrodes, glycerol sensors and electrochromic materials.

The work was carried out within the doctoral research of Eduardo Guilherme Cividini Neiva, under the guidance of Professor Aldo José Gorgatti Zarbin, in the Chemistry Post-Graduation Program of the Federal University of Paraná (UFPR). Neiva began his research on nickel nanoparticles during his undergraduate years, guided by Professor Zarbin. In the master’s program, still with Zarbin, he developed a preparation route of nickel metal nanoparticles for electrochemical applications. After completing the master’s program, Neiva and Zarbin set out to continue the research in Neiva’s doctorate, including graphene in the preparation of nickel metal based nanoparticles to obtain nickel and graphene nanocomposites with different properties. “Most of my scientific interests focus on the preparation of materials with carbon nanostructures, such as nanotubes and graphene,” states Professor Zarbin, who is the corresponding author of the article in Scientific Reports.

They were surprised by the first laboratory results. In the presence of graphene oxide (as a precursor of graphene in the preparation of the material), the process took a different course. At that time, Neiva and Zarbin saw the potential of these particularities: if well understood, they could be controlled and used to prepare nanocomposites, not only of nickel metal, but also of nickel hydroxide, which would open up new application possibilities. “There is a phrase by Louis Pasteur I like very much, which applies perfectly in this case: “Chance favors the prepared mind,” declares Zarbin.

Based on this, student and advisor created a simple and direct process for the fabrication of graphene and nickel hydroxide nanocomposites. In this innovative process, both components are synthesized together in a one-step reaction. Using this technique, Neiva manufactured the nanocomposites. Pure nickel hydroxide samples were also produced in order to compare them with the nanocomposites.

The samples were studied through a series of techniques: X-ray diffraction, Raman spectroscopy, Fourier transform infrared spectroscopy (FT-IR), thermogravimetry, field emission scanning electron microscope (FEG-MEV), and also by means of transmission electron microscopy (TEM) images carried out by Professor Marcela Mohallem Oliveira, from the Federal Technological University of Paraná (UTFPR). The comparison between the two materials was favorable to the nanocomposite. “Graphene played a key role in the stabilization of particles at the nanometer scale, increasing the chemical and electrochemical stability of the nanoparticles, and increasing the conductivity of the material, which is fundamental for an improvement in the desired applications,” acknowledges Aldo Zarbin.

Aldo José Gorgatti Zarbin (on the left side) and Eduardo Guilherme Cividini Neiva, the main authors of the paper, standing at the FEG-MEV equipment of the Materials Chemistry Group of UFPR.

The next stage consisted of

processing the nanocomposites and the nanoparticles of pure nickel hydroxide to obtain thin films, a format that allows using them in the desired applications. “The deposition of materials in the form of films, covering different surfaces, is a great technological challenge, even greater when dealing with multicomponent materials and insoluble, infusible and intractable materials (all characteristics of the material reported in this article)”, explains Zarbin.

To overcome this challenge, Neiva used a processing route, known as liquid/liquid interfacial method, developed in 2010 by the research group led by Zarbin, the Materials Chemistry Group of UFPR. This route, besides simple and cheap, explains Professor Zarbin, allows depositing complex materials in the form of homogeneous and transparent films on various types of materials, including plastics. “The route is based on the high energy at the interface of two immiscible liquids (e.g., water and oil), where the material is initially stabilized to minimize this energy, allowing its subsequent transfer to substrates of interest,” he explained.

With the nanocomposites, Neiva obtained thin transparent films of about 100 to 500 nm in thickness, with nanoparticles of about 5 nm in diameter, distributed homogeneously on the graphene sheets. The pure nickel hydroxide, however, generated films formed by porous spherical nanoparticles of 30 to 80 nm in diameter, distributed heterogeneously, forming agglomerates in some regions.

In the final phase of the work, the films deposited on glass and indium tin oxide were tested in three applications, in which the nanocomposite performed better than pure nickel hydroxide.  As a material for rechargeable alkaline battery electrodes, the nanocomposite exhibited high energy and high power – two positive points that are not easily found in the same material. The nanocomposite also showed good performance as an electrochemical sensor. In fact, experiments designed by Professors Márcio Bergamini and Luiz Marcolino Jr, also from UFPR, showed that the nanocomposite is a sensitive sensor of glycerol (a compound known commercially as glycerin and used in several industries). Finally, the nanocomposite acted as an efficient electrochromic material. With these characteristics, the films of the UFPR group have a chance to leave the laboratory and be part of innovative products. “This depends on partners who are interested in scaling the method and testing it on real devices,” says Zarbin.

For now, in addition to scientific articles such as the one published in the journal Scientific Reports, the work generated several patents, both on the deposition method of thin films and on their applications in gas sensors, transparent electrodes, photovoltaic devices and catalysts. “And we have now developed a flexible battery, which was only possible thanks to the film deposition technique we developed,”, adds Professor Zarbin.

The work, which was developed within the macro projects “INCT of carbon nanomaterials” and “Nucleus of Excellence in Nanochemistry and Nanomaterials”, received funding from the federal agencies Capes and CNPq, and the Araucária Foundation, an agency for scientific and technological development of the state of Paraná.

This figure, sent by the authors of the paper, summarizes the main contributions of the paper. In the center, a flask with two liquids and the film at the interface represents the processing method of thin films. A diagram of the film is on the left, with the nickel hydroxide nanoparticles on the graphene sheet. To the right, a photograph of the film deposited on a quartz substrate shows the homogeneity and transparency of the film (it is possible to read text below it). And to the right, from top to bottom, the three applications are shown by a discharge curve (battery), of a transmittance variation curve by the applied potential (electrochromism) and an analytical curve showing the linear variation of the intensity of the current as a function of glycerol concentration in the medium (sensor).
This figure, sent by the authors of the paper, summarizes the main contributions of the paper. In the center, a flask with two liquids and the film at the interface represents the method for thin films processing. A diagram of the film is on the left, with the nickel hydroxide nanoparticles on the graphene sheet. To the right, a photograph of the film deposited on a quartz substrate shows the homogeneity and transparency of the film (it is possible to read text below it). And to the right, from top to bottom, the three applications are shown by a discharge curve (battery), of a transmittance variation curve by the applied potential (electrochromism) and an analytical curve showing the linear variation of the intensity of the current as a function of glycerol concentration in the medium (sensor).