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2021
Graça, Manuel P., Silvia Soreto Teixeira, Sílvia R. Gavinho, Manuel Almeida Valente, Cristiana Salgueiro, José Nunes, Paula I. P. Soares, Maria Carmo Lança, Tânia Vieira, Jorge Carvalho Silva, and João Borges Borges. "Nanomaterials for magnetic hyperthermia." European Journal of Public Health 31 (2021): ckab120.066. AbstractWebsite

Cancer remains as one of the major causes of mortality worldwide. Recent advances in nanoparticles based therapy mark a new era on cancer treatment. Many groups have investigated biological/physical effects of nanoparticles on tumour cells and how these vary with physical parameters such as particle size, shape, concentration and distribution. Magnetic hyperthermia (MHT) can be an alternative or an add-value therapy with demonstrated effectiveness. MHT uses magnetic nanoparticles, which can be directly applied to the tumour, where, by applying an external ac magnetic field, will promote a localized temperature increment that can be controlled.

Teixeira, Silvia Soreto, Manuel P. F. Graça, José Lucas, Manuel Almeida Valente, Paula I. P. Soares, Maria Carmo Lança, Tânia Vieira, Jorge Carvalho Silva, João Paulo Borges, Luiza-Izabela Jinga, Gabriel Socol, Cristiane Mello Salgueiro, José Nunes, and Luís C. Costa. "Nanostructured LiFe5O8 by a Biogenic Method for Applications from Electronics to Medicine." Nanomaterials 11 (2021): 193. AbstractWebsite

The physical properties of the cubic and ferrimagnetic spinel ferrite LiFe5O8 has made it an attractive material for electronic and medical applications. In this work, LiFe5O8 nanosized crystallites were synthesized by a novel and eco-friendly sol-gel process, by using powder coconut water as a mediated reaction medium. The dried powders were heat-treated (HT) at temperatures between 400 and 1000 °C, and their structure, morphology, electrical and magnetic characteristics, cytotoxicity, and magnetic hyperthermia assays were performed. The heat treatment of the LiFe5O8 powder tunes the crystallite sizes between 50 nm and 200 nm. When increasing the temperature of the HT, secondary phases start to form. The dielectric analysis revealed, at 300 K and 10 kHz, an increase of ε′ (≈10 up to ≈14) with a tanδ almost constant (≈0.3) with the increase of the HT temperature. The cytotoxicity results reveal, for concentrations below 2.5 mg/mL, that all samples have a non-cytotoxicity property. The sample heat-treated at 1000 °C, which revealed hysteresis and magnetic saturation of 73 emu g−1 at 300 K, showed a heating profile adequate for magnetic hyperthermia applications, showing the potential for biomedical applications.

Tipa, Cezar, Maria Teresa Cidade, Tânia Vieira, Jorge Carvalho Silva, Paula I. P. Soares, and João Paulo Borges. "A New Long-Term Composite Drug Delivery System Based on Thermo-Responsive Hydrogel and Nanoclay." Nanomaterials 11 (2021): 25. AbstractWebsite

Several problems and limitations faced in the treatment of many diseases can be overcome by using controlled drug delivery systems (DDS), where the active compound is transported to the target site, minimizing undesirable side effects. In situ-forming hydrogels that can be injected as viscous liquids and jellify under physiological conditions and biocompatible clay nanoparticles have been used in DDS development. In this work, polymer–clay composites based on Pluronics (F127 and F68) and nanoclays were developed, aiming at a biocompatible and injectable system for long-term controlled delivery of methylene blue (MB) as a model drug. MB release from the systems produced was carried out at 37 °C in a pH 7.4 medium. The Pluronic formulation selected (F127/F68 18/2 wt.%) displayed a sol/gel transition at approx. 30 °C, needing a 2.5 N force to be injected at 25 °C. The addition of 2 wt.% of Na116 clay decreased the sol/gel transition to 28 °C and significantly enhanced its viscoelastic modulus. The most suitable DDS for long-term application was the Na116-MB hybrid from which, after 15 days, only 3% of the encapsulated MB was released. The system developed in this work proved to be injectable, with a long-term drug delivery profile up to 45 days.

2019
Cristovão, Ana Filipa, David Sousa, Filipe Silvestre, Inês Ropio, Ana Gaspar, Célia Henriques, Alexandre Velhinho, Ana Catarina Baptista, Miguel Faustino, and Isabel Ferreira. "Customized tracheal design using 3D printing of a polymer hydrogel: influence of UV laser cross-linking on mechanical properties." 3D Printing in Medicine 5 (2019): 12. AbstractWebsite

Background
The use of 3D printing of hydrogels as a cell support in bio-printing of cartilage, organs and tissue has attracted much research interest. For cartilage applications, hydrogels as soft materials must show some degree of rigidity, which can be achieved by photo- or chemical polymerization. In this work, we combined chemical and UV laser polymeric cross-linkage to control the mechanical properties of 3D printed hydrogel blends. Since there are few studies on UV laser cross-linking combined with 3D printing of hydrogels, the work here reported offered many challenges.

Methods
Polyethylene glycol diacrylate (PEGDA), sodium alginate (SA) and calcium sulphate (CaSO4) polymer paste containing riboflavin (vitamin B2) and triethanolamine (TEOHA) as a biocompatible photoinitiator was printed in an extrusion 3D plotter using a coupled UV laser. The influence of the laser power on the mechanical properties of the printed samples was then examined in unconfined compression stress-strain tests of 1 × 1 × 1 cm3 sized samples. To evaluate the adhesion of the material between printed layers, compression measurements were performed along the parallel and perpendicular directions to the printing lines.

Results
At a laser density of 70 mW/cm2, Young’s modulus was approximately 6 MPa up to a maximum compression of 20% in the elastic regime for both the parallel and perpendicular measurements. These values were within the range of biological cartilage values. Cytotoxicity tests performed with Vero cells confirmed the cytocompatibility.

Conclusions
We printed a partial tracheal model using optimized printing conditions and proved that the materials and methods developed may be useful for printing of organ models to support surgery or even to produce customized tracheal implants, after further optimization.

Raminhos, Joana, João Borges Borges, and Alexandre Velhinho. "Development of polymeric anepectic meshes: auxetic metamaterials with negative thermal expansion." Smart Materials and Structures 28 (2019): 045010. AbstractWebsite

his paper reports the application of additive manufacturing technology to fabricate bi-dimensional lightweight composite meshes capable of demonstrating auxetic properties (negative Poisson's ratio (NPR)) in combination with negative thermal expansion (NTE) behaviour, using as constituent materials polymers that do not exhibit NTE behaviour. To describe the combination of NPR and NTE characteristics, the designation of 'anepectic' is being proposed. Each mesh, obtained from varying either the material combination or the design parameters, was tested on a heated silicone bath to study the effects of the different combinations on the coefficient of thermal expansion (CTE). It was found that all meshes studied demonstrated a successful combination of NPR and NTE behaviours, and it was revealed that there is a possibility to tailor the meshes to activate the NTE behaviour within a chosen range of temperatures. For an extreme case, a Poisson's ratio of −0.056, along with a CTE of −1568 × 10−6 K−1 has been achieved.

Vieira, Tânia, Jorge Carvalho Silva, Botelho A. M. do Rego, João Borges Borges, and Célia Henriques. "Electrospun biodegradable chitosan based-poly(urethane urea) scaffolds for soft tissue engineering." Materials Science and Engineering: C 103 (2019): 109819. AbstractWebsite

The composition and architecture of a scaffold determine its supportive role in tissue regeneration. In this work, we demonstrate the feasibility of obtaining a porous electrospun fibrous structure from biodegradable polyurethanes (Pus) synthesized using polycaprolactone-diol as soft segment and, as chain extenders, chitosan (CS) and/or dimethylol propionic acid. Fourier transform infrared spectroscopy and proton nuclear magnetic resonance confirmed the syntheses. Fibre mats' properties were analysed and compared with those of solvent cast films. Scanning electron microscopy images of the electrospun scaffolds revealed fibres with diameters around 1 μm. From tensile tests, we found that Young's modulus increases with CS content and is higher for films (2.5 MPa to 6.5 MPa) than for the corresponding fibre mats (0.8 MPa to 3.2 MPa). The use of CS as the only chain extender improves recovery ratio and resilience. From X-ray diffraction, a higher crystalline degree was identified in fibre mats than in the corresponding films. Films' wettability was enhanced by the presence of CS as shown by the decrease of water contact angle. X-ray photoelectron spectroscopy revealed that while ester groups are predominant at the films' surface, ester and urethanes are present in similar concentrations at fibres' surface, favouring the interaction with water molecules. Both films and fibres undergo hydrolytic degradation. In vitro evaluation was performed with human dermal fibroblasts. No PU sample revealed cytotoxicity. Cells adhered to fibre mats better than to films and proliferation was observed only for samples of CS-containing PUs. Results suggest that electrospun fibres of CS-based polyurethanes are good candidate scaffolds for soft tissue engineering.

Chaparro, Catarina IP, Liliana R. Loureiro, Manuel Almeida Valente, Paula A. Videira, João Paulo Borges, and Paula I. P. Soares. "Synthesis and Characterization of Magnetic Nanoparticles and their internalization on Tumor Cell Lines." 2019 IEEE 6th Portuguese Meeting on Bioengineering (ENBENG) (2019): 1-4. AbstractWebsite

Truncated sialylated O-glycans, such as cell-surface carbohydrate antigen sialyl-Tn (STn) are overexpressed by several cancer types, but not by the respective normal tissues. STn expression is associated with oncogenesis and metastatic ability of cancer cells, with reduced overall survival and lack of response to chemotherapy. Advances in nanomedicine have resulted in rapid development of biocompatible superparamagnetic iron oxide nanoparticles (SPIONs) with considerable potential in cancer treatment. Therefore, in this study SPIONs coated with oleic acid (OA) or dimercaptosuccinic acid (DMSA) were developed and characterized for internalization in two breast cancer cell lines: cell line expressing the STn antigen and the corresponding control. SPIONs with an average diameter of 8 nm showed superparamagnetic behavior and high potential to be used as magnetic hyperthermia agents. OA and DMSA coating provided high stability of SPIONs in physiological conditions while not changing their main properties. NPs internalization studies showed a higher accumulation of DMSA coated NPs in the breast cancer MDA-MB-231 WT cell line. In MDA-MB-231 cell line expressing STn both coated NPs showed a similar accumulation. Therefore, STn antigen can act as a receptor capable of detecting and covalently bind to the molecules present on NPs surface and induce their cellular uptake by endocytosis.

2018
Matos, Ricardo, Catarina Chaparro, Jorge Carvalho Silva, Manuel Valente, João Paulo Borges, and Paula I. P. Soares. "Electrospun composite cellulose acetate/iron oxide nanoparticles non-woven membranes for magnetic hyperthermia applications." Carbohydrate polymers 198 (2018): 9-16. AbstractWebsite

In the present work composite membranes were produced by combining magnetic nanoparticles (NPs) with cellulose acetate (CA) membranes for magnetic hyperthermia applications. The non-woven CA membranes were produced by electrospinning technique, and magnetic NPs were incorporated by adsorption at fibers surface or by addition to the electrospinning solution. Therefore, different designs of composite membranes were obtained. Superparamagnetic NPs synthesized by chemical precipitation were stabilized either with oleic acid (OA) or dimercaptosuccinic acid (DMSA) to obtain stable suspensions at physiological pH. The incorporation of magnetic NP into CA matrix was confirmed by scanning and transmission electron microscopy. The results showed that adsorption of magnetic NPs at fibers’ surface originates composite membranes with higher heating ability than those produced by incorporation of magnetic NPs inside the fibers. However, adsorption of magnetic NPs at fibers’ surface can cause cytotoxicity depending on the NPs concentration. Tensile tests demonstrated a reinforcement effect caused by the incorporation of magnetic NPs in the non-woven membrane.

Vieira, Tânia, Jorge Carvalho Silva, João Paulo Borges, and Célia Henriques. "Synthesis, electrospinning and in vitro test of a new biodegradable gelatin-based poly(ester urethane urea) for soft tissue engineering." European Polymer Journal 103 (2018): 271-281. AbstractWebsite

Biodegradable polyurethanes have been studied as scaffolds for tissue engineering due to their adjustable physico-chemical properties. In this work, we synthesized a biodegradable gelatin-based poly(urethane urea) using polycaprolactone-diol, as soft segment, and isophorone diisocyanate and gelatin from cold water fish skin as hard segment. The synthesis was confirmed by Fourier transform infrared spectroscopy and proton nuclear magnetic resonance and the influence of the amount of gelatin introduced in the polymer backbone was analyzed by thermal analysis. Gelatin-based poly(urethane urea) electrospun fibrous mats and solvent cast films were then produced and their physico-chemical and biological properties studied. They present an amorphous structure, elastomeric behavior and water contact angles typical of hydrophobic surfaces. Hydrolytic degradation was analyzed in phosphate buffer saline (PBS), lipase and trypsin solutions. No mass changes were detected during 37 days in PBS and trypsin while significant degradation by lipase was observed. Human foetal foreskin fibroblasts were seeded on the fibrous mats and films. Populations were evaluated by colorimetric cell viability assays and morphology by fluorescence imaging. The substrates supported cell adhesion and proliferation. The novel gelatin-based poly(urethane urea) fibrous mats offer attractive physico-chemical and biological properties for soft tissue engineering applications.

2017
João, Carlos, Coro Echeverria, Alexandre Velhinho, Jorge Carvalho Silva, Maria Helena Godinho, and João Paulo Borges. "Bio-inspired production of chitosan/chitin films from liquid crystalline suspensions." Carbohydrate polymers 155 (2017): 372-381. AbstractWebsite

Inspired by chitin based hierarchical structures observed in arthropods exoskeleton, this work reports the capturing of chitin nanowhiskers’ chiral nematic order into a chitosan matrix. For this purpose, highly crystalline chitin nanowhiskers (CTNW) with spindle-like morphology and average aspect ratio of 24.9 were produced by acid hydrolysis of chitin. CTNW were uniformly dispersed at different concentrations in aqueous suspensions. The suspensions liquid crystalline phase domain was determined by rheological measurements and polarized optical microscopy (POM). Chitosan (CS) was added to the CTNW isotropic, biphasic and anisotropic suspensions and the solvent was evaporated to allow films formation. The Films’ morphologies as well as the mechanical properties were explored. A correlation between experimental results and a theoretical model, for layered matrix’ structures with fibers acting as a reinforcement agent, was established. The results evidence the existence of two different layered structures, one formed by chitosan layers induced by the presence of chitin and another formed by chitin nanowhiskers layers. By playing on the ratio chitin/chitosan one layered structure or the other can be obtained allowing the tunning of materials’ mechanical properties.

Prezas, Pedro, Bruno Melo, Luís Costa, Manuel Valente, Maria Carmo Lança, José Ventura, Luís Pinto, and Manuel Prezas. "TSDC and impedance spectroscopy measurements on hydroxyapatite, β-tricalcium phosphate and hydroxyapatite/β-tricalcium phosphate biphasic bioceramics." Applied Surface Science 424 (2017): 28-38. AbstractWebsite

Bone grafting and surgical interventions related with orthopaedic disorders consist in a big business, generating large revenues worldwide every year. There is a need to replace the biomaterials that currently still dominate this market, i.e., autografts and allografts, due to their disadvantages, such as limited availability, need for additional surgeries and diseases transmission possibilities. The most promising replacement materials are biomaterials with bioactive properties, such as the calcium phosphate-based bioceramics group. The bioactivity of these materials, i.e., the rate at which they promote the growth and directly bond with the new host biological bone, can be enhanced through their electrical polarization.
In the present work, the electrical polarization features of pure hydroxyapatite (Hap), pure β-tricalcium phosphate (β-TCP) and biphasic hydroxyapatite/β-tricalcium phosphate composites (HTCP) were analyzed by measuring thermally stimulated depolarization currents (TSDC). The samples were thermoelectrically polarized at 500 °C under a DC electric field with a magnitude of 5 kV/cm. The biphasic samples were also polarized under electric fields with different magnitudes: 2, 3, 4 and 5 kV/cm. Additionally, the depolarization processes detected in the TSDC measurements were correlated with dielectric relaxation processes observed in impedance spectroscopy (IS) measurements.
The results indicate that the β-TCP crystalline phase has a considerable higher ability to store electrical charge compared with the Hap phase. This indicates that it has a suitable composition and structure for ionic conduction and establishment of a large electric charge density, providing great potential for orthopaedic applications.

2014
João, Carlos, Joana Vasconcelos, Jorge Carvalho Silva, and João Paulo Borges. "An Overview of Inverted Colloidal Crystal Systems for Tissue Engineering." Tissue Engineering Part B-Reviews 20 (2014): 437-454. AbstractWebsite

Scaffolding is at the heart of tissue engineering but the number of techniques available for turning biomaterials into scaffolds displaying the features required for a tissue engineering application is somewhat limited. Inverted colloidal crystals (ICCs) are inverse replicas of an ordered array of monodisperse colloidal particles, which organize themselves in packed long-range crystals. The literature on ICC systems has grown enormously in the past 20 years, driven by the need to find organized macroporous structures. Although replicating the structure of packed colloidal crystals (CCs) into solid structures has produced a wide range of advanced materials (e.g., photonic crystals, catalysts, and membranes) only in recent years have ICCs been evaluated as devices for medical/pharmaceutical and tissue engineering applications. The geometry, size, pore density, and interconnectivity are features of the scaffold that strongly affect the cell environment with consequences on cell adhesion, proliferation, and differentiation. ICC scaffolds are highly geometrically ordered structures with increased porosity and connectivity, which enhances oxygen and nutrient diffusion, providing optimum cellular development. In comparison to other types of scaffolds, ICCs have three major unique features: the isotropic three-dimensional environment, comprising highly uniform and size-controllable pores, and the presence of windows connecting adjacent pores. Thus far, this is the only technique that guarantees these features with a long-range order, between a few nanometers and thousands of micrometers. In this review, we present the current development status of ICC scaffolds for tissue engineering applications.

2013
Baptista, Ana Catarina, Isabel Ferreira, and João Borges. "Cellulose-based bioelectronic devices." In Cellulose - Medical, Pharmaceutical and Electronic Applications, edited by Theo van de Ven and Louis Godbout. InTech, 2013.
2012
Pimenta, Andreia F. R., Ana Catarina Baptista, Tânia Carvalho, Pedro Brogueira, Nuno Lourenço, Carlos Afonso, Susana Barreiros, Pedro Vidinha, and João Paulo Borges. "Electrospinning of Ion Jelly fibers." Materials Letters 83 (2012): 161-164. AbstractWebsite

Ion Jelly materials combine the chemical versatility and conductivity of an ionic liquid (IL) with the morphological versatility of a biopolymer (gelatin). They exhibit very interesting properties, such as conductivities up to 10− 4 S cm− 1, and high thermostability up to 180 °C, and have been used successfully to design electrochromic windows. In this work we report on the preparation of Ion Jelly fibers through electrospinning in order to obtain high surface area conductive materials. We have used the IL 1-(2-hydroxyethyl)-3-methyl-imidazolium tetrafluoroborate ([C2OHmim]BF4), which exhibits conveniently high ionic conductivity (over 10− 3 S cm− 1) and electrochemical stability (electrochemical window over 6.0 V). The morphology of the obtained fibers was quantified using Scanning Electron Microscopy (SEM) and Atomic Force Microscopy (AFM). We found that on average the effect of the IL on fiber diameter differs for lower and higher IL concentrations and that this effect was correlated with the initial conductivity and viscosity of Ion Jelly electrospinning solution. Moreover we also found that conductivities of Ion Jelly fibers are of the same order of magnitude as the conductivities of Ion Jelly dense films (~ 10− 4 S cm− 1). To the best of our knowledge, this is the first report on the incorporation of an IL into gelatin fibers using electrospinning. This opens up new opportunities for the application of gelatin fibers in electrochemical and biomedical devices.

2009
Henriques, Célia, Ricardo Vidinha, David Botequim, João Paulo Borges, and Jorge Carvalho Silva. "A systematic study of solution and processing parameters on nanofiber morphology using a new electrospinning apparatus." Journal of nanoscience and nanotechnology 9 (2009): 3535-3545. AbstractWebsite

We assembled a new electrospinning apparatus and used poly(ethylene oxide) as a model polymer to perform a systematic study on the influence of solution and processing parameters on the morphology of electrospun nanofibers. Solution parameters studied were polymer concentration and molecular mass. The solvent used, 60 wt% water,40 wt% ethanol, was the same throughout the study. Processing parameters analyzed were: solution feed rate, needle tip-collector distance and electrostatic potential difference between the needle and collector. Solution viscosity increased both with polymer concentration and molecular mass. Polymer concentration plays a decisive role on the outcome of the electrospinning process: a low concentration led to the formation of beaded fibers; an intermediate concentration yielded good quality fibers; a high concentration resulted in a bimodal size distribution and at even higher concentration a distributed deposition. Fiber diameter increased with polymer molecular mass and higher molecular masses are associated with a higher frequency of splaying events. Fiber diameter increased linearly with solution feed rate. While an increase in needle-collector distance represents a weaker electric field, a greater distance to be covered by the fibers and a longer flight time, presumably favoring the formation of thinner fibers, as solvent evaporation leads to a local increase of concentration and viscosity, viscoelastic forces opposing stretching caused an increase of fiber diameter with needle-collector distance. A higher voltage applied at the needle is associated with a higher charging of the polymer and a higher electrical current through it ultimately leading to incomplete solvent evaporation and merged fibers being produced. Controlling the charging of the polymer independently of the electric field strength was achieved by applying a voltage to the collector while distance and potential difference were kept constant. The increased electrostatic repulsion associated with an increase of the high voltage applied to the needle led to the disappearance of merged fibers.