Publications

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Book Chapter
Soares, Paula I. P., Isabel Ferreira, and João Paulo Borges. "Application of Hyperthermia for Cancer Treatment: Recent Patents Review." In Topics in Anti-Cancer Research, Vol. 3, edited by Atta-ur-Rahman and Khurshid Zaman, 342-383. Bentham Science Publishers, 2014. Abstract

Cancer is one of the main causes of death in the world and its incidence increases every day. Current treatments are insufficient and present many breaches. Hyperthermia is an old concept and was early established as a cancer treatment option, mainly in superficial cancers. More recently, the concept of intracellular hyperthermia emerged wherein magnetic particles are concentrated at the tumor site and remotely heated using an applied magnetic field to achieve hyperthermic temperatures (42-45ºC). Many patents have been registered in this area since the year 2000. This chapter presents the most relevant information organized in two main categories according to the use or not of nanotechnology. The patents without nanotechnology were divided into the following subcategories: 1) external Radio-Frequency devices; 2) hyperthermic perfusion; 3) frequency enhancers; 4) applying heat to the target site using a catheter; and 5) injection of magnetic and ferroelectric particles. The patents with nanotechnology were divided into three subcategories: 1) hyperthermia devices; 2) nanoparticles; and 3) nanostructures. The use of magnetic nanoparticles is a very promising treatment approach since it may be used for diagnostic and treatment. Magnetic nanoparticle could be applied to detect and diagnose the tumor and to carry a pharmacological active drug to be delivered in the tumor site or apply hyperthermia through an external magnetic field.

Baptista, Ana Catarina, Isabel Ferreira, and João Paulo Borges. "Cellulose-based composite systems for biomedical applications." In Biomass based Biocomposites, edited by Vijay Kumar Thakur and A. S. Singha, 47-60. U.K.: Smithers Rapra Technology, 2013.
João, Carlos, Jorge Carvalho Silva, and João Paulo Borges. "Chitin-Based Nanocomposites: Biomedical Applications." In Eco-friendly Polymer Nanocomposites, edited by Vijay Kumar Thakur and Manju Kumari Thakur, 439-457. Springer India, 2015. Abstract

Chitin, the second most abundant polymer in nature, is a renewable, nontoxic, biodegradable, and antibacterial polysaccharide. This semicrystalline biopolymer exhibits hierarchical structure from nano to micro-scale and is responsible for interesting living tissue properties. Recently, the scientific interest in chitin nanofibrils for applications in biomedical and tissue engineering fields has increased due to their particular capabilities such as matrix reinforcements, bioactivity and morphology similar to natural tissues. This chapter is focused on composite materials reinforced with chitin nanofibrils and their biomedical applications.

Soares, Paula I. P., Coro Echeverria, Ana Catarina Baptista, Carlos João, Susete Fernandes, Ana Almeida, Jorge Carvalho Silva, Maria Helena Godinho, and João Paulo Borges. "Hybrid polysaccharide-based systems for biomedical applications." In Hybrid Polymer Composite Materials: Applications, edited by Manju Kumari Thakur, Vijay Kumar Thakur and Asokan Pappu, 107-149. USA: Woodhead Publishing, Elsevier, 2017. Abstract

Hybrid materials have been widely studied for structural applications. Polysaccharide-based fibers, especially cellulosic fibers, have been explored in the last two decades as substitutes of the traditional reinforcements made of glass or carbon fibers due to their mechanical properties. However, their biocompatibility, biodegradability, and chemistry have attracted the researchers and new developments in the field of smart and functional materials arise in diverse applications. This chapter will focus on the biomedical applications of polysaccharide-based smart and functional materials, namely those concerning biosensors and actuators, theranostic systems, and tissue-engineering applications. Special attention will be given to cellulose- and chitin/chitosan-based hybrid materials because these are the two most abundant polysaccharides and probably the most promising for the development of hybrid materials for biomedical applications. Biomimetic strategies for the development of smart and functional hybrid materials will also be highlighted.

Baptista, Ana Catarina, Paula I. P. Soares, Isabel Ferreira, and João Paulo Borges. "Nanofibers and nanoparticles in biomedical applications." In Bioengineered Nanomaterials, edited by Atul Tiwari and Ashutosh Tiwari. USA: CRC Press (Taylor & Francis Group), 2013.
João, Carlos, Ana Catarina Baptista, Isabel Ferreira, Jorge Carvalho Silva, and João Paulo Borges. "Natural Nanofibres for Composite Applications." In Fibrous and Textile Materials for Composite Applications, edited by Sohel Rana and Raul Fangueiro, 261-299. Singapore: Springer Singapore, 2016. Abstract

Cellulose and chitin are the two most abundant natural polysaccharides. Both have a semicrystalline microfibrillar structure from which nanofibres can be extracted. These nanofibres are rod-like microcrystals that can be used as nanoscale reinforcements in composites due to their outstanding mechanical properties. This chapter starts by reviewing the sources, extraction methods and properties of cellulose and chitin nanofibres. Then, their use in the fabrication of structural and functional nanocomposites and the applications that have been investigated are reviewed. Nanocomposites are materials with internal nano-sized structures. They benefit from the properties of the nanofillers: low density, nonabrasive, nontoxic, low cost, susceptibility to chemical modifications and biodegradability. Diverse manufacturing technologies have been used to produce films, fibres, foams, sponges, aerogels, etc. Given their natural origin and high stiffness, these polymers have attracted a lot of attention not only in the biomedical and tissue engineering fields but also in areas such as pharmaceutics, cosmetics, agriculture, biosensors and water treatment.

Conference Proceedings
Strohmeier, P., C. Honnet, H. Perner-Wilson, M. Teyssier, B. Fruchard, Ana Catarina Baptista, and J. Steimle. Demo of PolySense: How to Make Electrically Functional Textiles In CHI Conference on Human Factors in Computing Systems., 2020. Abstract

We demonstrate a simple and accessible method for enhancing textiles with custom piezo-resistive properties. Based on in-situ polymerization, our method offers seamless integration at the material level, preserving a textile's haptic and mechanical properties. We demonstrate how to enhance a wide set of fabrics and yarns using only readily available tools. During each demo session, conference attendees may bring textile samples which will be polymerized in a shared batch. Attendees may keep these samples. While the polymerization is happening, attendees can inspect pre-made samples and explore how these might be integrated in functional circuits. Examples objects created using polymerization include rapid manufacturing of on-body interfaces, tie-dyed motion-capture clothing, and zippers that act as potentiometers.

Journal Article
Gavinho, Sílvia R., Manuel P. Graça, Pedro Prezas, João Borges Borges, Jorge Carvalho Silva, Eduardo Pires, Henrique Armês, and José Coucelo. "Antibacterial bioglass in dental implants: a canine clinical study." European Journal of Public Health 31 (2021): ckab120.006. AbstractWebsite

Background
Peri-implantitis is considered the most challenging biological complication in implantology, as untreated disease can progress and result in implant loss. Therefore, disease prevention is crucial in daily clinical practice. It has been reported that the use of bioactive glass, as an implant coating, can stimulate tissue integration and accelerate tissue regeneration. Besides these properties, it is possible to promote bacterial activity by inserting silver into the bioglass

Methods
Bioglass with composition 45S5 was synthesised by the fusion method, replacing the amount of Na2CO3 by AgNO3 (BG 2% wt). The implants were resealed by the CoBlast® technique. Clinical cases with pathology of the mandible/maxilla were selected and implants dimensioned for the canine bone structure were applied.

Results
Three months after implantation, imaging exams, namely CT scans, showed no signs of early rejection by septic or cytotoxic loss. No decrease or loss of peri-implant bone was observed. In all cases the implants remained without signs of instability, and with sufficient support for the application of the exo-prosthesis or dental crown. The results of histological analysis showed no signs of infection or osteolysis. The zone of peri-implant fibrosis was not observable in the samples, showing a good evolution in implant osteointegration.

Conclusions
The results show promising evidences for the use of this biomaterial as a coating, since aseptic rejection, later on, and that related to the shape and biomaterials used in the implant's design, usually begins during the first 3 months.

Soares, Paula I. P., Isabel Ferreira, Rui Igreja, Carlos Novo, and João Paulo Borges. "Application of Hyperthermia for Cancer Treatment: Recent Patents Review." Recent Patents on Anti-Cancer Drug Discovery 7 (2012): 64-73. AbstractWebsite

Cancer is one of the main causes of death in the world and its incidence increases every day. Current treatments are insufficient and present many breaches. Hyperthermia is an old concept and since early it was established as a cancer treatment option, mainly in superficial cancers. More recently the concept of intracellular hyperthermia emerged wherein magnetic particles are concentrated at the tumor site and remotely heated using an applied magnetic field to achieve hyperthermic temperatures (42-45°C). Many patents have been registered in this area since the year 2000. This review presents the most relevant information, organizing them according to the hyperthermic method used: 1) external Radio- Frequency devices; 2) hyperthermic perfusion; 3) frequency enhancers; 4) apply heating to the target site using a catheter; 5) injection of magnetic and ferroelectric particles; 6) injection of magnetic nanoparticles that may carry a pharmacological active drug. The use of magnetic nanoparticles is a very promising treatment approach since it may be used for diagnostic and treatment. An ideal magnetic nanoparticle would be able to detect and diagnose the tumor, carry a pharmacological active drug to be delivered in the tumor site, apply hyperthermia through an external magnetic field and allow treatment monitoring by magnetic resonance imaging.

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.

Faria, Jaime, Bruno Dionísio, Iris Soares, Ana Catarina Baptista, Ana Cláudia Marques, Lídia Gonçalves, Ana Bettencourt, Carlos Baleizão, and Isabel Ferreira. "Cellulose acetate fibres loaded with daptomycin for metal implant coatings." Carbohydrate polymers (2021): 118733. AbstractWebsite

Multifunctional polymeric coatings containing drug delivery vehicles can play a key role in preventing/reducing biofilm formation on implant surfaces. Their requirements are biocompatibility, good adhesion, and controllable drug release. Although cellulose acetate (CA) films and membranes are widely studied for scaffolding, their applications as a protective coating and drug delivery vehicle for metal implants are scarce. The reason is that adhesion to stainless steel (SS) substrates is non-trivial. Grinding SS substrates enhances the adhesion of dip-coated CA films while the adhesion of electrospun CA membranes is improved by an electrosprayed chitosan intermediate layer. PMMA microcapsules containing daptomycin have been successfully incorporated into CA films and fibres. The released drug concentration of 3 x10-3 mg/mL after 120 minutes was confirmed from the peak luminescence intensity under UV radiation of simulated body fluid (SBF) after immersion of the fibres.

Baptista, Ana Catarina, Inês Ropio, Beatriz Romba, Joana Nobre, Célia Henriques, Jorge Carvalho Silva, J. I. Martins, João Paulo Borges, and Isabel Ferreira. "Cellulose-based electrospun fibers functionalized with polypyrrole and polyaniline for fully organic batteries." Journal of Materials Chemistry A 6 (2018): 256-265. AbstractWebsite

A novel cellulose-based bio-battery made of electrospun fibers activated by biological fluids has been developed. This work reports a new concept for a fully organic bio-battery that takes advantage of the high surface to volume ratio achieved by an electrospun matrix composed of sub-micrometric fibers that acts simultaneously as the separator and the support of the electrodes. Polymer composites of polypyrrole (PPy) and polyaniline (PANI) with cellulose acetate (CA) electrospun matrix were produced by in situ chemical oxidation of pyrrole and aniline on the CA fibers. The structure (CA/PPy|CA|CA/PANI) generated a power density of 1.7 mW g−1 in the presence of simulated biological fluids, which is a new and significant contribution to the domain of medical batteries and fully organic devices for biomedical applications.

João, Carlos, Ana Teresa Kullberg, Jorge Carvalho Silva, and João Paulo Borges. "Chitosan Inverted Colloidal Crystal scaffolds: Influence of molecular weight on structural stability." Materials Letters 193 (2017): 50-53. AbstractWebsite

Chitosan with three different molecular weights (538 ± 48, 229 ± 45 and 13 ± 3 kDa) was used to develop biodegradable Inverted Colloidal Crystal (ICC) scaffolds with uniform pore size and interconnected pore network. Mass loss and compression modulus were analyzed after hydrolytic degradation in order to understand the influence of molecular weight on structural and mechanical degradation of chitosan ICC structures. Results show that medium molecular weight chitosan (229 ± 45 kDa) retains ICC structure and compression modulus for an extended period (4 weeks) and is therefore the preferred one for the production of ICC for soft tissue engineering.

Soares, Paula I. P., Ana Isabel Sousa, Jorge Carvalho Silva, Isabel Ferreira, Carlos Novo, and João Paulo Borges. "Chitosan-based nanoparticles as drug delivery systems for doxorubicin: optimization and modelling." Carbohydrate polymers 147 (2016): 304-312. AbstractWebsite

In the present work, two drug delivery systems were produced by encapsulating doxorubicin into chitosan and O-HTCC (ammonium-quaternary derivative of chitosan) nanoparticles. The results show that doxorubicin release is independent of the molecular weight and is higher at acidic pH (4.5) than at physiological pH. NPs with an average hydrodynamic diameter bellow 200 nm are able to encapsulate up to 70% and 50% of doxorubicin in the case of chitosan and O-HTCC nanoparticles, respectively. O-HTCC nanoparticles led to a higher amount of doxorubicin released than chitosan nanoparticles, for the same experimental conditions, although the release mechanism was not altered. A burst effect occurs within the first hours of release, reaching a plateau after 24 h. Fitting mathematical models to the experimental data led to a concordant release mechanism between most samples, indicating an anomalous or mixed release, which is in agreement with the swelling behavior of chitosan described in the literature.

Zamora-Mora, Vanessa, Paula I. P. Soares, Coro Echeverria, Rebeca Hernández, and Carmen Mijangos. "Composite chitosan/agarose ferrogels for potential applications in magnetic hyperthermia." Gels 1 (2015): 69-80. AbstractWebsite

Composite ferrogels were obtained by encapsulation of magnetic nanoparticles at two different concentrations (2.0 and 5.0 % w/v) within mixed agarose/chitosan hydrogels having different concentrations of agarose (1.0, 1.5 and 2.0% (w/v)) and a fixed concentration of chitosan (0.5% (w/v)). The morphological characterization carried out by scanning electron microscopy showed that dried composite ferrogels present pore sizes in the micrometer range. Thermogravimetric measurements showed that ferrogels present higher degradation temperatures than blank chitosan/agarose hydrogels without magnetic nanoparticles. In addition, measurements of the elastic moduli of the composite ferrogels evidenced that the presence of magnetic nanoparticles in the starting aqueous solutions prevents to some extent the agarose gelation achieved by simply cooling chitosan/agarose aqueous solutions. Finally, it is shown that composite chitosan/agarose ferrogels are able to heat in response to the application of an alternating magnetic field so that they can be considered as potential biomaterials to be employed in magnetic hyperthermia treatments.

Marques, Susana, Paula I. P. Soares, Coro Echeverria, Maria Helena Godinho, and João Paulo Borges. "Confinement of thermoresponsive microgels into fibres via colloidal electrospinning: experimental and statistical analysis." RSC Advances 6 (2016): 76370-76380. AbstractWebsite

The strategy of confining stimuli-responsive microgels in electrospun fibres would allow the fabrication of polymeric networks that combine the microgels swelling ability and properties with the interest features of the electrospun fibres. Colloidal electrospinning is an emerging method in which fibres containing microgels can be produced by a single-nozzle and designed through the solution carrier materials. The incorporation of poly(N-isopropylacrylamide) (PNIPAAM) and PNIPAAM-chitosan (PNIPAAM-CS) in poly(ethyleneoxyde) (PEO) fibres via colloidal electrospinning producing composite fibres was the main purpose of the present work{,} which was confirmed by means of Scanning Electron Microscopy (SEM). Dynamic light scattering was used to analyse the microgels hydrodynamic diameter ranging up to 900 nm depending on the composition and temperature of the surrounding medium. By performing a statistical analysis the relationship of the processing variables over the fibre size was evaluated following the response surface methodology (RSM). From the set of parameters aimed to minimize the fibre diameter{,} composite fibres with an average diameter of 63 nm were produced. Only the as-prepared microgels with higher monodispersity provided {"}bead-on-a-string{"} morphologies.

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.

Soares, Paula I. P., Joana Romão, Ricardo Matos, Jorge Carvalho Silva, and João Paulo Borges. "Design and engineering of magneto-responsive devices for cancer theranostics: Nano to macro perspective." Progress in Materials Science 116 (2021): 100742. AbstractWebsite

Design, research, and development of new and improved smart multifunctional devices is one of the main topics in the advanced functional materials agenda for the next decade. Smart materials that can be triggered by external stimuli are seen with high potential for innovative treatments and improved drug delivery systems by regulatory agencies like the FDA and EMA. The incorporation of magnetic nanostructures into complex systems produces multifunctional devices that can be spatiotemporally controlled by an external magnetic field. These magneto-responsive devices can be used for a multitude of biomedical applications, from diagnostic to the treatment of tumors, and are actively being developed and tested for cancer theranostics. Herein, we review the development of magneto-responsive devices for cancer theranostics, starting from the most straightforward architecture, single nanoparticles. We give some theoretical concepts about the design and production of such systems while providing a critical review of applications in clinical practice. Naturally, the review evolves to more complex architectures, from one-dimensional to three-dimensional magneto-responsive systems, demonstrating higher complexity and multifunctionality, and consequently, higher interest for clinical practice. The review ends with the main challenges in the design and engineering of magneto-responsive devices for cancer theranostics and future trends in this biomedical field.

Ribeiro, Maximiano P., Ana Espiga, Daniela Silva, Patricia Baptista, Joaquim Henriques, Catarina Ferreira, Jorge Carvalho Silva, João Paulo Borges, Eduardo Pires, Paula Chaves, and Ilídio J. Correia. "Development of a new chitosan hydrogel for wound dressing." Wound repair and regeneration 17 (2009): 817-824. AbstractWebsite

Wound healing is a complex process involving an integrated response by many different cell types and growth factors in order to achieve rapid restoration of skin architecture and function. The present study evaluated the applicability of a chitosan hydrogel (CH) as a wound dressing. Scanning electron microscopy analysis was used to characterize CH morphology. Fibroblast cells isolated from rat skin were used to assess the cytotoxicity of the hydrogel. CH was able to promote cell adhesion and proliferation. Cell viability studies showed that the hydrogel and its degradation by-products are noncytotoxic. The evaluation of the applicability of CH in the treatment of dermal burns in Wistar rats was performed by induction of full-thickness transcutaneous dermal wounds. Wound healing was monitored through macroscopic and histological analysis. From macroscopic analysis, the wound beds of the animals treated with CH were considerably smaller than those of the controls. Histological analysis revealed lack of a reactive or a granulomatous inflammatory reaction in skin lesions with CH and the absence of pathological abnormalities in the organs obtained by necropsy, which supported the local and systemic histocompatibility of the biomaterial. The present results suggest that this biomaterial may aid the re-establishment of skin architecture.

dos Santos, Renato, Ângelo Rocha, Ana Matias, Catarina Duarte, Isabel Sá-Nogueira, Nuno Lourenço, and João Paulo Borges. "Development of antimicrobial Ion Jelly fibers." RSC Advances 3 (2013): 24400-24405. Abstract

We report a method to obtain electrospun fibers based on ionic liquids and gelatin, exhibiting antimicrobial properties.

Baptista, Ana Catarina, Alexandre Botas, Ana Almeida, Ana Nicolau, Bruno Falcão, Manuel Soares, Joaquim Pratas Leitão, Rodrigo Martins, João Paulo Borges, and Isabel Ferreira. "Down conversion photoluminescence on PVP/Ag-nanoparticles electrospun composite fibers." Optical Materials 39 (2015): 278-281. AbstractWebsite

The influence of Ag nanoparticles (Ag NPs) on the luminescence of electrospun nonwoven mats made of polyvinylpyrrolidone (PVP) has been studied in this work. The PVP fibers incorporating 2.1–4.3 nm size Ag NPs show a significant photoluminescence (PL) band between 580 and 640 nm under 325 nm laser excitation. The down conversion luminescence emission is present even after several hours of laser excitation, which denotes the durability and stability of fibers to consecutive excitations. As so these one-dimensional photonic fibers made using cheap methods is of great importance for organic optoelectronic applications, fluorescent clothing or counterfeiting labels.

Soares, Paula I. P., Sérgio Dias, Carlos Novo, Isabel Ferreira, and João Paulo Borges. "Doxorubicin vs. ladirubicin: methods for improving osteosarcoma treatment." Mini reviews in medicinal chemistry 12 (2012): 1239-1249. AbstractWebsite

Osteosarcoma is the most common primary bone tumor in children and adolescents, with a 5-year disease free survival rate of 70%. Current chemotherapy regimens comprise a group of chemotherapeutic agents in which doxorubicin is included. However, tumor resistance to anthracyclines and cardiotoxicity are limiting factors for its usage. Liposomal formulations of doxorubicin improve its anti-cancer effects but are still insufficient. The research in this area has lead to the production of anthracyclines analogues, such as ladirubicin, the leading compound of alkylcyclines. This new anticancer agent has shown promising results in vivo and in vitro, being effective against osteosarcoma cell lines, including those with a multidrug resistant phenotype. In phase I clinical trials, this molecule caused mild side effects and did not induce significant cardiotoxicity at doses ranging from 1 to 16 mg/m2, resulting in a peak plasma concentration (Cmax) ranging from 0.5 to 1.5 μM. The recommended doses for phase II studies were 12 and 14 mg/m2 in heavily and minimally pretreated/non-pretreated patients, respectively. Phase II clinical trials in ovary, breast, colorectal cancer, NSCLC and malignant melanoma are underway. Given the improved molecular targeting efficacy of these new compounds, ongoing approaches have sought to improve drug delivery systems, to improve treatment efficacy while reducing systemic toxicity. The combination of these two approaches may be a good start for the discovery of new treatment for osteosarcoma.

Soares, Paula I. P., Ana Alves, Laura Pereira, Joana Coutinho, Isabel Ferreira, Carlos Novo, and João Paulo Borges. "Effects of surfactants on the magnetic properties of iron oxide colloids." Journal of Colloid and Interface Science 419 (2014): 46-51. AbstractWebsite

Iron oxide nanoparticles are having been extensively investigated for several biomedical applications such as hyperthermia and magnetic resonance imaging. However, one of the biggest problems of these nanoparticles is their aggregation.
Taking this into account, in this study the influence of three different surfactants (oleic acid, sodium citrate and Triton X-100) each one with various concentrations in the colloidal solutions stability was analyzed by using a rapid and facile method, the variation in the optical absorbance along time.
The synthesized nanoparticles through chemical precipitation showed an average size of 9 nm and a narrow size distribution. X-ray diffraction pattern and Fourier Transform Infrared analysis confirmed the presence of pure magnetite. SQUID measurements showed superparamagnetic properties with a blocking temperature around 155 K. In addition it was observed that neither sodium citrate nor Triton X-100 influences the magnetic properties of the nanoparticles. On the other hand, oleic acid in a concentration of 64 mM decreases the saturation magnetization from 67 to 45 emu/g. Oleic acid exhibits a good performance as stabilizer of the iron oxide nanoparticles in an aqueous solution for 24 h, for concentrations that lead to the formation of the double layer.

Ferreira, José Luis, Susana Gomes, Célia Henriques, João Paulo Borges, and Jorge Carvalho Silva. "Electrospinning polycaprolactone dissolved in glacial acetic acid: Fiber production, nonwoven characterization, and In Vitro evaluation." Journal of Applied Polymer Science 131 (2014): 41068. AbstractWebsite

The electrospinning of polycaprolactone (PCL) dissolved in glacial acetic acid and the characterization of the resultant nonwoven fiber mats is reported in this work. For comparison purposes, PCL fiber mats were also obtained by electrospinning the polymer dissolved in chloroform. Given the processing parameters chosen, results show that 14 and 17 wt % PCL solutions are not viscous enough and yield beaded fibers, 20 and 23 wt % solutions give rise to high quality fibers and 26 wt % solutions yield mostly irregular and fused fibers. The nonwoven mats are highly porous, retain the high tensile strain of PCL, and the fibers are semicrystalline. Cells adhere and proliferate equally well on all mats, irrespective of the solvent used in their production. In conclusion, mats obtained by electrospinning PCL dissolved in acetic acid are also a good option to consider when producing scaffolds for tissue engineering. Moreover, acetic acid is miscible with polar solvents, which may allow easier blending of PCL with hydrophilic polymers and therefore achieve the production of electrospun nanofibers with improved properties.

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.

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.

Franco, Patrícia Q., Carlos João, Jorge Carvalho Silva, and João Paulo Borges. "Electrospun hydroxyapatite fibers from a simple sol–gel system." Materials Letters 67 (2012): 233-236. AbstractWebsite

This work reports the production of hydroxyapatite (HA) sub-micron fibers by combining electrospinning and a non-alkoxide sol–gel system, using cheap precursors. Phosphorus pentoxide (P2O5) and calcium nitrate tetrahydrate (Ca(NO3)2.4H2O) were used as precursors of phosphorus and calcium, respectively. The fibers were electrospun from a mixture of the gel formed from the system Ca(NO3)2.4H2O/P2O5 with polymeric solutions of polyvinylpyrrolidone (PVP) in water and ethanol/water mixtures. The fibers were analyzed for their morphology (Scanning Electron Microscopy, SEM), chemical composition (Fourier Transform Infrared Spectroscopy, FTIR) and structure (X-ray diffraction, XRD). The fibers obtained were composed mainly of type B carbonated HA with traces of β-tricalcium phosphate (β-TCP). SEM analysis revealed that increasing the concentration of water in the solvent system, used in the preparation of electrospinning solutions, led to fibers with smaller diameters and narrower diameter distribution.

Echeverria, Coro, Susete N. Fernandes, Maria Helena Godinho, João Borges Borges, and Paula I. P. Soares. "Functional Stimuli-Responsive Gels: Hydrogels and Microgels." Gels 4 (2018): 54. AbstractWebsite

One strategy that has gained much attention in the last decades is the understanding and further mimicking of structures and behaviours found in nature, as inspiration to develop materials with additional functionalities. This review presents recent advances in stimuli-responsive gels with emphasis on functional hydrogels and microgels. The first part of the review highlights the high impact of stimuli-responsive hydrogels in materials science. From macro to micro scale, the review also collects the most recent studies on the preparation of hybrid polymeric microgels composed of a nanoparticle (able to respond to external stimuli), encapsulated or grown into a stimuli-responsive matrix (microgel). This combination gave rise to interesting multi-responsive functional microgels and paved a new path for the preparation of multi-stimuli “smart” systems. Finally, special attention is focused on a new generation of functional stimuli-responsive polymer hydrogels able to self-shape (shape-memory) and/or self-repair. This last functionality could be considered as the closing loop for smart polymeric gels.

Gonçalves, Adriana, Filipe V. Almeida, João Paulo Borges, and Paula I. P. Soares. "Incorporation of Dual-Stimuli Responsive Microgels in Nanofibrous Membranes for Cancer Treatment by Magnetic Hyperthermia." Gels 7 (2021): 28. AbstractWebsite

The delivery of multiple anti-cancer agents holds great promise for better treatments. The present work focuses on developing multifunctional materials for simultaneous and local combinatory treatment: Chemotherapy and hyperthermia. We first produced hybrid microgels (MG), synthesized by surfactant-free emulsion polymerization, consisting of Poly (N-isopropyl acrylamide) (PNIPAAm), chitosan (40 wt.%), and iron oxide nanoparticles (NPs) (5 wt.%) as the inorganic component. PNIPAAm MGs with a hydrodynamic diameter of about 1 μm (in their swollen state) were successfully synthesized. With the incorporation of chitosan and NPs in PNIPAAm MG, a decrease in MG diameter and swelling capacity was observed, without affecting their thermosensitivity. We then sought to produce biocompatible and mechanically robust membranes containing these dual-responsive MG. To achieve this, MG were incorporated in poly (vinyl pyrrolidone) (PVP) fibers through colloidal electrospinning. The presence of NPs in MG decreases the membrane swelling ratio from 10 to values between 6 and 7, and increases the material stiffness, raising its Young modulus from 20 to 35 MPa. Furthermore, magnetic hyperthermia assay shows that PVP-MG-NP composites perform better than any other formulation, with a temperature variation of about 1 °C. The present work demonstrates the potential of using multifunctional colloidal membranes for magnetic hyperthermia and may in the future be used as an alternative treatment for cancer.

Carrêlo, Henrique, Paula I. P. Soares, João Borges Borges, and Maria Teresa Cidade. "Injectable Composite Systems Based on Microparticles in Hydrogels for Bioactive Cargo Controlled Delivery." Gels 7 (2021): 147. AbstractWebsite

Engineering drug delivery systems (DDS) aim to release bioactive cargo to a specific site within the human body safely and efficiently. Hydrogels have been used as delivery matrices in different studies due to their biocompatibility, biodegradability, and versatility in biomedical purposes. Microparticles have also been used as drug delivery systems for similar reasons. The combination of microparticles and hydrogels in a composite system has been the topic of many research works. These composite systems can be injected in loco as DDS. The hydrogel will serve as a barrier to protect the particles and retard the release of any bioactive cargo within the particles. Additionally, these systems allow different release profiles, where different loads can be released sequentially, thus allowing a synergistic treatment. The reported advantages from several studies of these systems can be of great use in biomedicine for the development of more effective DDS. This review will focus on in situ injectable microparticles in hydrogel composite DDS for biomedical purposes, where a compilation of different studies will be analysed and reported herein.

Cidade, Maria Teresa, Diogo J. Ramos, Jenifer Santos, Núria Calero, J. Muñoz, and João Paulo Borges. "Injectable hydrogels based on pluronic/water systems filled with alginate microparticles: Rheological characterization." Publisher Logo Conference Proceedings 1981 (2018): 020091. AbstractWebsite

In this paper the rheological characterization of Pluronic/water systems filled with alginate microparticles is presented. The rheological characterization of the Pluronic/water systems allowed for the choice of the best Pluronic concentration taking into account its applications as injectable hydrogels for tissue repair. The effect on the rheological behavior of the addition of alginate microparticles, to be loaded with the drug, was analyzed and the maximum concentration of microparticles determined.

Soares, Paula I. P., César Laia, Alexandra Carvalho, Laura Pereira, Joana Coutinho, Isabel Ferreira, Carlos Novo, and João Paulo Borges. "Iron oxide nanoparticles stabilized with a bilayer of oleic acid for magnetic hyperthermia and MRI applications." Applied Surface Science 383 (2016): 240-247. AbstractWebsite

Iron oxide nanoparticles (Fe3O4, IONPs) are promising candidates for several biomedical applications such as magnetic hyperthermia and as contrast agents for magnetic resonance imaging (MRI). However, their colloidal stability in physiological conditions hinders their application requiring the use of biocompatible surfactant agents. The present investigation focuses on obtaining highly stable IONPs, stabilized by the presence of an oleic acid bilayer. Critical aspects such as oleic acid concentration and pH were optimized to ensure maximum stability. NPs composed of an iron oxide core with an average diameter of 9 nm measured using transmission electron microscopy (TEM) form agglomerates with an hydrodynamic diameter of around 170 nm when dispersed in water in the presence of an oleic acid bilayer, remaining stable (zeta potential of −120 mV). Magnetic hyperthermia and the relaxivities measurements show high efficiency at neutral pH which enables their use for both magnetic hyperthermia and MRI.

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.

Gavinho, Sílvia R., Pedro R. Prezas, Diogo J. Ramos, Isabel Sá-Nogueira, João Borges Borges, Carmo M. Lança, Jorge Carvalho Silva, Célia Henriques, Eduardo Pires, Jakka Suresh Kumar, and Manuel P. Graça. "Nontoxic glasses: Preparation, structural, electrical and biological properties." Applied Ceramics Technology 16 (2019): 1885-1894. AbstractWebsite

Bacterial infections affect about 1 in 5 patients who receive a dental implant within 5 years of surgery. To avoid the implant rejection it is necessary for the development of innovative biomaterials, with addition or substitution of the ions, for implant coatings that promote a strong bond with the new host bone and antibacterial action. The objective of this work was to synthesize a bioactive glass with different silver concentrations to evaluate their antibacterial performance. The glasses were synthesized with up to 2% silver content by melt-quenching. Structural, morphological, biological, and electrical properties of all samples were studied. The biological behavior was evaluated through cytotoxicity tests and antibacterial activity. The structural analysis shows that the introduction of silver do not promote significant changes, not altering the advantageous properties of the bioglass of the bioglass. It was verified that the glasses with a silver content from 0.5% to 2%, completely prevented the growth of both Staphylococcus aureus and Escherichia coli while being nontoxic toward mammalian cells. Therefore, these bioglasses are promising materials to be used in the production of dental implants with antimicrobial activity.

Echeverria, Coro, Paula I. P. Soares, Ana Robalo, Laura Pereira, Carlos Novo, Isabel Ferreira, and João Paulo Borges. "One-pot synthesis of dual-stimuli responsive hybrid PNIPAAm-chitosan microgels." Materials & Design 86 (2015): 745-751. AbstractWebsite

The incorporation of magnetic nanoparticles into poly(N-isopropylacrylamide) (PNIPAAm) and chitosan microgels gives rise to hybrid systems that combine the microgels swelling capacity with the interesting features presented in magnetic nanoparticles. The presence of chitosan that act as surfactant for magnetic nanoparticles provides a simplistic approach which allows the encapsulation of magnetic nanoparticles without any previous surface modification. Spherical and highly monodisperse microgels with diameters in the range of 200 to 500 nm were obtained. The encapsulation of magnetic nanoparticles in the polymer matrix was confirmed by high resolution Scanning Electron Microscopy in transmission mode. Volume phase transition of the microgels was accessed by Dynamic Light Scattering measurements. It was observed that the thermosensitivity of the PNIPAM microgels still persists in the hybrid microgels; however, the swelling ability is compromised in the microgels with highest chitosan content. The heating performance of the hybrid magnetic microgels, when submitted to an alternating magnetic field, was also evaluated demonstrating the potential of these systems for hyperthermia treatments.

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.

Gavinho, Sílvia R., Mariana Castro Soares, João Borges Borges, Jorge Carvalho Silva, Isabel Sá Nogueira, and Manuel P. Graça. "Preparation and Characterization of Zinc and Magnesium Doped Bioglasses." Nanoscience and Nanotechnology in Security and Protection against CBRN Threats (2020): 465-475. AbstractWebsite

Peri-implantitis is an infectious disease that affects about one of five patients who receive a dental implant within 5 years after the surgery. To minimize this reaction the development of new biomaterials with antibacterial action is needed that can be used as a coating material in orthodontic implants. In addition, these biomaterials can be doped with several ions, which add specific properties that may act at the cellular level, such as increasing the angiogenesis efficiency. In this work, 45S5 Bioglass® has been used as the base material because it presents higher bioactivity compared to other biomaterials. To add antibacterial function and increase positive effects on bone metabolism, zinc and magnesium ions were introduced in the glass network. The main objective was the synthesis of the 45S5 glass by melt-quenching and study the biological performance as function of the zinc and magnesium concentrations. The structural and biological properties of the prepared samples are discussed.

Mano, Francisca, Marta Martins, Isabel Sá-Nogueira, Susana Barreiros, João Paulo Borges, Rui Reis, Ana Rita Duarte, and Alexandre Paiva. "Production of Electrospun Fast-Dissolving Drug Delivery Systems with Therapeutic Eutectic Systems Encapsulated in Gelatin." AAPS PharmSciTech 18 (2017): 2579-2585. AbstractWebsite

Fast-dissolving delivery systems (FDDS) have received increasing attention in the last years. Oral drug delivery is still the preferred route for the administration of pharmaceutical ingredients. Nevertheless, some patients, e.g. children or elderly people, have difficulties in swallowing solid tablets. In this work, gelatin membranes were produced by electrospinning, containing an encapsulated therapeutic deep-eutectic solvent (THEDES) composed by choline chloride/mandelic acid, in a 1:2 molar ratio. A gelatin solution (30% w/v) with 2% (v/v) of THEDES was used to produce electrospun fibers and the experimental parameters were optimized. Due to the high surface area of polymer fibers, this type of construct has wide applicability. With no cytotoxicity effect, and showing a fast-dissolving release profile in PBS, the gelatin fibers with encapsulated THEDES seem to have promising applications in the development of new drug delivery systems.