Nanocomposite polymer beads for cell detection

Circulating tumor cells (CTCs) may induce metastases when detached from the primary tumor. The numbers of these cells in blood offers a valuable prognostic indication. Magnetoresistive sensing is an attractive option for CTC counting. In this technique, cells are labeled with nancomposite polymer beads that provide the magnetic signal. Bead properties such as size and magnetic content must be optimized in order to be used as a detection tool in a magnetoresistive platform. Another important component of the platform is the magnet required for proper sensing. Both components are addressed in this work. Nanocomposite polymer beads were produced by nano-emulsion and membrane emulsification. Formulations of the oil phase comprising a mixture of aromatic monomers and iron oxide were employed. The effect of emulsifier (surfactant) concentration on bead size was studied. Formulations of polydimethilsiloxane (PDMS) with different viscosities were also prepared with nano-emulsion method resulting in colloidal beads. Polycaprolactone (PCL) beads were also synthetized by the membrane emulsification method. The beads were characterized by different techiques such as dynamic light scattering (DLS), thermogravimetric analysis (TGA) and scanning electron microscopy (SEM). Additionally, the magnet dimensions of the platform designed to detect CTCs were optimized through a COMSOL multiphysics simulation

High performance magnetoelectric nanocomposite morphologies for advanced applications

Tese de Doutoramento em Engenharia de MateriaisThe magnetoelectric (ME) effect is characterized by the variation of the electrical polarization of a material with an applied magnetic field and the variation of the magnetization of a material with an applied electric field. Single-phase materials with intrinsic ME effect are not generally used for practical applications since they typically show weak ME coupling at room temperatures. Such problem has been overcome by the development of ME composites. Strong ME effect at room temperature has been obtained, particularly in those composed by a piezoelectric and a magnetostrictive phase. In such materials, a strain is induced on the magnetostrictive phase once a magnetic field is applied to the composite. This strain is transmitted to the piezoelectric constituent, which undergoes a change in the electrical polarization. In an analogous way, the reverse effect can occur. The main objective of the thesis was the development of high performance polymer-based ME materials, that were characterized, optimized and their potential applications evaluated. Particulate ME composites were produced from materials with strong piezoelectric - poly(vinylidene fluoride) (P(VDF)) - and magnetostrictive - Cobalt iron oxide (CoFe2O4 - CFO) - responses in the form of film, membrane, fibers, and spheres. Related piezoelectric materials, such as the copolymer of P(VDF), poly(vinylidene fluoride-trifluoroethylene) (P(VDF-TrFE)), and magnetic nanoparticles, such as magnetite (Fe3O4), goethite (δ-FeO(OH)) and CoFeO(OH), were also used. All developed morphologies show the presence of the ME effect. The studies on film morphology addressed the relevance of the magnetostrictive filler dispersion on ME composite response, suggesting that the use of surfactants or ultrasounds to improve the dispersion leads to the same ME response. The filler size and shape shows an important role on the ME measurements. Studies with Fe3O4 nanoparticle with sizes of 9, 30 and 50 nm within a P(VDF-TrFE) matrix show that the largest α31 = 0.97 mV.cm-1Oe-1 is obtained for the lowest nanoparticle size. The shape of the same filler was studied and the results shows that a rod shape, comparing with a spherical, nucleate the β-phase of P(VDF), due to the high interface interaction between the polymer and the filler. Anisotropic nanosheet fillers of δ-FeO(OH) and CoFeO(OH) were synthetized and evaluated for the preparation of ME composites. Thus, δ-FeO(OH) /P(VDF-TrFE) composites lead to a maximum ME response of 0.4 mV.cm-1.Oe-1, which depends on filler content, alignment state as well as on both incident magnetic field direction and magnitude. A new ME effect is proposed based on the magnetic rotation of the nanosheets inside the piezoelectric polymer matrix. New CoFeO(OH) highly magnetostrictive (λ = 507 ppm) and anisotropic nanostructures were synthesized by a coprecipitation method using a modified gas-slugs microfluidic system. CoFeO(OH) /P(VDF-TrFE) composites reveal an interfacial ME coupling strongly dependent on the angle between HDC and filler length direction, with a maximum α31 = 5.10 mV.cm-1.Oe-1. ME membranes were also produced in CFO/P(VDF-TrFE) composites. The porous morphology and ME response were evaluated. The porous composite shows piezoelectricity with an effective piezoelectric coefficient (d33) of -22 pC.N-1, a maximum magnetization of 12 emu.g-1 and a maximum ME coefficient of 9 mV.cm-1.Oe-1. ME nanofibers and microspheres of CFO/P(VDF) produced by electrospinning and electrospray technique, respectively, were studied and evaluated. The average diameter of the nanofibers is ≈325 nm, independently of filler content, and the amount of crystalline polar β-phase was strongly enhanced when compared to pure P(VDF) polymer fibers, due to the introduction of the magnetostrictive fillers. The piezoelectric response of these electroactive nanofibers was modified by an applied magnetic field, thus evidencing the ME character of the CFO/P(VDF) composites. The CFO nanoparticles content in the ME microspheres (3-7 µm diameter) reached values up to 27 wt.%, despite their concentration in the starting solution reaching values up to 70 wt.%. No relevant effect on β-phase content (≈60 %), crystallinity (40 %) and onset degradation temperature (460-465 °C) of the polymer matrix was observed. The ME microspheres show a maximum|d33|≈30 pC.N-1, leading to a ME response of ∆|d33|≈5 pC.N-1 obtained when a 220 mT DC magnetic field was applied. Its also shown that the interface between CFO and P(VDF) (0-55 %) has a strong influence on the ME response of the microspheres. The simplicity and the scalability of the processing methods used in the present work as well as the excellent ME response in a large variety of composite morphologies suggest a large application potential of the developed polymer-based ME composites in areas such as sensors and actuators and tissue engineering, among others.O efeito magnetoelétrico (ME) é caraterizado pela variação da polarização elétrica do material na presença de um campo magnético e pela variação da magnetização do material quando um campo elétrico é aplicado. Os materiais de fase única com o efeito ME intrínseco não são usualmente utilizados em aplicações uma vez que possuem fraco acoplamento ME à temperatura ambiente. Este problema é então ultrapassado com o desenvolvimento de compósitos MEs. Nestes, verifica-se um forte efeito ME obtido à temperatura ambiente, particularmente quando constituídos por uma fase piezoelétrica e outra magnetostritiva. Nestes materiais, a deformação é induzida na fase magnetostritiva quando um campo magnético é aplicado ao compósito. Essa deformação é transmitida ao constituinte piezoelétrico que provoca uma mudança na polarização elétrica do material. O efeito contrário pode ser também observado. O objetivo principal desta tese foi o desenvolvimento de materiais ME de base polimérica com alta performance, caracterização, otimização e avaliação para potencial aplicação. Foram produzidos compósitos ME particulados a partir de materiais com uma forte resposta piezoelétrica – poli(fluoreto de vinilideno) (P(VDF)) – e magnetostritiva – CoFe2O4 (CFO) – em forma de filme, membrana, fibras e esferas. O polímero piezoelétrico como o copolimero do P(VDF), poli(fluoreto de vinilideno-trifluoretileno) (P(VDF-TrFE)), e nanopartículas como Fe3O4, δ-FeO(OH) e CoFeO(OH) foram também estudados. Todos as morfologias desenvolvidas mostram a presença do efeito ME. Os estudos realizados na morfologia de filmes mostram a relevância da dispersão do material de reforço nos compósitos ME. Estes sugerem que tanto o uso de surfactantes como do ultrassons, para dispersar, têm a mesma influência nas medidas ME dos compósitos. O tamanho e a forma do material de reforço têm um papel importante nas medidas ME. Estudos com nanopartículas de Fe3O4 com tamanhos de 9, 30 e 50 nm no interior da matriz polimérica de P(VDF-TrFE), mostram que o maior α31 (0.97 mV.cm-1Oe-1) é obtido para a nanopartícula de menor tamanho. A influência da forma do material de reforço foi estudada e os resultados mostram que a forma de bastão, comparada com a esférica, nucleiam a fase β do P(VDF) devido à alta interação na interface entre o polímero e o material de reforço. Foram também sintetizadas e avaliadas as nanofolhas anisotrópicas de δ-FeO(OH) e CoFeO(OH) para a preparação de compósitos ME. Compósitos de δ-FeO(OH)/P(VDF-TrFE) com um máximo de ≈0.4 mV.cm-1.Oe-1, variam consoante a concentração do material de reforço, alinhamento e a direção e intensidade dos dois campos magnéticos incidentes. Um novo efeito ME é proposto baseado na rotação magnética das nanofolhas no interior da matriz polímérica. Sintetizou-se uma nova nanoestrutura anisotrópica de CoFeO(OH) com alta magnetostrição (λ = 507 ppm), pelo método de coprecipitação, com uma modificação no sistema microfluídico “gas-slugs”. Nanocompósitos de CoFeO(OH) /P(VDF-TrFE) revelam um acoplamento ME fortemente dependente do ângulo entre o HDC e o comprimento do CoFeO(OH), com um máximo α31 de 5.10 mV.cm-1.Oe-1. Membranas ME foram igualmente produzidas em compósitos CFO/P(VDF-TrFE). A morfologia porosa e a resposta ME foram avaliadas. O compósito poroso apresenta uma resposta piezoelétrica com um coeficiente piezoelétrico efetivo (d33) de -22 pC.N-1, uma magnetização máxima de 12 emu.g-1 e um coeficiente ME máximo de 9 mV.cm-1.Oe-1. Foram estudadas e avaliadas nanofibras e microesferas de CFO/P(VDF) produzidas por electrospinning e electrospray, respetivamente. O diâmetro médio das nanofibras foi de ≈325 nm, independentemente da quantidade de material de reforço e da quantidade da fase polar β, que é fortemente aumentada com a introdução do material de reforço magnetoestritivo quando comparada com as fibras puras de P(VDF). A resposta piezoelétrica das nanofibras eletroativas é modificada com a aplicação de um campo magnético, evidenciando assim o carácter ME do compósito CFO/P(VDF). Microesferas ME (3-7 µm de diâmetro) com nanopartículas de CFO foram preparadas com concentrações que chegam aos 27 % em peso, apesar de a solução inicial ter 70 %. Não foram verificadas alterações de fase β (≈60 %), cristalinidade (40 %) e temperatura de degradação onset (460-465 °C) do polímero. As microesferas ME apresentam um máximo |d33|≈30 pC.N-1, com a uma resposta ME de ∆|d33|≈5 pC.N-1 quando um campo magnético DC (220 mT) é aplicado. Verificou-se que a interface entre as nanopartículas de CFO e o P(VDF) (0-55 %) tem uma forte influência na resposta ME das microesferas. A simplicidade e a escalabilidade dos métodos de processamento apresentados neste trabalho, assim como a distinta resposta ME numa ampla variedade de morfologias, sugerem uma potencial aplicabilidade dos compósitos ME de base polimérica, em áreas como sensores e atuadores, engenharia de tecidos, entre outros

Biomedical Applications of Protein Films and Polymeric Nanomaterials

Biomaterials are widely applied for the diagnosis and treatment of numerous diseases. In addition to fulfilling specific biological functions, biomaterials must also be non-toxic, biocompatible, and sterilizable to be regarded as safe-for-use. Polymers are excellent candidates for fabricating functional biomaterials due to their wide availability and varied properties and may be natural or synthetic. Polymer precursors are fabricated into coatings, foams, scaffolds, gels, composites, and nanomaterials for several biomedical applications. This dissertation focuses on two types of polymeric biomaterials – protein-based materials and synthetic polymeric nanoparticles. Proteins are biopolymers that naturally occur with a variety of structural and functional properties. However, the fabrication of protein-based materials is challenging due to their aqueous and mechanical instability. In this work we highlighted the development of an additive-free, thermal treatment approach that relies on heat-curing protein films in fluorous media (fluorous-curing). In doing so, we are able to minimize protein denaturation and retain surface properties. Charged protein films were utilized to prepare antimicrobial coatings and size-sorting devices. We also demonstrated the utility of fluorous-curing to enhance mechanical and enzymatic stability of collagen films with minimal denaturation. In the latter part of this work, we utilized ultrasound treatment to enhance the activity of biomaterials. Ultrasound is gaining interest as a tool used in combination with biomaterials for applications such as enhanced penetration of therapeutics into tissue, regulating drug release through ultrasound-responsive scaffolds, and sonodynamic therapy. However, these developments are limited and delayed due to the lack of effective in vitro models that prevent uncontrolled cell lysis during ultrasound. We developed 2D and 3D cell cultures for ultrasound treatment using collagen-based materials. We hypothesized that collagen would act as a support for the cells and absorb the energy exerted by ultrasound, thereby protecting the cells. We then utilized ultrasound in combination with antimicrobial polymeric nanomaterials for the synergistic eradication of bacterial biofilms. Antimicrobial polymer nanoparticles are an alternative to traditional antibiotics that prevent development of drug resistance. However, longer incubation durations and higher concentrations are required to allow for penetration into the bacterial biofilms which results in toxicity to mammalian cells. Ultrasound enhances the penetration of these nanoparticles into the biofilm EPS thereby reducing the incubation time and enhancing antimicrobial activity, with minimal toxicity to mammalian cells. Overall, this dissertation discusses significant developments in polymeric materials for varied potential applications as diagnostic sensors, antimicrobial materials, wound-healing, tissue engineering, and drug delivery applications

Recent Advances on Nanocomposite Resists With Design Functionality for Lithographic Microfabrication

Nanocomposites formed by a phase-dispersed nanomaterial and a polymeric host matrix are highly attractive for nano- and micro-fabrication. The combination of nanoscale and bulk materials aims at achieving an effective interplay between extensive and intensive physical properties. Nanofillers display size-dependent effects, paving the way for the design of tunable functional composites. The matrix, on the other hand, can facilitate or even enhance the applicability of nanomaterials by allowing their easy processing for device manufacturing. In this article, we review the field of polymer-based nanocomposites acting as resist materials, i.e. being patternable through radiation-based lithographic methods. A comprehensive explanation of the synthesis of nanofillers, their functionalization and the physicochemical concepts behind the formulation of nanocomposites resists will be given. We will consider nanocomposites containing different types of fillers, such as metallic, magnetic, ceramic, luminescent and carbon-based nanomaterials. We will outline the role of nanofillers in modifying various properties of the polymer matrix, such as the mechanical strength, the refractive index and their performance during lithography. Also, we will discuss the lithographic techniques employed for transferring 2D patterns and 3D shapes with high spatial resolution. The capabilities of nanocomposites to act as structural and functional materials in novel devices and selected applications in photonics, electronics, magnetism and bioscience will be presented. Finally, we will conclude with a discussion of the current trends in this field and perspectives for its development in the near future.Fil: Martínez, Eduardo David. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Ciudad Universitaria. Unidad Ejecutora Instituto de Nanociencia y Nanotecnologia. Unidad Ejecutora Instituto de Nanociencia y Nanotecnologia - Nodo Bariloche | Comision Nacional de Energia Atomica. Unidad Ejecutora Instituto de Nanociencia y Nanotecnologia. Unidad Ejecutora Instituto de Nanociencia y Nanotecnologia - Nodo Bariloche.; ArgentinaFil: Prado, A.. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Ciudad Universitaria. Unidad Ejecutora Instituto de Nanociencia y Nanotecnologia. Unidad Ejecutora Instituto de Nanociencia y Nanotecnologia - Nodo Bariloche | Comision Nacional de Energia Atomica. Unidad Ejecutora Instituto de Nanociencia y Nanotecnologia. Unidad Ejecutora Instituto de Nanociencia y Nanotecnologia - Nodo Bariloche.; ArgentinaFil: Gonzalez, M.. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Ciudad Universitaria. Unidad Ejecutora Instituto de Nanociencia y Nanotecnologia. Unidad Ejecutora Instituto de Nanociencia y Nanotecnologia - Nodo Bariloche | Comision Nacional de Energia Atomica. Unidad Ejecutora Instituto de Nanociencia y Nanotecnologia. Unidad Ejecutora Instituto de Nanociencia y Nanotecnologia - Nodo Bariloche.; ArgentinaFil: Anguiano, S.. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Ciudad Universitaria. Unidad Ejecutora Instituto de Nanociencia y Nanotecnologia. Unidad Ejecutora Instituto de Nanociencia y Nanotecnologia - Nodo Bariloche | Comision Nacional de Energia Atomica. Unidad Ejecutora Instituto de Nanociencia y Nanotecnologia. Unidad Ejecutora Instituto de Nanociencia y Nanotecnologia - Nodo Bariloche.; ArgentinaFil: Tosi, Leandro. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Ciudad Universitaria. Unidad Ejecutora Instituto de Nanociencia y Nanotecnologia. Unidad Ejecutora Instituto de Nanociencia y Nanotecnologia - Nodo Bariloche | Comision Nacional de Energia Atomica. Unidad Ejecutora Instituto de Nanociencia y Nanotecnologia. Unidad Ejecutora Instituto de Nanociencia y Nanotecnologia - Nodo Bariloche.; ArgentinaFil: Salazar Alarcón, Leonardo. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Ciudad Universitaria. Unidad Ejecutora Instituto de Nanociencia y Nanotecnologia. Unidad Ejecutora Instituto de Nanociencia y Nanotecnologia - Nodo Bariloche | Comision Nacional de Energia Atomica. Unidad Ejecutora Instituto de Nanociencia y Nanotecnologia. Unidad Ejecutora Instituto de Nanociencia y Nanotecnologia - Nodo Bariloche.; ArgentinaFil: Pastoriza, Hernan. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Ciudad Universitaria. Unidad Ejecutora Instituto de Nanociencia y Nanotecnologia. Unidad Ejecutora Instituto de Nanociencia y Nanotecnologia - Nodo Bariloche | Comision Nacional de Energia Atomica. Unidad Ejecutora Instituto de Nanociencia y Nanotecnologia. Unidad Ejecutora Instituto de Nanociencia y Nanotecnologia - Nodo Bariloche.; Argentin

Produção de emulsões tipo Pickering por processos de alta e baixa energia

Orientadores: Rosiane Lopes da Cunha, David A. WeitzTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Engenharia de Alimentos, Harvard UniversityResumo: Partículas de quitosana (Ch) e celulose (nanofibras de celulose; CNFs e cristais de celulose; CCrys) foram utilizadas como estabilizantes de emulsões Pickering óleo em água (O/A) produzidas por técnicas de alta (ultrassom e homogeneizador a alta pressão) e baixa energia (dispositivos de microfluídica). As características das partículas e emulsões foram avaliadas frente às variáveis de processo de emulsificação e condições gastrointestinais. Em uma primeira etapa, Ch foram produzidas e caracterizadas quanto aos efeitos da variação da potência aplicada e tempo de processamento em ultrassom sobre a estabilidade destas partículas e das emulsões. Os intensos efeitos de cavitação gerados com altas potências de ultrassom foram capazes de quebrar as partículas de quitosana e as gotas de óleo em menores tamanhos promovendo a formação de uma rede tridimensional entre gotas. Além disso, a alta estabilidade das emulsões foi associada à redução da tensão interfacial entre o óleo e a água e aumento da hidrofobicidade das partículas. Os efeitos das condições de emulsificação usando ultrassom e homogeneizador a alta pressão sobre as propriedades das CNFs obtidas da casca da banana e das emulsões Pickering foram avaliados na segunda etapa deste projeto. O fenômeno de coalescência foi observado nas emulsões produzidas no homogeneizador a alta pressão, enquanto que, a floculação das gotas ocorreu naquelas obtidas em ultrassom de alta intensidade. Nesta última, a estabilidade à coalescência foi associada com o ligeiro aumento da viscosidade da emulsão e rompimento das CNFs durante o processo de ultrassonicação. Em uma terceira etapa, um protocolo de digestibilidade in vitro foi utilizado para elucidar o papel das partículas (Ch, CNFs and CCrys) na taxa de digestão lipídica das emulsões tipo Pickering. A alta carga positiva das emulsões estabilizadas por quitosana levou à desagregação das gotas após a etapa gástrica, o que favoreceu a maior digestão lipídica na etapa intestinal. Por outro lado, a emulsão estabilizada com CNFs apresentou menor digestão lipídica e a forte aderência das partículas de CCrys na interface das gotas tornou-as resistentes ao deslocamento por componentes tensoativos. Na última etapa, a formação e propriedades de emulsões estabilizadas por CCrys foi estudada usando um dispositivo microcapilar. Gotas de óleo altamente monodispersas e emulsões estáveis ao longo do tempo foram produzidas a partir do balanço entre o tempo de geração das gotas e adsorção das partículas. Por outro lado, grandes gotas de óleo e emulsões menos estáveis foram obtidas após a ocorrência de eventos de coalescência dentro do microcanal ou devido ao aumento da viscosidade da fase dispersa. A abordagem microfluídica contribuiu para uma melhor compreensão das condições dinâmicas de estabilização das emulsões Pickering dentro e fora dos microcanais revelando eventos discretos que geralmente estão escondidos em emulsões produzidas por métodos convencionais de emulsificaçãoAbstract: High-energy (ultrasound and high-pressure homogenizer) and low-energy (microfluidic devices) processes were used to obtain oil-in-water (O/W) Pickering emulsions stabilized by food-grade particles (chitosan nanoparticles; Ch, cellulose nanofibers; CNFs and cellulose crystals; CCrys). In the first step, the effect of time and ultrasound power on physicochemical properties of Ch and O/W Pickering emulsions were evaluated using an ultrasonic device. The surface activity of chitosan particles was evidenced with the reduction of interfacial tension between oil-water phases. The emulsion stability mechanism by deprotonated chitosan particles was also associated to an increase of the particle hydrophobicity and the formation of a droplet network structure due to the intense effects of cavitation generated at higher ultrasonication power. The effects of the emulsification conditions using ultrasound and high-pressure homogenization on the properties of the CNFs obtained from the banana peel and Pickering emulsions were evaluated in the second step. Coalescence phenomenon was observed in the emulsions produced using high-pressure homogenizer, whereas droplets flocculation occurred in emulsions processed by ultrasound. In the latter, coalescence stability was associated with effects of cavitation forces acting on the CNFs breakup. In the third step, an in vitro digestibility protocol was used to elucidate the role of different emulsifying polysaccharides particles (Ch, CNFs and CCrys) on the lipid digestion rate of oil-in-water Pickering emulsions. The highly positive charge of the emulsions stabilized by chitosan led to the disaggregation of droplets after the gastric step, which favored a more intense lipid digestion in the intestinal step. On the other hand, Tween 80, CCrys and CNFs were able to inhibit lipid digestion and no changes on droplet mean size were observed following intestinal step. CNFs-stabilized emulsion showed the lowest lipid digestion, whereas the strong adherence of the CCrys particles onto the droplet interface became them resistant to displacement by surface-active components. In the last step, the formation and stability of oil droplets in the presence of cellulose nanocrystals was studied using a microcapillary device. Monodisperse oil droplets and stable emulsions over time were produced from a balance between droplets generation time and particles adsorption. On the other hand, large oil droplets and less stable emulsions were obtained after coalescence events inside the microchannel or due to the increase on the dispersed phase viscosity. Microfluidic approach contributed to a better understanding of the dynamic conditions of stabilization inside and outside the microchannels revealing discrete events that usually are hidden in emulsions produced by conventional emulsification methodsDoutoradoEngenharia de AlimentosDoutora em Engenharia de Alimentos140710/2015-9; 204109/2017-5CNP

Production of Pure Drug Nanocrystals and Nano Co-crystals by Confinement Methods

The use of drug nanocrystals in the drug formulation is increasing due to the large number of poorly water-soluble drug compounds synthetized and due to the advantages brought by the nanonization process. The downsizing processes are done using a top-down approach (milling and homogenization currently employed at the industrial level), while the crystallization process is performed by bottom-up techniques (e.g., antisolvent precipitation to the use of supercritical fluids or spray and freeze drying). In addition, the production of nanocrystals in confined environment can be achieved within microfluidics channels. This review analyzes the processes for the preparation of nanocrystals and co-crystals, divided by top-down and bottom-up approaches, together with their combinations. The combination of both strategies merges the favorable features of each process and avoids the disadvantages of single processes. Overall, the applicability of drug nanocrystals is highlighted by the widespread research on the production processes at the engineering, pharmaceutical, and nanotechnology level.Peer reviewe

On the synthesis of polymeric, inorganic and hybrid nanoparticles for controlled drug delivery applications. From a molecular level to a whole-body distribution

En esta tesis doctoral, se han desarrollado vectores de liberación de fármacos basados en materiales híbridos para demostrar que es posible una liberación pulsada de fármacos mediante activación externa, haciéndolas potencialmente atractivas para aquellas patologías que necesitan la liberación puntual de una cantidad determinada de fármaco (como por ejemplo tratamientos contra el dolor o desajustes hormonales). Se ha tomado como punto de partida polímeros termosensibles ya conocidos y bien estudiados combinándolos con nanopartículas plasmónicas sensibles a la radiación en el rango del infrarrojo cercano (NIR). Además, se ha considerado la Bupivacaina como fármaco modelo debido a su uso habitual para el tratamiento del dolor crónico asociado a enfermedades del nervio ciático actuando como bloqueo del nervio. En el desarrollo de este trabajo, se han seguido numerosos pasos: desde la síntesis y la caracterización de las nanopartículas plasmónicas y poliméricas hasta el desarrollo de nano y micropartículas híbridas cargadas de fármaco con la habilidad de liberar el fármaco a demanda de manera reversible cuando son activadas externamente con luz. Para conseguir este objetivo, se ha aprovechado la combinación de nuevos métodos de síntesis, como el uso de plataformas de microfluídica, junto con métodos convencionales de síntesis en discontinuo.Por otro lado, se han tenido en cuenta diferentes puntos de vista en el desarrollo de estos vectores de liberación de fármacos. Se han llevado a cabo simulaciones basadas en dinámica molecular para entender las interacciones fármaco-polímero a escala molecular y con ello conseguir mejores y optimizadas cargas de fármaco. Para ello, se ha realizado el análisis de sistemas sencillos formados por cadenas poliméricas basadas en los polímeros termosensibles usados experimentalmente y la bupivacaina como fármaco modelo. Finalmente, el estudio de la persistencia in vivo de algunos de estos vectores de liberación de fármacos ha acercado el estudio de los mismos a su aplicación final para evaluar su comportamiento y destino final en modelos animales.Drug delivery vectors based on hybrid materials were developed to demonstrate that an externally activated pulsatile drug release is possible, making it potentially attractive for those pathologies that need the release of a specific drug amount at a specific time point (i.e., pain, hormonal disorders, etc.). The starting point were well-known thermoresponsive polymers combined with Near Infrared (NIR) sensitive plasmonic nanoparticles and a selected model drug (i.e., Bupivacaine), normally used for the treatment of chronic pain associated to sciatic nerve disease acting as a peripherial nerve blocker. Different steps were needed to follow to fulfill the aim of the research: from the synthesis and characterization of those polymeric and plasmonic inorganic nanoparticles, to the development of drug-loaded hybrid nano- and micro- drug delivery vectors with reversible ability to release a drug on-demand when externally activated with light. In order to achieve this aim, it was considered the combination of new synthesis methodologies such as the use of microfluidic continuous platforms together with conventional batch approaches. On the other hand, different points of view in the development of those drug delivery vectors were taken into account. Molecular dynamics simulations were carried out to understand drug-polymer interactions at molecular level and achieve large drug loadings. These analysis involved simple systems containing polymeric chains, based on those thermoresponsive materials, and the model drug chosen, bupivacaine. Additionally, in vivo persistence study brought some of these drug delivery vectors close to their final purpose in order to evaluate their in vivo persistence and fate.<br /

Additive manufacturing of sustainable biomaterials for biomedical applications

Biopolymers are promising environmentally benign materials applicable in multifarious applications. They are especially favorable in implantable biomedical devices thanks to their excellent unique properties, including bioactivity, renewability, bioresorbability, biocompatibility, biodegradability, and hydrophilicity. Additive manufacturing (AM) is a flexible and intricate manufacturing technology, which is widely used to fabricate biopolymer-based customized products and structures for advanced healthcare systems. Three-dimensional (3D) printing of these sustainable materials is applied in functional clinical settings including wound dressing, drug delivery systems, medical implants, and tissue engineering. The present review highlights recent advancements in different types of biopolymers, such as proteins and polysaccharides, which are employed to develop different biomedical products by using extrusion, vat polymerization, laser, and inkjet 3D printing techniques in addition to normal bioprinting and four-dimensional (4D) bioprinting techniques. This review also incorporates the influence of nanoparticles on the biological and mechanical performances of 3D-printed tissue scaffolds. This work also addresses current challenges as well as future developments of environmentally friendly polymeric materials manufactured through the AM techniques. Ideally, there is a need for more focused research on the adequate blending of these biodegradable biopolymers for achieving useful results in targeted biomedical areas. We envision that biopolymer-based 3D-printed composites have the potential to revolutionize the biomedical sector in the near future

Efficient Photoacoustic Conversion in Optical Nanomaterials and Composites

Photoacoustic pulses generated by pulsed laser irradiation have the characteristics of high frequency and wide bandwidth, which are desirable for imaging and sensing. Efficient photoacoustic composites have been developed for fabricating photoacoustic transmitters capable of generating high‐amplitude ultrasound. Here, recent advances in photoacoustic transmitters are reviewed from an application perspective, starting with the fundamental aspects of photoacoustic generation. The topics discussed include various composite materials for photoacoustic generation, and their applications such as high‐amplitude therapy, imaging and sensing, and photoacoustic waveform control.Photoacoustic transmitters using pulsed laser irradiation onto optical nanomaterials have been developed for generating strong photoacoustic pulses, enabling interesting applications. Recent advances in photoacoustic transmitters are reviewed from an application perspective, starting with the fundamental aspects of photoacoustic generation.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147165/1/adom201800491_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147165/2/adom201800491.pd

Porous nanosystems for biological applications

The present thesis aims to provide suitable information on the fundamentals about the controlled manipulation and targeted application of nanoscale porous materials. The research interests in this work are focused on the controlled colloidal synthesis and functionalization of two specific porous materials based on porous coordination polymers (PCPs) and calcium carbonate polymeric nanoparticles (CCPNs), as nanocarriers for intended biological and catalytic applications