Surface topography is known to be important in biomedical applications such as scaffolds for tissue regeneration and has been shown to affect wettability and cell behaviour. Traditionally, topographical effects such as surface texturing have been generated using methods such as photolithography, soft lithography, thermal embossing, and laser/electron beam techniques. This thesis introduces a relatively new technique known as photoembossing to create surface texturing for biomedical applications. Photoembossing is used to produce surface texturing on polymer surfaces by patterned ultraviolet (UV) exposure of a photopolymer blend without an etching step or an expensive mould. After a short general introduction and a literature review, the first experimental chapters describe surface patterning of poly(methyl methacrylate) (PMMA) photopolymer substrates by photoembossing. PMMA is blended with an acrylate monomer and photoinitiator by dissolution in a volatile solvent and processed into films by wire bar coating, and fibres are produced by electrospinning. Surface texture is achieved on both films and fibres by photoembossing. Endothelial cell culture shows that the substrates are biocompatible and cells readily adhere to the surface. In tissue regeneration applications, scaffold degradation is often important to allow tissue in-growth. Thus, in subsequent studies polylactide-co-glycolide (PLGA) is used as a polymer binder. PLGA blended with a triacrylate monomer showed partial degradation after 10 weeks, with a cross-linked acrylate network remaining. Endothelial cell adhesion was even better on the PLGA photopolymer substrates compared to PMMA. Furthermore, surface texture improved cell adhesion and proliferation on the PLGA photopolymer. To obtain completely degradable substrates, thiol monomer was used in addition to the acrylate to produce ester bonds after the thiol-ene reaction, which is cleavable by hydrolysis. Accelerated degradation in sodium hydroxide (NaOH) showed complete degradation of this photopolymer system. The degradation rate of the photopolymer could be tuned by the molecular weight of the acrylate monomer, with low molecular weight monomers degrading more slowly than high molecular weight species. Furthermore, the height of the surface relief structures could be enhanced by using low-molecular-weight acrylate monomers. Endothelial cell culture revealed biocompatibility of the blend and cells were able to adhere after 24 hours of seeding. This thesis demonstrates that photoembossing is a viable technique in producing surface texture for tissue engineering applications. This surface texture can be achieved on both biocompatible and biodegradable photopolymer films and fibres.

Due to their unique structure and flexible choice of materials, electrospun degradable and biocompatible polymer fibres are considered to be extremely suitable for biomedical applications such as tissue engineering and drug delivery, either on their own or integrated within composites. Conventional electrospun fibre composites are typically based on non-woven mats and therefore limited to simple-curved geometries (films, membranes, etc.). For aqueous composites such as hydrogels, the hydrophobicity of the materials sometimes prohibits fibres to be easily integrated or distributed in these composites. In this thesis, a review on the topic is firstly presented in Chapter 2, introducing and discussing engineering of electrospun fibre as well as their biomedical applications. In Chapter 3, electrospun polylactide (PLA) fibres reinforced poly(trimethylene carbonate) (PTMC) composites are prepared. The composites are loaded with both continuous and short PLA fibres, achieving significant mechanical enhancement and offering opportunities to produce composites conveniently using liquid formulations. Chapter 4 presents the development of shape memory polymer composites based on a combination of PLA fibres and a PTMC matrix. By loading different amounts of short fibres with different aspect ratios or by using plasticisers, the shape memory behaviour is modulated; and composites of more complex geometries are produced. In Chapter 5, PTMC-PLA fibre composites are made into drug release system. Dexamethasone-loaded PLA fibres are integrated into a PTMC matrix, showing sustained drug release and stimulating stem cell osteogenic differentiation. This concept gives promise to loading various drugs into photo-crosslinked structures without denaturation. In Chapter 6, electrospun PLA fibres are functionalized by amphiphilic block copolymer polylactide-block-poly[2-(dimethylamino)ethyl methacrylate] (PLA-b-PDMAEMA) for the development of carboxymethylcellulose composites hydrogels. Functionalization of PLA fibres not only allows for easy integration and dispersion into the hydrogel, but also enhances the interfacial bonding between fibre and hydrogel. In the last chapter (Chapter 7), some conclusions are drawn and future works are discussed.

There is an ever-increasing desire to develop novel materials that could control the release of active compounds and increase their stability. Replacing petroleum-based synthetic polymers with sustainable materials has many advantages, such as reducing the dependence on fossil fuels, and diminishing environmental pollution. Recently, cellulose nanocrystal (CNC) obtained by acid hydrolysis of cellulose fibres has gained a lot of interest. The high mechanical strength, large and negatively charged surface area, and the presence of several hydroxyl groups that allow for modification with different functionalities make CNC an excellent candidate for various applications in the biomedical field. This thesis explores (i) the surface modification and characterization of modified CNC and (ii) the biomedical applications of these novel sustainable nanomaterials. In the first part, amine functionalized CNC was prepared. Ammonium hydroxide was reacted with epichlorohydrin (EPH) to produce 2-hydroxy-3-chloro propylamine (HCPA), which was then grafted to CNC using an etherification reaction. A series of reactions were carried out to determine the optimal conditions. The final product (CNC-NH2(T)) was dialyzed for one week. Further purification via centrifugation yielded the sediment (CNC-NH2(P)) and supernatant (POLY-NH2). The presence of amine groups was confirmed by FT-IR and the amine content was determined by potentiometric titration and elemental analysis. A high amine content of 2.2 and 0.6 mmol amine/g was achieved for CNC-NH2(T) and CNC-NH2(P), respectively. Zeta potential measurements confirmed the charge reversal of amine CNC from negative to positive when the pH was decreased from 10 to 3. TEM images showed similar structural properties of the nanocrystals along with some minor aggregation. This simple, yet effective synthesis method can be used for further conjugation as required for various biomedical applications. Moreover, the surface of CNC was modified with chitosan oligosaccharide (CSos). First, the primary alcohol groups of CNC were selectively oxidized to carboxyl groups using the catalyst, 2,2,6,6- tetramethylpiperidine-1-oxyl radical (TEMPO), and were then reacted with the amino groups of CSos via the carbodiimide reaction using N-hydroxysuccinimide (NHS) and 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC). The appearance of C=O peak in FT-IR spectrum of oxidized CNC (CNC-OX), accompanied by calculations based on potentiometric titration revealed that CNC was successfully oxidized with a degree of oxidation of 0.28. The grafting of CSos on oxidized CNC was confirmed by the following observations: (i) the reduction of the C=O peak in FT-IR of CNC-CSos and the appearance of new amide peaks; (ii) the significant reduction of the carbonyl peak at 175 ppm in the 13C NMR spectrum for CNC-CSos; (iii) a higher decomposition temperature in TGA of CNC-CSos; (iv) a positive zeta potential of CNC-CSos at acidic pH; and (v) a degree of substitution of 0.26, which is close to the DO (0.28), indicating that 90% of COOH groups on CNC-OX were involved in the formation of amide bonds with CSos. TEM and AFM studies also revealed a completely diff erent morphology for CNC-CSos. In the second part, the potential of exploiting CNCs as delivery carriers for two cationic model drugs, procaine hydrochloride (PrHy) and imipramine hydrochloride (IMI), were investigated. IMI displayed a higher binding to CNC derivatives compared to PrHy. Isothermal titration calorimetry (ITC), transmittance and zeta potential measurements were used to elucidate the complexation between model drugs and CNC samples. It was observed that the more dominant exothermic peak observed in the ITC isotherms leading to the formation of larger particle-drug complexes could explain the increased binding of IMI to CNC samples. Drug selective membranes were prepared for each model drug that displayed adequate stability and rapid responses. Different in vitro release profiles at varying pH conditions were observed due to the pH responsive properties of the systems. Both drugs were released rapidly from CNC samples due to the ion-exchange e ffect, and CNC-CSos displayed a more sustained release profile. Furthermore, the antioxidant properties of CNC samples and the potential of CNC-CSos as a carrier for the delivery of vitamin C was investigated. CNC-CSos/vitamin C complexes (CNCS/VC) were formed between CNC-CSos and vitamin C via ionic complexation using sodium tripolyphosphate (TPP). The complexation was confirmed via DSC and UV-Vis absorbance measurements. TEM images showed complexes with a size of approximately 1 micron. The encapsulation efficiency of vitamin C was higher (91%) at pH 5 compared to pH 3 (72%). The in vitro release of vitamin C from CNCS/VC complexes exhibited a sustained release of up to 3 weeks, with the released vitamin C displaying higher stability compared to a control vitamin C solution. Antioxidant activity and kinetics of various CNC samples were studied using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. CNC-CSos possessed a higher scavenging activity and faster antioxidant activity compared to its precursors, CNC-OX and CSos, and their physical mixture. Therefore, by loading vitamin C into CNC-CSos particles, a dynamic antioxidant system was produced. Vitamin C can be released over a prolonged time period displaying enhanced and sustained antioxidant properties since the carrier CNC-CSos also possesses antioxidant properties. As a result of this doctoral study, knowledge on the surface modification of CNC with amine groups and CSos have been advanced. The in vitro drug release and antioxidant studies suggest that systems comprising of CNC could be further explored as potential carriers in biomedical applications.

Doctor Scientiae - DSc / Semiconductor nanocrystals or quantum dots (QDs) are fluorescent nanometer-sized particles which have physical dimensions that are smaller than the excitonic Bohr radius, large surface area-to-volume ratios, broad absorption spectra and very large molar extinction coefficients. Biomedical applications of QDs are mainly based on II-VI QDs containing cadmium, such as CdSe/ZnS. These cadmium-based systems are associated with high toxicity due to cadmium. As a result, potential replacements of cadmium-based QDs in biological applications are needed. In this study, InP/ZnSe QDs were synthesized for the first time using a one-pot hot injection method. Furthermore, a growth-doping method was used for silver, cobalt and iron incorporation into the InP core. Water compatibility was achieved through ligand exchange with 3- mercaptopropionic acid. In vitro cytotoxicity and imaging/internalization of the as-prepared MP A-InP/ZnSe and MP A-capped CdTe/ZnS QDs were evaluated. InP/ZnSe QDs were successfully synthesized with ZnSe shell causing a 1.4 times reduction in trap-related emission.

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Orientadores: Marcelo Knobel, Daniela Zanchet / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Fisica Gleb Wataghin / Made available in DSpace on 2018-08-08T20:01:50Z (GMT). No. of bitstreams: 1 Alves_TatianaMidoriMartinsTelles_M.pdf: 13757564 bytes, checksum: 9fff2bc36efd863f581707b11f77fa22 (MD5) Previous issue date: 2007 / Resumo: Neste trabalho são realizados estudos de propriedades morfológicas, estruturais e magnéticas de nanopartículas de óxidos de ferro sintetizadas por métodos químicos. Procuramos relacionar os parâmetros de síntese às características das partículas produzidas com a finalidade de melhorar sua qualidade em relação às amostras comerciais e avaliar sua aplicabilidade em biomedicina. Foram adotados os métodos de síntese por co-precipitação de sais em solução aquosa e de decomposição térmica de dois diferentes precursores organometálicos: acetilacetonato de ferro III (Fe(acac)3) e ferro pentacarbonil (Fe(CO). Para caracterização desses sistemas, foram utilizadas as técnicas de microscopia eletrônica de transmissão convencional e de alta resolução, microscopia eletrônica de varredura com canhão de emissão de campo, difração de raios-X e medidas de magnetização, além de experimentos de transfecção em células HeLa e posterior detecção por imagens de ressonância magnética. Os estudos mostraram que as partículas sintetizadas por co-precipitação não apresentam muitas vantagens em relação às amostras comerciais, pois possuem larga distribuição de tamanhos. Através da síntese por decomposição térmica de Fe(acac)3, partículas com distribuição mais estreita foram produzidas e resultados positivos de incorporação por células HeLa e detecção por imagens de ressonância magnética foram obtidos. Com as partículas geradas pela decomposição térmica de Fe(CO)5 foram realizados tratamentos térmicos em atmosfera ambiente que proporcionaram aumento do grau de cristalização, aumento do diâmetro médio e estabilização de suas propriedades magnéticas, em detrimento da perda dos contornos esféricos e aumento na dispersão de tamanhos. De uma maneira geral, foi possível demonstrar que a decomposição térmica de compostos organometálicos em solventes orgânicos produz partículas mais homogêneas em relação àquelas produzidas por co-precipitação e às comercialmente disponíveis, e essa qualidade apresenta um grande potencial para aplicações biomédicas mais sofisticadas / Abstract: In this work, morphological, structural and magnetic investigations were performed in iron oxide nanoparticles synthesized by chemical methods. Our goal was to correlate the synthesis parameters to the characteristics of the produced particles to improve their quality when compared to commercial samples and to evaluate their applicability in biomedicine. The synthetic methods were the co-precipitation of metal salts in aqueous solution and the thermal decomposition of two different organometallic precursors: iron (III) acetylacetonate (Fe(acac)3) and iron pentacarbonil (Fe(CO)5). The following techniques were used for the characterization of these systems: transmission electron microscopy, high resolution transmission electron microscopy, field emission gun scanning electron microscopy, X-ray diffraction and magnetic measurements, in addition to incorporation experiments by HeLa cells and their detection by magnetic resonance imaging. The studies showed that nanoparticles synthesized by the co-precipitation method present no advantage over the commercial samples, once they have the same broad size distribution. Through thermal decomposition of Fe(acac)3, particles with narrower size distribution were produced and positive results on their incorporation by HeLa cells and magnetic resonance imaging detection were obtained. Thermal treatments under air atmosphere were performed in the particles generated by thermal decomposition of Fe(CO)5, giving rise to crystallization, an increase of the mean diameter and stabilization of their magnetic properties, with the disadvantages of loss of the spherical shape and increase of the size dispersion. In summary, it was possible to demonstrate that thermal decomposition of organometallic compounds in hot organic solvents produces more homogeneous particles when compared with those produced by co-precipitation and commercially available ones, and this quality presents great potential for more sophisticated biomedical applications / Mestrado / Física da Matéria Condensada / Mestre em Física

La fusion sélective par laser (SLM), en tant que technologie de fabrication additive émergente, permet la fabrication de pièces complexes et de conception avancée. Cette technologie est particulièrement adaptée aux applications biomédicales, telles que la production d'implants personnalisés. Les alliages de titane, en particulier le Ti6Al4V, sont largement utilisés dans les industries médicales en raison de leurs excellentes propriétés mécaniques et de leur biocompatibilité. Afin de développer une substitution osseuse spécifique, l'étude présente s'est concentré sur les propriétés mécaniques, le post-traitement, la conception légère et les propriétés biologiques d'un matériau en Ti6Al4V fabriqué par SLM. Les résultats les plus importants de ce travail sont répertoriés ci-après.La microstructure des échantillons de Ti6Al4V ainsi formée s’est avérée dominée par la phase martensite α aciculaire. Le traitement par compression isostatique à chaud (HIP) entraîne une réduction significative des défauts internes, tels que les pores résiduels et les fissures internes. L'échantillon fabriqué n’ayant pas subi de traitement possède une faible résistance à la fatigue et un comportement en ductilité peu satisfaisant. Au contraire, l'échantillon traité thermiquement (HT) présente une résistance à la traction réduite. Toutefois, le comportement à la traction et la résistance à la fatigue sont améliorés par rapport à l'échantillon n’ayant pas subi de traitement. Le traitement HIP a également entraîné une réduction de la résistance à la traction mais a amélioré la ductilité et le comportement à la fatigue grâce à l'élimination des défauts internes.Afin d'améliorer la résistance à la fatigue d'un matériau en Ti6Al4V fabriqué par SLM, une technologie avancée de traitement par attrition mécanique de surface (SMAT) a été appliquée au cours de ce travail. Les résultats indiquent qu'un traitement de type SMAT peut introduire une couche nanostructurée sur la surface de l'échantillon. La nanostructure peut entraîner une augmentation de la résistance mécanique et des contraintes résiduelles de compression dans la couche de surface. En conséquence, l’échantillon traité par SMAT a montré une amélioration significative de la résistance à la fatigue par rapport à celui non traité dans les régimes de fatigue à cyclage faible et élevé. De plus, une oxydation par micro-arc (MAO) a été proposée pour améliorer l'activité biologique en formant un film oxydé avec du calcium (Ca) et du phosphore (P) sur la surface du Ti6Al4V fabriqué par SLM. La microstructure, la morphologie et les compositions chimiques du film de MAO préparé pour différentes tensions ont été caractérisées. Les résultats montrent qu'un revêtement comportant une proportion de Ca et de P est formé en surface du matériau Ti6Al4V fabriqué par SLM, et que cette couche a bien adhéré au substrat après le traitement au MAO. On peut en conclure que le traitement par MAO peut améliorer l'activité biologique du Ti6Al4V fabriqué par SLM.Des unités octaédriques avec des tailles de pores de 500, 600 et 700 μm et un taux de porosité de 60% et 70% ont été conçues, puis les structures poreuses correspondantes ont été fabriquées par SLM. Les effets du diamètre des pores et de la porosité sur les propriétés mécaniques des échafaudages poreux en Ti6Al4V fabriqués par SLM ont été systématiquement étudiés. Afin d'évaluer les performances biologiques, des tests in vitro/vivo ont été menés pour étudier la prolifération, la différenciation des cellules et la croissance osseuse sur les échafaudages poreux de Ti6Al4V fabriqués par SLM. L'étude indique que l'échafaudage poreux avec une taille de pore de 500 μm et une porosité de 60% est relativement prometteur pour la reproduction des défauts osseux. / Selective laser melting (SLM), as an emerging additive manufacturing technology, enables manufacturing complex parts with advanced design. This technology is particularly suitable for biomedical applications, such as the production of personalized implants. Titanium alloys, and particularly Ti6Al4V, are widely used in medical industries because of their excellent mechanical properties and biocompatibility. In order to develop a specific bone substitution, the present research focuses on mechanical properties, post-treatment, light design and biological properties of SLM Ti6Al4V. The most important advances of this work are listed below.The microstructure of SLM Ti6Al4V samples was found to be dominated by acicular martensitic phase. Hot Isostatic Pressing (HIP) treatment resulted in a significant reduction of internal defects, such as residual pores and internal cracks. Untreated samples showed a poor fatigue resistance and low ductility. Heat treated samples (HT) exhibited a reduced tensile strength. However, the tensile behavior and fatigue resistance were improved in comparison with untreated samples. HIP treatment also reduced the tensile strength but improved ductility and fatigue behavior by eliminating internal defects.In order to improve the fatigue resistance of SLM Ti6Al4V, an advanced Surface Mechanical Attrition (SMAT) treatment technology was applied in the frame of this work. The results indicate that SMAT can introduce a nanostructured layer on the surface of samples. This nanostructure may result in an increase in mechanical strength and provide residual compressive stresses in the surface layer. As a result, SMAT samples demonstrated a significant improvement in fatigue strength in comparison with untreated samples, in both low and high cycling fatigue regimes. In addition, micro-arc oxidation (MAO) was performed to enhance the biological activity by forming an oxidized film with calcium (Ca) and phosphorus (P) on the surface of SLM Ti6Al4V. The microstructure, morphology and chemical compositions of the MAO film prepared with different voltages were characterized. The results show that a coating with Ca and P was formed on the surface of SLM Ti6Al4V, and that it bonded well to the substrate after MAO treatment. It can be concluded that MAO treatment can improve the biological activity of SLM Ti6Al4V parts.Octahedral scaffold structures with a pore size of 500, 600 and 700 μm and porosity levels of 60% and 70% were designed, and corresponding porous structures were manufactured by SLM. The effects of pore diameter and porosity level on mechanical properties of SLM Ti6Al4V porous scaffolds, were systematically studied. In order to evaluate biological performances, in vitro / vivo tests were conducted to study proliferation, cell differentiation and bone growth on SLM Ti6Al4V porous scaffolds. The study indicates that porous scaffolds with a pore size of 500 μm and a porosity level of 60% is promising for the reproduction of bone defects.

Graphene-based materials (GBM) have recently generated great interest due to their unique two-dimensional (2D) carbon geometry, which confers exceptional physicochemical properties that hold great promise in many fields, including biomedicine. An understanding of how these novel 2D materials interact with the biological milieu is therefore fundamental for their development and use. Graphene oxide (GO) has been proven more biologically friendly than the highly hydrophobic pristine graphene. Therefore, the main aim of this study was to prepare well-characterised GO derivatives and test the hypothesis of their possible use for biomedical applications. GO was prepared reproducibly by a modified Hummers' method and further functionalised by using a radio-metal chelating agent, namely 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) to form GO-DOTA. The constructs were extensively studied using structural, optical and surface characterisation techniques. GO prepared from different forms of graphite demonstrated differences mainly in structure and production yields. However, all GO constructs were found biocompatible, with the mammalian cell cultures tested; furthermore, the biocompatibility of GO prepared as papers was retained when they were used as substrates for cell growth. Radiolabelling of GO-DOTA was further carried out to yield highly stable radio-labelled constructs, both in vitro and in vivo. These constructs were used for in vivo whole-body imaging and biodistribution studies in mice after intravenous administration. Extensive urinary excretion and accumulation mainly in the reticuloendothelial system (RES), including the spleen, liver and lungs, was the main fate of all the GO derivatives used in this thesis. The physicochemical characteristics were determined to play a central role for their preferential fate and accumulation. While the thicker sheets tended to accumulate mainly in the RES, the thinner ones were mostly excreted via the kidneys. Finally, it was crucial to perform safety investigations involving the structure and function of organs at high risk of injury (mainly the kidney and spleen). Our results revealed that no severe structural damage or histopathologic or functional abnormality of these vital organs. However, some preliminary inflammatory responses were detected that require further investigation. In summary, this study helped gain a better understanding of how thin 2D materials interact with biological barriers and the results indicate that these materials could be potential candidates for biological applications. Nevertheless, further investigations are necessary to confirm our findings.