Dental restorative cements are placed in a harsh oral environment where they are subjected to thermal shock, chemical degradation, and repeating masticatory force. The ideal restorative dental cements should have superior mechanical properties, chemical stability, aesthetic, good handling properties, biocompatibility, antibacterial properties, and preferably bioactivity. This thesis presents research on dental restorative cements with enhanced properties. The overall aim was to increase the bioactivity and antibacterial properties of dental restorative cements without affecting their other properties. The effect from adding calcium silicate to glass ionomer cement (GIC) was investigated. The results showed that calcium silicate could increase the bioactivity and reduce the cytotoxicity of conventional glass ionomer cement without compromising its setting and mechanical properties. Hydroxyapatite (HA) with a high aspect ratio and thin nacreous-layered monetite sheets were also synthesized. Nano HA particles with an aspect ratio of 50 can be synthesized by both precipitation and hydrothermal methods. The aspect ratio was controlled via the pH of reaction medium. Thin nacreous-layered monetite sheets were synthesized through a self-assembly process in the presence of an amine based cationic quaternary surfactant. Temperature, pH, and presence of surfactant played essential roles in forming the nacreous-layered monetite sheets. Then the effect from adding silver doped HA and monetite particles was investigated. The results showed that the antibacterial properties of GIC could be increased by incorporating silver doped HA and monetite particles. Further examination showed that the pH change, F- ion release, and concentration of released Ag+ ions were not responsible for the improved antibacterial properties. The quasi-static strengths and compressive fatigue limits of four types of the most commonly used dental restorations were evaluated. In our study, resin modified GIC and resin-based composite showed superior static compressive strength and fatigue limits compared to conventional GIC. The static compressive strength of dental cements increased with the aging time. However, aging had no effect on the compressive fatigue limit of resin modified GIC and resin-based composite. The compressive fatigue limit of conventional GIC even showed a drastic decrease after aging.

Calcium phosphate cements are used in medicine to fill bone defects or give support to screws and plates in fracture fixation. The cements are formed via mixing a powder with water and the mixture harden through a dissolution-precipitation reaction. Today the cement mixing is performed in the operating room and consists of several complicated steps that need to be performed under sterile conditions. This renders the mixing a risk factor, potentially leading to harm for the patient e.g. unsatisfactory healing or infection. To reduce this risk, premixed cements have been developed using glycerol as mixing liquid. The premixed cement sets when it is exposed to body liquids. Therefore, premixed cement can be delivered to the operating room in prefilled syringes ready for use, thus eliminating the mixing step. The aim of this thesis is to describe differences between premixed and water-mixed cements and their advantages and drawbacks. The differences will be discussed based on results obtained from bench testing of specific cement properties as function of cement formulations as well as in vitro and in vivo studies. Several cement formulations were evaluated e.g. the influence of powder to liquid ratio (P/L), powder particle size and addition of water on key properties. The results showed that premixed cements have excellent handling properties and have mechanical properties similar to water-based cements. Both P/L and particle size can be used to control these properties. It was shown that small amounts of water improve certain cement properties while dry raw materials were important for long shelf life. To better understand the setting of premixed cements new methods for evaluating working time and setting of premixed cements were developed. In vivo studies showed that the formulations developed in this thesis are biocompatible, resorbable and show good tissue response in bone. This thesis concludes, that the premixed cements are a promising biomaterial with excellent handling properties and good biological response. The most important challenge for the premixed cements, in order to become commercially successful, is to obtain clinically relevant setting time and shelf life simultaneously. An increasing use of premixed cements in the clinics should shorten operation times and reduce infection rates to the benefit of both patients and medical staff.

More than one million people worldwide receive some kind of bone graft each year. Grafts are often needed following bone tumour removal or traumatic fractures to fill voids in the bone and to aid in the healing process. The most common method involves bone transplantation, in which bone tissue is taken from one site to fill the defect in another site. The procedure thus involves two surgeries, which leads to an increased risk of complications. New, synthetic graft materials that can be used to fill defects and minimise the complications associated with bone tissue harvesting are therefore necessary. The synthetic materials available today lack the inherent biological factors of bone that stimulate the bone regeneration process. Much of today’s research concerning synthetic bone graft materials aims to solve this issue and researchers have suggested several different strategies. The purpose of this thesis is to improve the performance of acidic calcium phosphate cements, which are materials used as synthetic bone grafts. By combining these cements with drugs or ion additives, local delivery could be achieved with the potential to stimulate bone formation. Two different combinations were attempted in this thesis: cement in combination with simvastatin, or cement in combination with strontium halide salts. Both simvastatin and strontium are known to positively affect bone formation. The efficacy of the cements with the additives was evaluated using different bone cell cultures. The results regarding simvastatin showed that the cement’s mechanical property was not affected upon drug loading, and that the drug was released by a diffusion-controlled mechanism. Moreover, results showed that simvastatin stimulated the bone-forming cells (osteoblasts) to produce more bone tissue, while it inhibited bone-degrading cells (osteoclasts) from degrading the cement. These findings suggest that simvastatin could aid in the bone regeneration process in the local area surrounding the cement. The main purpose of the study using strontium halide salts was to increase the cement’s X-ray contrast, which is a property used to monitor cement during injection. In addition, strontium is believed to positively affect bone cells. The X-ray contrast did increase after the addition of 10 wt% strontium bromide or strontium iodide, while the cell study results did not indicate any significant effects on the bone-forming cells. In the last section of this thesis, zebrafish were used as a model to evaluate bone formation upon treatment with degradation products from synthetic bone grafts. The zebrafish is a small organism with 70 % gene homology to humans; due to its transparency, fast development and ease of handling, it is an interesting model for high-throughput studies. Silicate, which is an ionic degradation product of many different bone substitute materials, was used as a proof-of-concept to visualise bone formation in these fish. The results showed an increased bone formation upon treatment with 0.625 μM silicate ions. The results suggest that this model could be used as a complement to bone cell culture studies in pre-clinical evaluations of the degradation products of bone substitute materials, thus helping researchers to design materials with degradation products that could stimulate bone formation.

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La presente Tesis Doctoral se titula "Obtención y caracterización de nuevos cementos óseos de fosfatos de calcio en el sistema DCP&#8213;alfa-TCP". Los cementos de fosfatos de calcio (CFC) son materiales biocompatibles que tienen la propiedad de endurecer en condiciones fisiológicas formando una estructura porosa de cristales interconectados de hidroxiapatita, i.e. la fase mineral de los tejidos óseos. Estos materiales pueden ser diseñados para que sean inyectables y tengan distintos porcentajes de porosidad. Este hecho permite obtener cementos con distintas tasas de reabsorción ósea que pueden aplicarse con técnicas de mínima invasión. En general, estas propiedades otorgan a estos biomateriales un excelente interés en campos de aplicación de prevención, reconstrucción o estabilización ósea (p.e.: osteoporosis, cirugía craneofacial, vertebroplastia, cifoplastia).Esta Tesis Doctoral consta de 6 capítulos. El Capítulo 1 (Cementos óseos de fosfatos de calcio) recoge el estado del arte de los CFC. Se realiza una revisión bibliográfica crítica de toda la información de interés. Se concluye la necesidad de realizar estudios cinéticos que expliquen adecuadamente las propiedades de fraguado de estos cementos y permitan diseñar cementos con mejores propiedades. El Capítulo 2 (Materiales y métodos utilizados en la fabricación y caracterización de cementos óseos de fosfatos de calcio) describe el protocolo de trabajo seguido para caracterizar los CFC física y químicamente. Este protocolo permite establecer correlaciones entre la microestructura y las propiedades macroscópicas. El Capítulo 3 (Estudio de la cinética de la reacción de fraguado de un cemento óseo de fosfato de calcio) investiga la cinética de fraguado de un cemento octocálcico en el sistema DCP&#8213;alfa-TCP. Los resultados mostraron que: (a) sólo el alfa-TCP reaccionó para dar una hidroxiapatita deficiente en calcio (CDHA); (b) el porcentaje de reacción y la resistencia mecánica a compresión estaban correlacionadas; (c) el cemento presentó una estructura de cristales interconectados con distinto grado de compacidad. El Capítulo 4 (Estudio de nuevas formulaciones de cementos de fosfatos de calcio en el sistema DCP&#8213;alfa-TCP) investiga las propiedades de fraguado y de resistencia mecánica de cementos del sistema DCP&#8213;alfa-TCP en el intervalo de relaciones Calcio/Fósforo (Ca/P) 1.26<Ca/P<1.50. Se estudia cómo varían la trabajabilidad, los tiempos de fraguado y la resistencia a la compresión. También se estudia el efecto de la adición de carbonato cálcico (CC) sobre las propiedades de fraguado ya que se espera obtener como producto final de la reacción de fraguado una hidroxiapatita deficiente en calcio carbonatada y, por lo tanto, más semejante a la apatita de la fase mineral ósea. Los resultados mostraron que la adición de un 10 % de CC produjo un efecto fluidificante sobre los cementos con un incremento en los valores de los tiempos de fraguado. El análisis de la evolución de la resistencia a la compresión con el tiempo demostró que el CC actúa como un retardador. Sin embargo, la resistencia final alcanzada representa en muchos casos un incremento de más del 40 %. El Capítulo 5 (Discusión general) discute los resultados más relevantes analizados a lo largo de los Capítulos 3 y 4 para comprender las posibilidades clínicas que este tipo de materiales nos ofrece. El Capítulo 6 (Conclusiones) presenta una serie de conclusiones obtenidas a partir de los resultados de los Capítulos 3 y 4. Son conclusiones extraídas a partir del análisis de los resultados de determinadas poblaciones de muestras. Como los intervalos de variabilidad de los parámetros de cada población son diferentes, muchas de las conclusiones no son generalizables a todo el sistema DCP&#8213;alfa-TCP, sino que se han de leer dentro de este sistema y en las condiciones experimentales estudiadas. Finalmente, la Tesis Doctoral lista el conjunto de referencias bibliográficas utilizadas en este trabajo de investigación.

Made available in DSpace on 2015-05-14T13:21:41Z (GMT). No. of bitstreams: 1 arquivototal.pdf: 3447802 bytes, checksum: 02d388c8470f315b5afc4d1f65e6f9b7 (MD5) Previous issue date: 2012-05-18 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Calcium phosphate ceramics have been investigated due their properties such as absence of toxicity and biocompatibility, enabling their use in medicine field being applied as a substitute for bone implants. However, other characteristics are required such as bioaffinity, mechanical and chemical resistances. Due to the difficulty of obtaining such properties in the pure phosphates, composites were proposed by combining the mechanical and physical properties of bio inert materials to the biological properties of bioceramics. In this work, nanocomposites of calcium phosphates and titanium oxide were synthesized, by the controlled hydrolysis of titanium tetrabutoxide in compositions between 1 and 10% in aqueous solutions of calcium chloride and ammonium phosphate. The solids were characterized by X-ray diffraction, infrared spectroscopy, thermogravimetric analysis and scanning electron microscopy. The results showed the incorporation of titanium oxide onto phosphate surface without loss of crystallinity and morphological changes. Evaluation of chemical stability of the nanocomposites showed that they were resistant to dissolution at pH below 6.0. The bioactivity tests showed that the nanocomposite containing 2% of titanium oxide was performed better than others / As cerâmicas de fosfato de cálcio têm sido investigadas devido as suas propriedades tais como biocompatibilidade e ausência de toxicidade, possibilitando sua utilização na área médica sendo aplicadas como substituto do tecido ósseo em implantes. No entanto, outras características são importantes tais como bioafinidade, resistência mecânica e química. Devido à dificuldade de se obter tais propriedades nos fosfatos puros, nanocompósitos foram propostos por combinarem as propriedades mecânicas e físicas dos materiais bioinertes com as propriedades biológicas das biocerâmicas. Assim neste trabalho, nanocompósitos do fosfato de cálcio monetita (CaHPO4) com dióxido de titânio foram sintetizados pela hidrólise controlada de tetrabutóxido de titânio em composições variando de 1 a 10% em soluções aquosas de cloreto de cálcio e fosfato de amônio. Os sólidos foram caracterizados por difratometria de raios-X, espectroscopia na região do infravermelho, análise termogravimétrica e microscopia eletrônica de varredura. Os resultados mostraram que houve uma incorporação do dióxido de titânio na superfície da monetita sem perda da cristalinidade e alteração morfológica. A avaliação da estabilidade química dos materiais mostrou que os nanocompósitos apresentaram resistência à dissolução em pH abaixo de 6,0. Os ensaios de bioatividade indicaram que o nanocompósito M2 apresentou melhor desempenho que os demais

The in vitro production of ceramic implants used for cranial defect repair can be challenging and complex. In this thesis, a raw material in such a production has been mapped in order to optimize the production process. The current production leaves variations in the handling properties of the calcium phosphate cement (CPC), such as the viscosity and setting performance. The problems originate from the in-house recrystallization of the raw material monocalcium phosphate monohydrate (MCPM) with a 70% ethanol solution. The treatment of MCPM is strongly dependent on the relative humidity and the current process is not reliable and leaves unwanted fluctuations in the quality of MCPM. Various material and process parameters were investigated to get a deeper knowledge of MCPM in the specific process. The mapping resulted in new information about how the MCPM recrystallizes and how it depends on the evaporation of the ethanol solution during the treatment. Other findings were that the particle size distribution of MCPM is not the only factor controlling the viscosity of the CPC; the density and shape of the MCPM particles may also influence the handling properties. The mapping led to a process optimization suggestion where the amount of ethanol solution is adjusted to the relative humidity during the recrystallization to neutralize the effect of the humidity. The adjustment of ethanol solution volume means the evaporation can be controlled and in theory, constant quality of MCPM can be maintained. Unfortunately, the new method needs additional data to be fully effective but shows great potential.

Made available in DSpace on 2015-05-14T13:21:08Z (GMT). No. of bitstreams: 1 arquivototal.pdf: 4018152 bytes, checksum: 7560bbf38d03b95122bd3a1ec4fe0fec (MD5) Previous issue date: 2011-09-19 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / The main application of calcium phosphates is as biomaterials, which are used as graft or bone implants. The preparation of mesoporous bioceramics allowed the use of these materials as drug carriers, as drugs incorporated into porous structure would be subsequently released upon grafting/implantation into the surrounding tissue in a controlled manner, with well-established kinetics. Improved chemical stability, particulary toward acids is a desirable feature of these biomaterials, as calcium phosphates dissolve at pH<4.00. The objectives of this work included the synthesis, characterization and application of calcium phosphate biomaterials, i.e., mesoporous hydroxyapatites and monetite/silica nanocomposites. The mesoporous hydroxyapatite was studied as drug carriers. The stability of the nanocomposites, prepared via the sol-gel method by varying the content of TEOS, were investigated with respect to chemical (acid) and thermal stability, including a detailed study on the thermal decomposition kinetics of for the second mass loss of monetite and the nanocomposite CaPSil2. Among the twenty one porous hydroxyapatites prepared using two cationic surfactants, the hexadecyltrimethylammonium bromide and myristyltrimethylammonium bromide and sodium dodecyl sulfate as anionic surfactant, at various concentrations, heating rates, and calcination temperatures, only HA-MTAB-60-673/5 was mesoporous, whereas the remaining one were nanoporous, as indicated by N2 adsorption isotherms. HA-MTAB-60-673/5 was forwarded to drug uptake and release studies. This material was synthesized using 60 mmol.dm-3 myristyltrimethylammonium bromide as surfactant; the hybrid mesostructure intermediate was heated at 5 K.min-1 to 673 K and calcinated isothermally at 673 K for 6 h under O2 to yield HA-MTAB-60-673/5 with surface area of 89 m2.g-1, pore volume of 0,56 cm3.g-1, and average pore diameter of 23.96 nm. Increasing calcination heating rate did not increase crystallinity. The solid was able to uptake the antibiotic benzyl penicillin-G in a 2012 mg.g-1 ratio (drug/support) in 10 min, which was ~ 9-fold greater than that of precursor hydroxyapatite. The drug release profile followed the Higuchi model with the release of 52% of the drug in a time of 41 h. The covalent incorporation of silica onto the monetite surface yielded four monetite/silica nanocomposites that had unit cell volume and crystallinity reduced as silica content increased. Increased immobilization reduced Q3 species, as shown by 29Si NMR, and contributed substantially to mass loss on TG studies. Calcium phosphate/silica nanocomposites were more stable toward acid dissolution than the respective phosphate precursor, particularly at pH<4.00. The kinetics of the second mass loss stage of the thermal decomposition of monetite and CaPSil2 was studied by non-isothermal methods. FWO method provided activation energies (Ea) of 200.87 and 228.14 kJ.mol-1 and Coats-Redfern method provided activation energies (Ea) of 178.43 and 165.84 kJ.mol-1 and pre-exponential factors (A) of 9.53 x 1013 and 1.16 x 1013 s-1 for monetite and CaPSil2, respectively. A good description of experimental data was achieved by using the Avrami-Erofeev nucleation model (A2). / A principal aplicação dos fosfatos de cálcio é como biomateriais, para serem usados como enxerto ou implante ósseo. A obtenção de biocerâmicas mesoporosas permitiu o uso destes materiais como carreadores de fármacos, que são incorporados à estrutura porosa para serem subsequentemente liberados de forma controlada do enxerto ou implante ósseo para o tecido adjacente e com uma cinética bem estabelecida. Outra característica desejável aos biomateriais é possuir uma boa estabilidade química para não serem dissolvidos em meios ácidos, particularmente em pH<4,00. Os objetivos deste trabalho incluíram a síntese, caracterização e aplicação de biomateriais de fosfatos de cálcio, como hidroxiapatitas mesoporosas e nanocompósitos de monetita/sílica. A hidroxiapatita mesoporosa foi avaliada em ensaios de liberação de fármaco. A estabilidade dos nanocompósitos, preparados pelo método sol-gel, variando a concentração do TEOS nas sínteses, foi investigada com respeito à estabilidade química em sistemas ácidos, incluindo um estudo detalhado da cinética de decomposição térmica da segunda etapa de perda de massa da monetita e do nanocompósito CaPSil2. Das vinte e uma hidroxiapatitas porosas preparadas usando dois surfactantes catiônicos, o brometo de hexadeciltrimetilamônio e o brometo de miristiltrimetilamônio e o surfactante aniônico dodecilsulfato de sódio, variando-se as concentrações, as razões de aquecimento e as temperaturas de calcinação, somente a amostra HA-MTAB-60-673/5 foi mesoporosa, enquanto as demais foram nanoporosas, como indicaram as isotermas de adsorção de N2. A matriz HA-MTAB-60-673/5 foi aplicada em ensaios de liberação controlada de fármaco. Este material foi sintetizado usando o surfactante brometo de miristiltrimetilamônio na concentração de 60 mmol.dm-3; a mesoestrutura híbrida intermediária foi calcinada a uma razão de aquecimento de 5 K.min-1, na temperatura de 673 K por 6 h em condições isotérmicas e em O2, resultando na HAMTAB- 60-673/5 com área superficial de 89 m2.g-1, volume de poro de 0.56 cm3.g-1 e diâmetro médio de poro de 23.96 nm. As hidroxiapatitas nanoporosas apresentaram uma redução na cristalinidade. A matriz mesoporosa foi aplicada na liberação controlada do antibiótico benzil penicilina-G, tendo uma retenção (Nf) de 2012 mg.g-1 (fármaco/suporte) em 10 min, que foi aproximadamente nove vezes maior que a hidroxiapatita precursora. O perfil de liberação seguiu o modelo de Higuchi, com uma liberação de 52% do fármaco em um tempo de 41 h. A incorporação covalente da sílica na superfície da monetita resultou em quatro nanocompósitos de monetita/sílica com volume de célula unitária reduzido e menos cristalinos à medida que aumenta a quantidade sílica nas estruturas dos sólidos. O aumento da imobilização reduziu as espécies Q3, conforme RMN de 29Si, que contribuíram substancialmente para a perda de massa observada pela TG. Pelos ensaios de estabilidade química, os nanocompósitos de fosfato de cálcio e sílica tornaram-se mais estáveis quimicamente em relação ao fosfato precursor, particularmente em pH<4.00. A cinética de decomposição térmica da segunda etapa de perda de massa da monetita e CaPSil2 foi estudada por métodos não-isotérmicos. O FWO forneceu uma energia de ativação (Ea) de 200,87 e 228,14 kJ.mol-1 e o método de Coats-Redfern resultou em Ea de 178,43 e 165,84 kJ.mol-1 e fator pré-exponencial (A) de 9,53.1013 e 1,16.1013 s-1, para monetita e CaPSil2, respectivamente. Uma boa descrição dos dados experimentais foi obtida ao empregar o modelo de nucleação (A2) de Avrami-Erofeev.

Calcium phosphate cements (CPCs) are used as bone void fillers and as complements to hardware in fracture fixation. The aim of this thesis was to investigate the possibilities and limitations of the CPCs’ mechanical properties, and find out if these ceramic bone cements can carry application-specific loads, alone or as part of a construct. Recently developed experimental brushite and apatite cements were found to have a significantly higher strength in compression, tension and flexion compared to the commercially available CPCs chronOS™ Inject and Norian® SRS®. By using a high-resolution measurement technique the elastic moduli of the CPCs were determined and found to be at least twice as high compared to earlier measurements, and closer to cortical bone than trabecular bone. Using the same method, Poisson's ratio for pure CPCs was determined for the first time. A non-destructive porosity measurement method for wet brushite cements was developed, and subsequently used to study the porosity increase during in vitro degradation. The compressive strength of the experimental brushite cement was still higher than that of trabecular bone after 25 weeks of degradation, showing that the cement can carry high loads over a time span sufficiently long for a fracture to heal. This thesis also presents the first ever fatigue results for acidic CPCs, and confirms the importance of testing the materials under cyclic loading as the cements may fail at stress levels much lower than the material’s quasi-static compressive strength. A decrease in fatigue life was found for brushite cements containing higher amounts of monetite. Increasing porosity and testing in a physiological buffer solution (PBS), rather than air, also decreased the fatigue life. However, the experimental brushite cement had a high probability of surviving loads found in the spine when tested in PBS, which has previously never been accomplished for acidic CPCs. In conclusion, available brushite cements may be able to carry the load alone in scenarios where the cortical shell is intact, the loading is mainly compressive, and the expected maximum stress is below 10 MPa. Under such circumstances this CPC may be the preferred choice over less biocompatible and non-degradable materials.