Smart materials are intelligent materials that change their structural, chemical, mechanical, or thermal properties in response to an external stimulus such as heat, light, and magnetic and electric fields. With the increase in usage of smart materials in many sensitive applications, the need for a remote, wireless, efficient, and biologically safe stimulus has become crucial. This dissertation addresses this requirement by using high intensity focused ultrasound (HIFU) as the external trigger. HIFU has a unique capability of maintaining both spatial and temporal control and propagating over long distances with reduced losses, to achieve the desired response of the smart material. Two categories of smart materials are investigated in this research; shape memory polymers (SMPs) and piezoelectric materials. SMPs have the ability to store a temporary shape and returning to their permanent or original shape when subjected to an external trigger. On the other hand, piezoelectric materials have the ability to convert mechanical energy to electrical energy and vice versa. Due to these extraordinary properties, these materials are being used in several industries including biomedical, robotic, noise-control, and aerospace. This work introduces two novel concepts: First, HIFU actuation of SMP-based drug delivery capsules as an alternative way of achieving controlled drug delivery. This concept exploits the pre-determined shape changing capabilities of SMPs under localized HIFU exposure to achieve the desired drug delivery rate. Second, solving the existing challenge of low efficiency by focusing the acoustic energy on piezoelectric receivers to transfer power wirelessly. The fundamental physics underlying these two concepts is explored by developing comprehensive mathematical models that provide an in-depth analysis of individual parameters affecting the HIFU-smart material systems, for the first time in literature. Many physical factors such as acoustic, material and dynamical nonlinearities, acoustic standing waves, and mechanical behavior of materials are explored to increase the developed models' accuracy. These mathematical frameworks are designed with the aim of serving as a basic groundwork for building more complex smart material-based systems under HIFU exposure. / Doctor of Philosophy / Smart materials are a type of intelligent materials that have the ability to respond to external stimuli such as heat, light, and magnetic fields. When these materials respond, they can change their structural, thermodynamical, mechanical or chemical nature. Due to this extraordinary property, smart materials are being used in many applications including biomedical, robotic, space, microelectronics, and automobile industry. However, due to increased sensitivity and need for safety in many applications, a biologically safe, wireless, and efficient trigger is required to actuate these materials. In this dissertation, sound is used as an external trigger to actuate two types of smart materials: shape memory polymers (SMPs) and piezoelectric materials. SMPs have an ability to store a temporary (arbitrarily deformed) shape and return to their permanent shape when exposed to a trigger. In this dissertation, focused sound induced thermal energy acts as a trigger for these polymers. A novel concept of focused ultrasound actuation of SMP-based drug delivery capsules is proposed as a means to solve some of the challenges being faced in the field of controlled drug delivery. Piezoelectric materials have an ability to generate electric power when an external mechanical force is applied and vice versa. In this study, sound pressure waves supply the external force required to produce electric current in piezoelectric disks, as a method for achieving power transfer wirelessly. This study aims to solve the current problem of low efficiency in acoustic power transfer systems by focusing sound waves. This dissertation addresses the fundamental physics of high intensity focused ultrasound actuation of smart materials by developing comprehensive mathematical models and systematic experimental investigations, that have not been performed till now. The developed models enable an in-depth analysis of individual parameters including nonlinear material behavior, acoustic nonlinearity and resonance phenomena that affect the functioning of these smart systems. These mathematical frameworks also serve as groundwork for developing more complex systems.

Nanoparticle mediated drug delivery approaches provide potential opportunities for targeting and killing of intracellular bacteria. Among them, the porous silica nanoparticles deserve special attention due to their multifunctional properties such as high drug loading, controlled drug release and targeting of organs/cells. A review of the functional requirements of an ideal drug delivery system is provided. A general comparison between different drug delivery carriers and key issues to be addressed for intracellular drug delivery is discussed. Acid catalyzed and acid-base catalyzed, sol-gel derived, silica xerogel systems were investigated for sustained release of an aminoglycosides antimicrobial against salmonella infection in a mouse model. The release of gentamicin from the inner hollow part of the carrier is delayed. Further, the higher porosity of the acid–base catalyzed silica xerogel allows for high drug loading compared to the acid catalyzed silica xerogel system. Efficacy of these particles in killing intracellular bacteria (salmonella) was determined by administering three doses of porous silica loaded gentamicin. This proved to be useful in reducing the salmonella in the liver and spleen of infected mice. Furthermore, the presence of silanol groups provides the ability to functionalize the silica xerogel system with organic groups, poly (ethylene glycol) (PEG), to further increase the hydrophilicity of the silica xerogel matrix and to modify the drug release properties. Increase in the hydrophilicity of the matrix allows for faster drug release rate. In order to facilitate controlled drug release, magnetic porous silica xerogels were fabricated by incorporating iron particles within the porous silica. The particles were fabricated using an acid-base catalyzed sol-gel technique. The in-vitro drug release studies confirm that the release rate can be changed by the magnetic field "ON-OFF" mechanism. This novel drug release methodology combined with the property of high drug loading capacity proves to be influential in treating salmonella intracellular bacteria. The potential application of any drug delivery carrier relies on the ability to deliver the requisite drug without adversely affecting the cells over the long term. We have developed silica/calcium nanocomposites and evaluated their solubility behavior. The solubility of particles was characterized by particle size measurements for different periods of time. It was found that the solubility behaviour of the silica/calcium particles was dependent on their calcium content. The results obtained demonstrate the potential to use mesoporous silica/calcium nano-composites for drug delivery applications. The significant contribution of this research to drug delivery technology is on design and development of the novel porous core-shell silica nano-structures. This new core-shell nano-structure combines all the above mentioned properties (high drug loading, magnetic field controlled drug release, and solubility). The main aim of preparing these porous core-shell particles is to have a control over the solubility and drug release property, which is a significant phenomenon, which has not been achieved in any other drug delivery systems. The shell layer acts as a capping agent which dissolves at a controllable rate. The rate at which the shell layer dissolves depends on the composition of the particles. This shell prevents the drug "leakage" from the particles before reaching the target site. The core layer drug loading and release rate was modified by application of a magnetic field. Additionally, inclusion of the calcium ions in the core layer destabilizes the silica network and allows the particles to dissolve at an appropriate rate (which can be controlled by the concentration of the calcium ions). / Ph. D.

[EN] The present PhD thesis, which is entitled "Design of new bio-gated nanodevices for advanced communication processes and targeted controlled release of therapeutic agents" is focused on the development of new functional hybrid organic-inorganic materials for applications in the field of the controlled delivery of target molecules. The first chapter of the present thesis gives an introduction to the organic-inorganic hybrid materials functionalized with "molecular gates" and its application in controlled release processes. The second chapter of this thesis is focused on the development of a new nanodevice able to deliver its cargo as a function of the glucose concentration. The nanodevice is based on mesoporous silica nanoparticles loaded with a suitable fluorophore and functionalized with propylbenzymidazole moieties on the pore outlets. The mesopores are then capped with an active cyclodextrin modified glucose oxidase enzyme (through the formation of an inclusion complex between the cyclodextrins and the propylbenzymidazole group anchored to the solid support). When glucose is added its enzymatic oxidation produced gluconic acid. This acid induced a decrease in the pH of the medium and the protonation of the benzymidazole group that might result in the inclusion complex dethreading and the subsequent cargo release. The third chapter of the thesis is focused on the development of a new redox-responsive material for the controlled delivery of cytotoxic drugs in cancer cells. The system is based on mesoporous silica nanoparticles loaded with a reporter (safranin O) and functionalized with two different sized polyethylene glycol chains in the pore outlets using a disulfide linkage. In presence of glutathione, the disulfide bonds are cleaved allowing the release of the entrapped cargo. Once confirmed the aperture protocol, the uptake of the gated nanoparticles and their ability to deliver the cargo (fluorophore or cytotoxic agent) in HeLa cells were tested. Moreover, cell viability assays were also performed. The fourth chapter of the thesis is focused on the preparation and the study of a nanodevice for the controlled delivery in senescent cells in a murine model of pulmonary fibrosis. The material is prepared using mesoporous silica nanoparticles (as an inorganic support) and galactoligosaccharide (molecular gate) moieties anchored on the external surface. In presence of senescent cells, which overexpress ß-galactosidase enzyme, the hydrolysis of the galactooligosaccharide capping molecules take place and the cargo release from the inner of the pores is produced (rhodamine B). After the in vitro studies, the ability of nanoparticles to accumulate and release their payload in tissues with abundance of senescent cells was evaluated in vivo. For that purpose, mice with induced pulmonary fibrosis, pathogenesis with associated increased alveolar senescence, were treated with the synthesized material and subsequently examined to assess its ability to accumulate and release its payload (fluorophore) in lung's damaged areas. In the fifth chapter of the thesis it has been explored the concept of cascade chemical communication using different types of nanodevices, each of them loaded with a certain messenger and externally functionalized with a gate-like entity that controls the release of the payload. When the enzyme able to hydrolyze the molecular gate that blocks the pores of the first type of nanoparticles (S1), is added to an aqueous suspension containing the three nanoparticles, the delivery of the chemical messenger 1 is produced. This messenger is able to open the second type of nanoparticles (S2) which delivers the messenger 2. Finally, the messenger 2 triggers the aperture of the third group of gated system (S3), which ultimately delivers its load (a dye) as a final response. / [ES] La presente tesis doctoral titulada "Diseño de nuevos nanodispositivos para procesos avanzados de comunicación y liberación controlada y dirigida de agentes terapéuticos" está centrada en el desarrollo de nuevos materiales híbridos orgánico-inorgánicos funcionales para aplicaciones en el campo de la liberación controlada de moléculas de interés. El primer capítulo de la tesis ofrece una introducción a los materiales híbridos orgánico-inorgánicos funcionalizados con "puertas moleculares" y su aplicación en procesos de liberación controlada. En el segundo capítulo de la tesis se aborda el desarrollo de un nanodispositivo capaz de responder y liberar su carga en función de la concentración de glucosa. Este nanodispositivo está basado en nanoparticulas de sílice mesoporosa funcionalizadas en su superficie externa con grupos benzimidazol y con los poros cargados con un fluoróforo. Los poros se cierran al añadir la enzima glucosa oxidasa funcionalizada con ciclodextrinas (por formación de un complejo de inclusión entre el benzimidazol y los oligosacáridos cíclicos). Al adicionar glucosa se produce su oxidación enzimática dando ácido glucónico. Este ácido induce una bajada del pH del medio con la consiguiente protonación de los benzimidazoles y la ruptura de los complejos de inclusión. Esta ruptura provoca la salida de la enzima de la superficie y la liberación del colorante atrapado en los poros. El tercer capítulo de la tesis se ha centrado en el desarrollo de un material para la liberación controlada de agentes citotóxicos en células cancerosas en respuesta a cambios en el potencial redox. De nuevo se emplean nanopartículas de sílice mesoporosa con los poros cargados con un colorante (safranina O) y la superficie externa funcionalizada con dos polietilenglicoles conteniendo enlaces disulfuro. En presencia de glutatión se produce la reducción del enlace disulfuro con la consiguiente liberación del colorante. Una vez confirmado el protocolo de apertura, se estudió la internalización y la liberación de un fluoróforo y de un agente citotóxico en el modelo celular HeLa, realizando además ensayos de viabilidad. En el cuarto capítulo de la tesis se ha preparado y ensayado un nanodispositivo para la liberación controlada en células senescentes en un modelo murino de fibrosis pulmonar. El material se prepara empleando nanopartículas de sílice mesoporosa y un galactooligosacárido anclado en la superficie externa. En presencia de células senescentes, que sobreexpresan la enzima ¿-galactosidasa, se produce la hidrólisis del oligosacárido con la consiguiente liberación de la carga atrapada en los poros del soporte (rodamina B). Tras los estudios in vitro, la capacidad del nanodispositivo de acumularse y liberar su carga en tejidos ricos en células senescentes se evaluó in vivo. Para ello, ratones con fibrosis pulmonar inducida, patología en la que se ha descrito la aparición de senescencia, se trataron con el material sintetizado y posteriormente fueron examinados para comprobar la capacidad de acumularse y liberar su carga (fluoróforo) en la zona pulmonar dañada. En el quinto capítulo se ha explorado el proceso de comunicación química en cascada empleando tres tipos de nanopartículas mesoporosas de sílice cargadas con diferentes mensajeros y funcionalizadas con tres puertas moleculares distintas. Cuando sobre una suspensión de las tres nanopartículas se añade la enzima capaz de hidrolizar la puerta molecular que bloquea los poros del primer tipo de nanopartículas (S1), se produce la liberación del mensajero 1. Este mensajero es capaz de inducir la apertura del segundo tipo de nanopartículas (S2), que a su vez liberan al medio el mensajero 2. Por último, el mensajero 2 es capaz de abrir la puerta molecular del tercer tipo de nanopartículas (S3), que liberan finalmente su carga (un colorante) como respuesta final. / [CA] La present tesis doctoral titulada "Disseny de nous nanodispositius per a processos avançats de comunicació i lliberació controlada i dirigida d'agents terapèutics" està centrada en el desenvolupament de nous materials híbrids orgànic-inorgànic funcionals per a aplicacions en el camp de la lliberació controlada de molècules d'interès. El primer capítol de la tesis ofereix una introducció als materials híbrids orgànic-inorgànic funcionalitzats amb "portes moleculars" i la seua aplicació en processos de lliberació controlada. En el segon capítol de la tesis s'aborda el desenvolupament d'un nanodispositiu capaç de respondre i lliberar la seua càrrega en funció de la concentració de glucosa. Este nanodispositiu està basat en nanopartícules de sílice mesoporoses funcionalitzades a la seua superfície externa amb grups benzimidazol i amb els pors carregats amb un fluoròfor. Els pors queden bloquejats al afegir el enzim glucosa oxidasa funcionalitzada amb ciclodextrines (per formació d'un complex d'inclusió entre el benzimidazol i els oligosacàrids cíclics). Al afegir glucosa es produeix la seua oxidació enzimàtica donant lloc a àcid glucònic. Este àcid indueix una baixada del pH del medi amb la consegüent protonació dels benzimidazols i el trencament dels complexes d'inclusió. Este trencament provoca l'eixida del enzim de la superfície i la lliberació del colorant atrapat als pors. El tercer capítol de la tesis s'ha centrat en la preparació d'un material per a la lliberació controlada d'agents citotòxics en cèl¿lules canceroses en resposta a canvis en el potencia redox. De nou s'empren nanopartícules de sílice mesoporoses amb els pors carregats amb un colorant (safranina O) i la superfície externa funcionalitzada amb dos polietilenglicols (de diferent pes molecular) contenint enllaços disulfur. En presència de glutatió es produeix la reducció del enllaç disulfur amb la consegüent lliberació del colorant. Una volta confirmat el protocol d'obertura, es va estudiar la internalització i la lliberació d'un fluoròfor i d'un agent citotòxic en el model cel¿lular HeLa, realitzant ademés assajos de viabilitat. En el quart capítol de la tesis s'ha preparat i s'ha estudiat un nanodispositiu per a la lliberació controlada en cèl¿lules senescents, en un model murí de fibrosis pulmonar. El material es prepara emprant nanopartícules de sílice mesoporoses i un galactooligosacàrid anclat a la superfície externa del material. En presència de cèl¿lules senescents, que sobreexpresen el enzim ¿-galactosidasa, es produeix la hidròlisis del oligosacàrid amb el consegüent alliberament de la càrrega atrapada en els pors del suport (rodamina B). Després dels estudis in vitro, la capacitat del nanodispositiu d'acumular-se i lliberar la càrrega en teixits rics en cèl¿lules senecents es va evaluar in vivo. Amb este propòsit, ratolins amb fibrosis pulmonar induïda, patologia en la que s'ha descrit l'aparició de senescència en els teixits danyats, es van tractar amb el material sintetitzat i posteriorment van ser examinats per a comprovar la capacitat d'acumular-se i lliberar la seua càrrega (fluoròfor) en la zona dels pulmons afectada. En el quint capítol s'ha explorat el procés de comunicació química en cascada utilitzant tres tipus de nanopartícules mesoporoses de sílice carregades amb diferents missatgers i funcionalitzades amb tres portes moleculars diferents. Quan, sobre una suspensió de les tres nanopartícules, s'afegeix l'enzim capaç d'hidrolitzar la porta molecular que bloqueja els pors del primer tipus de nanopartícules (S1), es produeix la lliberació del missatger 1 des de S1. Este missatger és capaç d'induir l'obertura del segon tipus de nanopartícules (S2), les quals lliberen al medi el missatger 2. Per últim, el missatger 2 és capaç d'obrir la porta molecular del tercer tipus de nanopartícules (S3), que lliberen finalment la seua càrr / Giménez Morales, C. (2016). Design of new bio-gated nanodevices for advanced communication processes and targeted controlled release of therapeutic agents [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/62822

Tesis por compendio / La presente tesis doctoral, titulada "Nanotecnología y química supramolecular en procesos de liberación controlada y reconocimiento molecular para aplicaciones biomédicas", se centra en dos temas importantes: el reconocimiento molecular y los procesos de liberación controlada. Esta tesis doctoral está estructurada en cuatro capítulos. El primer capítulo introduce el concepto de materiales híbridos orgánicos-inorgánicos funcionalizados con puertas moleculares y sus aplicaciones biomédicas como nanomateriales para dirigir y controlar la liberación controlada de fármacos. Además se introduce una breve descripción sobre sensors colorimétricos basados en la base de la quimica supramolecular, particularmente en los procesos de reconocimiento molecular. En particular, el capítulo 2 describe la preparacion de cinco nanodispositivos que responden a enzimas. Estos materiales híbridos se componen de dos unidades principales: un soporte mesoporoso basado en sílice inorgánica, capaz de encapsular moléculas orgánicas y un compuesto orgánico anclado en la superficie externa del soporte mesoporoso inorgánico que actúa como puerta molecular. Todos los sistemas propuestos utilizan puertas moleculares peptídicas que responden a temperatura o enzimas como estímulo. La segunda parte de esta tesis doctoral se centra en el diseño y desarrollo de un nuevo compuesto químico capaz de detectar monóxido de carbono in vivo. En resumen, para todos los resultados antes mencionados podemos decir que esta tesis doctoral constituye una contribución científica original al desarrollo de la química supramolecular. Sus resultados derivados de los estudios presentados dejan rutas abiertas para continuar el estudio y el desarrollo de nuevos materiales híbridos y sensors químicos más eficientes para aplicaciones biomédicas y terapeuticas. / This PhD thesis entitled "Nanotechnology and supramolecular chemistry in controlled release and molecular recognition processes for biomedical applications", is focused on two important subjects: molecular recognition and controlled delivery processes. This PhD thesis is structured in four chapters. The first chapter introduces the concept of organic-inorganic hybrid materials containing switchable "gate-like" ensembles and their biomedical applications as nanomaterials for targeting and control drug delivery. Furthermore, is introduced a short review about chromo-fluorogenic chemosensors based on basic principles of supramolecular chemistry, particulary in molecular recognition processes. In particular, in chapter 2 is focus on the development of enzymatic-driven nanodevices. These hybrid materials are composed of two main units: an inorganic silica based mesoporous scaffold, able to store organic molecules and an organic compound anchored on the external surface of the inorganic mesoporous support than acts as molecular gate. All the systems proposed use peptidic gates that respond to temperature or enzimatic stimulis. The second part of this PhD thesis is focused on the design and development of a new chemical compound capable of detecting carbon monoxide in vivo. In summary, for all the results above mentioned we can say that this PhD thesis constitutes an original scientific contribution to the development of supramolecular chemistry. Its results derived from the studies presented leaves open routes to continue the study and development of new hybrid materials and more efficient chemical sensors with biomedical and therapeutic applications. / La present tesi doctoral, titulada "Nanotecnologia i química supramolecular en processos d'alliberament controlat i reconeixement molecular per a aplicacions biomèdiques", es centra en dos temes importants de la química: el reconeixement molecular i els processos d'alliberament controlat. Aquesta tesi doctoral està estructurada en quatre capítols. El primer capítol introdueix el concepte de materials híbrids orgànics-inorgànics funcionalitzats amb portes moleculars i les seves aplicacions biomèdiques com nanomaterials per dirigir i controlar l'alliberament controlat de fàrmacs. A més s'introdueix una breu descripció sobre sensors colorimètrics fonamentats en la base de la química supramolecular, particularment en els processos de reconeixement molecular. En particular, el capítol 2 descriu la preparació de cinc nanodispositius que responen a enzims. Aquests materials híbrids es componen de dues unitats principals: un suport mesoporos basat en sílice inorgànica, capaç d'encapsular molècules orgàniques i un compost orgànic ancorat a la superfície externa del suport mesoporós inorgànic que actua com a porta molecular. La segona part d'aquesta tesi doctoral es centra en el disseny i desenvolupaent d'un nou compost químic capaç de detectar monòxid de carboni in vivo. En resum, per a tots els resultats abans mencionats podem dir que esta tesi doctoral constituïx una contribució científica original al desenvolupament de la química supramolecular. Els seus resultats derivats dels estudis presentats deixen rutes obertes per a continuar l'estudi i el desenvolupament de nous materials hibrids i sensors químics més eficients per a aplicacions biomèdiques i terapeutiques. / De La Torre Paredes, C. (2017). Nanotechnology and supramolecular chemistry in controlled release and molecular recognition proceses for biomedical applications" [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/94043 / Compendio

O objetivo principal deste trabalho foi a formação de um material que possa responder aos estímulos pH e elétrico na liberação controlada de fármaco. Assim, hidrogéis condutores foram obtidos pela combinação do hidrogel de ácido acrílico com o polímero condutor polipirrol. O polipirrol foi eletroquimicamente polimerizado no interior do hidrogel e o material obtido (AA-PPi) conservou a propriedade de intumescimento que é característico dos hidrogéis e a eletroatividade, dos polímeros condutores. Além disso, o grau de intumescimento variou com a força iônica e pH. A liberação da safranina pelo hidrogel de AA-PPi foi estudada combinando os estímulos de pH e potencial e o resultado mais interessante foi a obtenção do perfil cuja velocidade de liberação foi constante, indicando uma cinética de ordem zero. Liberação do tipo liga-desliga foi estudada com o intuito de verificar se o AA-PPi pode ser controlado por pH e/ou potencial elétrico. Foi observado que dependendo da combinação de pH e potencial, o hidrogel pode ser controlado, por variação de pH ou de potencial elétrico. Outro hidrogel sintetizado foi o do hidrogel de AA contendo o poli(3,4-etilenodioxitiofeno):poli(estireno sulfonado), este por sua vez foi polimerizado quimicamente. Porém os resultados preliminares indicaram incompatibilidade entre os dois polímeros / The aim of this work was to obtain a material that can respond to both pH and potential stimuli for drug release. Thus, eletroactive hydrogels were synthesized by the combination of the properties of acrylic acid hydrogels with the conducting polymer polypyrrole. The polypyrrole was electrochemically polymerized into the hydrogel (AA-PPi), and the material retained the swelling properties that is characteristic of hydrogels and electroactivity of conducting polymers. Furthermore, the degree of swelling varied with the ionic strength and pH. The safranin release by AA-PPi was mensured under the combination of pH and potential stimuli and the most interesting result was obtained from the linear profile indicating a zero-order kinetics. On-off release profile was studied in order to verify if the AA-PPi can be controled by pH and/or electric potential. Depending on the combination of pH or electrochemical potential, the hydrogel had pH or electrochemical control. Other hydrogel synthesized was from AA hydrogel containing poly(3,4- ethylenedioxythiophene):polystyrene sulfonate, this, in other hand, was chemically polymerized. However, preliminary results indicate incompatibility between the two polymers

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.

O objetivo principal deste trabalho foi a formação de um material que possa responder aos estímulos pH e elétrico na liberação controlada de fármaco. Assim, hidrogéis condutores foram obtidos pela combinação do hidrogel de ácido acrílico com o polímero condutor polipirrol. O polipirrol foi eletroquimicamente polimerizado no interior do hidrogel e o material obtido (AA-PPi) conservou a propriedade de intumescimento que é característico dos hidrogéis e a eletroatividade, dos polímeros condutores. Além disso, o grau de intumescimento variou com a força iônica e pH. A liberação da safranina pelo hidrogel de AA-PPi foi estudada combinando os estímulos de pH e potencial e o resultado mais interessante foi a obtenção do perfil cuja velocidade de liberação foi constante, indicando uma cinética de ordem zero. Liberação do tipo liga-desliga foi estudada com o intuito de verificar se o AA-PPi pode ser controlado por pH e/ou potencial elétrico. Foi observado que dependendo da combinação de pH e potencial, o hidrogel pode ser controlado, por variação de pH ou de potencial elétrico. Outro hidrogel sintetizado foi o do hidrogel de AA contendo o poli(3,4-etilenodioxitiofeno):poli(estireno sulfonado), este por sua vez foi polimerizado quimicamente. Porém os resultados preliminares indicaram incompatibilidade entre os dois polímeros / The aim of this work was to obtain a material that can respond to both pH and potential stimuli for drug release. Thus, eletroactive hydrogels were synthesized by the combination of the properties of acrylic acid hydrogels with the conducting polymer polypyrrole. The polypyrrole was electrochemically polymerized into the hydrogel (AA-PPi), and the material retained the swelling properties that is characteristic of hydrogels and electroactivity of conducting polymers. Furthermore, the degree of swelling varied with the ionic strength and pH. The safranin release by AA-PPi was mensured under the combination of pH and potential stimuli and the most interesting result was obtained from the linear profile indicating a zero-order kinetics. On-off release profile was studied in order to verify if the AA-PPi can be controled by pH and/or electric potential. Depending on the combination of pH or electrochemical potential, the hydrogel had pH or electrochemical control. Other hydrogel synthesized was from AA hydrogel containing poly(3,4- ethylenedioxythiophene):polystyrene sulfonate, this, in other hand, was chemically polymerized. However, preliminary results indicate incompatibility between the two polymers

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