Biopharmaceuticals, including proteins, DNA and vaccines, are one of the fastest growing segments of the overall pharmaceutical market. While the hypodermic injection, the most common delivery method for these molecules, is effective, it also has limitations, including low patient compliance, need for medically trained personnel and biohazardous sharps after delivery. The overall goal of this thesis was to develop a new delivery system for biopharmaceuticals, based on dissolving polymer microneedles, which is effective and more patient compliant than the hypodermic needle. Microneedles are microscopic needles that are large enough to insert into the skin to deliver drugs effectively, while being short enough to avoid the pain causing nerves deep in the skin. An additional benefit of polymer microneedles is that the needles completely dissolve in the skin, leaving behind no biohazardous sharps. There are significant material and fabrication issues that must be overcome in the development of this new device. The first part of this thesis focused on the development of a new fabrication process, based on in situ photopolymerization, for the creation of polymer microneedles. These microneedles were shown to successfully insert into the skin, dissolving within a minute to deliver the encapsulated cargo, and retain full activity of encapsulated proteins. Next, we applied the microneedle technology to the delivery of the influenza virus. We found that the reformulation process required to encapsulate the influenza virus in polymer microneedles did not affect the antigenicity or immunogenicity of the virus. In addition, we used coated metal microneedles to successfully immunize mice with the influenza virus, verifying the delivery capabilities of a microneedle system. Finally, we used the dissolving polymer microneedles to successfully immunize mice with the influenza virus, resulting in full protection against lethal challenge after one immunization. This immune response was equivalent to the control intramuscular injection. In conclusion, we have developed dissolving polymer microneedles as an effective and patient compliant delivery system for biopharmaceuticals. This system could be especially applicable to mass immunization efforts or home use, since it can be self-administered and allows for easy disposal with no biohazardous sharps.

Medical devices are becoming more important in the health care sector. One of the major issues for companies developing and producing medical devices is to be updated on the regulatory requirements and implement them in the process. This thesis examines the regulatory requirements for medical devices in Argentina, Australia, Brazil, Canada, India, Japan, Mexico, Russia, South Korea and Taiwan and compares them with the requirements in the European Union. The conclusion of this thesis is that most countries have similar requirements for registration of medical devices and are striving to harmonize with the GHTF guidelines. A company goes far by following the requirements in EU, USA or the GHTF guidelines.

The unique performance offerings of NiTi based shape memory alloys (SMAs), which includes the shape memory effect (SME), pseudoelasticity (PE) and biocompatibility have led to widespread acceptance of these alloys as valuable engineering materials. Over the past several decades the complex metallurgy behind the SME and PE properties has for the most part been uncovered and the design and engineering knowhow has been demonstrated; facilitating successful application of NiTi devices in numerous industries. Specifically, more mature applications in the medical industry including medical devices such as, catheters, guide wires, orthodontic arch wires, maxillofacial reconstruction implants, minimally invasive surgical tools, and arterial and gastrointestinal stents, have become common practice in modern medicine. Recently however, there has been a drive for more demanding functionality of SMAs for example to locally modify properties creating tuneable or gradient SME and PE performance. Unique processing protocols are therefore necessary to meet these demands and allow SMAs to reach their full potential in a wider range of applications. The current thesis successfully details the application of pulsed Nd:YAG laser processing along with post-processing techniques to locally tune both the SME and PE functional properties of monolithic binary NiTi wires and strip, while maintaining confidence in the retained corrosion performance and limited release of biologically harmful Ni ions. This extensive study contains three distinct parts which include: i) application of a laser induced vaporization protocol to locally embed multiple memories in a monolithic wire actuator; ii) uncovering the process, structure, and performance relationship of combined laser, cold working, and heat treatment processes; and iii) comprehensive characterization of surface characteristics and their relationship with corrosion performance and Ni ion release from laser processed material.

The global burden of injury is severely underappreciated and disproportionately affects low-income countries. With timely, appropriate orthopaedic treatment disability and mortality can be prevented, yet appropriate health resources are seldom available. Without orthopaedic medical devices (OMDs), quality of orthopaedic care suffers and the burden of preventable injury is exacerbated. A qualitative case study of 45 key informant interviews was conducted in Uganda to explore accessibility of OMDs, such as plaster, external fixators and implants. Data analysis elicited four major themes as barriers preventing access to OMDs in Uganda: 1) Poor leadership in government and corruption; 2) inadequate human resources; 3) inefficient and insufficient health care infrastructure; and 4) high costs of OMDs and poverty. Potential solutions for improving access to orthopaedic care were categorized as policies prioritizing orthopaedic services, training more orthopaedic specialists and creating incentives for them to work in underserviced areas, and innovative strategies funding for orthopaedic services.

The global burden of injury is severely underappreciated and disproportionately affects low-income countries. With timely, appropriate orthopaedic treatment disability and mortality can be prevented, yet appropriate health resources are seldom available. Without orthopaedic medical devices (OMDs), quality of orthopaedic care suffers and the burden of preventable injury is exacerbated. A qualitative case study of 45 key informant interviews was conducted in Uganda to explore accessibility of OMDs, such as plaster, external fixators and implants. Data analysis elicited four major themes as barriers preventing access to OMDs in Uganda: 1) Poor leadership in government and corruption; 2) inadequate human resources; 3) inefficient and insufficient health care infrastructure; and 4) high costs of OMDs and poverty. Potential solutions for improving access to orthopaedic care were categorized as policies prioritizing orthopaedic services, training more orthopaedic specialists and creating incentives for them to work in underserviced areas, and innovative strategies funding for orthopaedic services.

La dématérialisation de l’accès aux tests génétiques apparaît comme un outil concourant à satisfaire l’ensemble des composantes du droit à la protection de la santé. En effet, en la matière, la spécialisation de la médecine induit une limitation des personnes habilitées à prescrire des tests génétiques. Aussi, la recherche de la meilleure sécurité sanitaire possible pour la réalisation des tests génétiques induit des problématiques d’égal accès aux laboratoires de biologie médicale autorisés à cet effet, mais auxquelles la dématérialisation peut apporter des réponses. Aussi, elle n’apparaît pas être antinomique de l’autonomie des patients, bien qu’elle présente des faiblesses. / The dematerialization of access to genetic testing appears to be a tool to satisfy all the aspects of the right to health protection. Indeed, in this field, the specialization of medicine induces a limitation of the numbers of persons entitled to prescribe genetic tests. The quest for the best quality and health security for the realization of the genetic tests induces problems of equal access to the laboratories of medical biology authorized for this purpose, but to which dematerialization can give answers. Also, dematerialization does not appear to be antinomic of patient autonomy, although it presents weaknesses.

Submitted by Emanuel Varela Cardoso (emanuel.varela@ufcg.edu.br) on 2018-08-31T22:34:35Z No. of bitstreams: 1 RONY MARCOLINO DE ANDRADE – DISSERTAÇÃO (PPGCC) 2016.pdf: 3165388 bytes, checksum: e26452f5e3e73c3c717d633f0d6743b7 (MD5) / Made available in DSpace on 2018-08-31T22:34:35Z (GMT). No. of bitstreams: 1 RONY MARCOLINO DE ANDRADE – DISSERTAÇÃO (PPGCC) 2016.pdf: 3165388 bytes, checksum: e26452f5e3e73c3c717d633f0d6743b7 (MD5) Previous issue date: 2016-03-02 / Os Sistemas Físico-Cibernéticos (SFC) são sistemas que surgiram da confluência da conectividade das redes, dos dispositivos embarcados e do controle computacional sobre processos físicos. Dessa forma os SFC se caracterizam como sistemas de controle, monitoramento e supervisão com componentes físicos e virtuais, que dependem de agentes humanos no processo. Nesse sentido, a combinação dos SFC à física dinâmica e complexa dos pacientes clínicos faz surgir uma classe distintas de sistemas médicos denominada de Sistemas Médicos Físico-Cibernéticos (SMFC). No domínio industrial há plantas que possuem sensores e atuadores que muitas vezes dependem de agentes humanos para manutenção e controle. Diferentemente, no domínio da saúde, o ser humano é o próprio processo a ser controlado, onde sensores e atuadores são os dispositivos médicos, e os agentes humanos são os cuidadores. Esse trabalho propõe uma abordagem para a construção de modelos de dispositivos médicos, como parte de um conjunto de artefatos para apoiar os testes de SMFC. Esta abordagem se baseia em modelos de referência que simulam o funcionamento de dispositivos médicos. Especificações técnicas fornecidas pelos fabricantes desses dispositivos, juntamente com diretrizes disponibilizadas por agências reguladoras, foram utilizadas para a definição da abordagem proposta. Além disso, um estudo de caso com três dispositivos médicos foi desenvolvido com o fim de validar a abordagem, criando artefatos e modelos de referência. / Cyber-Physical Systems (CPS) are systems that have emerged from the confluence of the connectivity of networks, embedded devices and computer control of physical processes. Thus, SFC are characterized as control, monitoring and supervision systems with physical and virtual components, which depend on human agents in the process. In this sense, the combination of SFC dynamic and complex physics of medical patients enable a distinct class of medical systems called Medical Cyber Physical Systems (MCPS). In the industrial area, there are plants with sensors and actuators that often rely on human agents for maintenance and control. On the other hand, in the field of health, human being is the process itself to be controlled, where sensors and actuators are medical devices and human agents are caregivers. MCPS perform monitoring and control of human health with high levels of security. This paper proposes an approach to build models of medical devices, as part of a set of artifacts to support MCPS testing. This approach is based on reference models which simulate the operation of medical devices. Technical specifications provide by manufacturers of these devices, along with guidelines provided by regulatory agencies, were used for the definition of the proposed approach. Moreover, a case study with three medical device was designed to validate the approach, creating some artifacts and reference models.

L'usage d'humains virtuels s'est démocratisé à de nombreuses activités ces dernières années.Au-delà de la chirurgie virtuelle, les corps virtuels sont de plus en plus utilisés pour concevoir des dispositifs médicaux, des véhicules et des outils de notre quotidien plus généralement.Ils se sont avérés être également d'extraordinaires supports à l'apprentissage de l'anatomie.De récents films (Avatar, Le seigneur des anneaux, etc) ont démontré que l'anatomie et la biomécanique peuvent être utilisées pour concevoir des personnages d'une grande qualité.Cependant, reproduire le comportement des structures anatomiques demeure une tâche complexe, et de nombreuses connaissances variées sont nécéssaires à la mise en place de simulation de qualité de nos organes. Ceci fait de la modélisation pour la simulation d'humains une problématique non résolue, une tâche fastidieuse, mais également un sujet de recherche fascinant.À travers ces travaux de thèse, nous abordons cette problématique de la construction de systèmes musculo-squeletiques pour ces domaines variés : animation, biomécanique et aide à l'apprentissage.Notre objectif est de simplifier le processus entier de création en le rendant plus intuitif et plus rapide.Notre approche consiste à pallier à chacune des difficultés, à savoir : la représentation et la manipulation de connaissances anatomiques, la modélisation géométrique et la simulation efficace de systèmes musculosquelettiques grâce à trois principalescontributions introduites durant ces travaux de recherche.Notre première contribution se focalise sur la construction biomécanique d'un modèle hybride du rachis lombaire.Dans ces travaux, nous montrons que les approches hybrides combinant des systèmes de corps rigides et des modèles éléments finis permettent d'obtenir des simulations en temps intéractifs, précises, et respectant les principes de l'anatomie et de la mécanique.Notre seconde contribution s'intéresse aux problématiques liées à la complexité des connaissances anatomiques, physiologiques et fonctionnelles. En se basant sur une ontologie de l'anatomie et une ontologie inédite de la physiologie humaine, nous introduisonsun pipeline pour la construction automatique de modèles simulant les fonctions de nos organes.Celles-ci permettent d'exploiter les connaissances anatomiques complexes via des requêtes simples.Les sorties de ces requêtes sont utilisées pour créer des modèles simulables retranscrivant les aspects fonctionnels tels qu'ils ont été formalisés et décrits par les anatomistes.Enfin, notre troisième contribution : le transfert d'anatomie, permet d'adapter les modèles géométriques et mécaniques à la morphologie de patients spécifiques.Cette nouvelle méthode de recalage permet de reconstruire automatiquement l'anatomie interne d'un personnage défini par sa peau en transférant les organes d'un personnage de référence.Elle permet de pallier à la nécessité de re-construire ces géometries pour chaque nouvelle simulation, et contribue ainsi à accélérer la mise en place de simulations spécifiques à une grande variété d'individus de morphologie différente. / The use of virtual humans has spread in various activities in recent years.Beyond virtual surgery, virtual bodies are increasingly used to design medical devices, vehicles, and daily life hardware more generally.They also turn out to be extraordinary supports to learn anatomy.Recent movies (Avatar, Lord of the Rings, etc) demonstrated that anatomy and biomechanics can be used to design high-quality characters.However, reproducing the behavior of anatomical structures remains a complex task, and a great amount and variety of knowledge is necessary for setting up high quality simulations.This makes the modeling of human body for simulation purposes an open problem, a tedious task, but also a fascinating research subject.Through this PhD, we address the problem of the construction of biomechanical models of the musculoskeletal systems for several domains : animation, biomechanics and teaching.Our goal is to simplify the entire process of model design by making it more intuitive and faster.Our approach is to address each difficulty : the representation and use of anatomical knowledge, the geometrical modeling and the efficient simulation of the musculoskeletal system thanks to three novel contributions introduced during these research works.Our first contribution focuses on the biomechanical construction of a hybrid model of lumbar spine.In this work, we show that hybrid approaches that combine both rigid body systems and finite element models allow interactive simulations, accurate, while respecting the principles of anatomy and mechanics.Our second contribution addresses the problem of the complexity of anatomical, physiological and functional knowledge.Based on a novel ontology of anatomical functions of the human body, we introduce a novel pipeline to automatically build models that simulate physiological functions of our bodies.The ontology allows us to extract detailed knowledge using simple queries.The outputs of these queries are used to set up simulation models of the functional aspects as they were formalized and described by anatomists.Finally our third contribution, the anatomy transfer, allows the mapping of available geometrical and mechanical models to the morphology of any specific individual.This novel registration method enables the automatic construction of the internal anatomy of any character defined by his skin, by transferring organs from a reference character.It allows to overcome the need to re-construct these geometries for each new simulation, and it contributes to accelerate the simulations setup for a range of people with different morph

Un grand nombre de pathologies cérébrales demeurent aujourd’hui incomprises par manque d’accès à l’information biologique contenue dans le tissu. L’anatomie complexe du système nerveux central et la distribution des grandes fonctions cognitives en réseaux d’aires fonctionnelles rend difficile la cartographie et la compréhension fine des mécanismes associés à la pathologie. Accéder au cerveau et se rendre capable d’y prélever du tissu sans dommages constitue donc un enjeu majeur. Ceci est d’autant plus vrai que, dans les populations occidentales, les cancers et les maladies neurodégénratives voient leurs incidences croître de manière quasi exponentielle, faisant d’elles un défi majeur en terme de santé publique dans les décennies qui viennent.Les travaux du laboratoire ont permis le développement d’un outil chirurgical innovant, basé sur l’utilisation de puces en silicium, pour autoriser le prélèvement de micro fragments de tissus dans le cerveau, de manière atraumatique. Ce concept d’ « empreinte » biologique sur silicium est en cours de validation chez l’Homme dans un essai clinique dédié à l’analyse des tumeurs. Cependant, plusieurs défis techniques restaient à solder pour préparer la voie à des versions ultérieures de ce dispositif. Ainsi, ce travail de thèse a permis de préparer une nouvelle stratégie matériau pour aborder non plus seulement les tumeurs cérébrales mais également les territoires profonds, ultra fonctionnels, impliqués dans les maladies d’Alzheimer ou de Parkinson, voire des pathologies d’autres organes (foie, poumon, prostate…). Un procédé de fabrication de silicium poreux a été entièrement validé en salle blanche, et nous avons testé l’ensemble de la cellule au gros animal, préparant un usage règlementaire chez l’Homme.Par ailleurs, dans l’idée d’améliorer la précision du geste chirurgical, nous avons pu évaluer la faisabilité d’associer notre concept avec un système de détection de fluorescence de type micro endoscopie confocale fibrée. Ce travail a permis de mettre en évidence un fort potentiel applicatif né du couplage, ayant été reconnu par le dépôt d’un brevet. De nombreux défis techniques restent sur la voie pour parvenir à un protoype robuste de « dispositif d’empreinte optiquement guidé dans le cerveau », mais nous parvenons à établir la faisabilité et à spécifier le cahier des charges pour un dispositif futur.En conclusion, nous avons pu, au travers de ce travail, préparer la voie pour un élargissement considérable du concept princeps, en intégrant dès les phases amont toutes les contraintes règlementaires pour viser un transfert rapide de ces développements au lit du malade. / Brain diseases today remain poorly understood due to the lack of access to the biological information contained in tissues. As cognitive functions are largely distributed in multiple functionnal areas in the brain, even as the CNS anatomy is complex, mapping and understanding of the molecular processes associated to diseases remain a challenging domain. Getting access to the brain and being able to sample tissues without any damages is a major stake. This is gaining in interest given the fact that neurodegenerative diseases and cancers are exponentially occuring in occidental population, thus becoming a public health problem.Our lab has recently developed, patented and validated an innovative surgical device allowing atraumatic tissue microfragments bioharvesting in the deep brain thanks to the use of silicon chips. This new concept, refered to as "tissue imprints", is under evaluation in a clinical trial dedicated to brain tumors investigation. Nevertheless, some technical and technological bets were to solve for extending that approach in next generations of that device. Thus, this PhD thesis has allowed the development of a new strategy regarding the material, paving the way to a use not only restricted to brain tumours but also for targeting highly functionnal, deep brain nuclei implied in neurodegenerative diseases (Alzheimer's disease, Parkinson's disease) and even other organs.A porous silicon fabrication process in clean rooms has arised and was fully validated from cell culture to big animals, preparing a clinical transfer of that approach. Additionnaly, in order to increase the accuracy of the surgical procedure, we evaluated the feasibility to couple the device with a fluorescence detection system. This work has highlighted the strong applicative potential of such a device coming from the coupling of both optical detection and molecular harvesting. Fully integrated prototype development will require some adjustments but we now are able to demonstrate that our approach is operationnal and we now can specify all the requirements.As a conclusion, this work constitutes a solid base for a large extension of our primary concept with the overall integration of all the prerequisites for a clinical transfer at patients' bedside.

Made available in DSpace on 2018-06-27T18:56:19Z (GMT). No. of bitstreams: 3 Nadia Marcia Dumke.pdf: 2321167 bytes, checksum: 449f4b9310f3670661f832eb53390630 (MD5) Nadia Marcia Dumke.pdf.txt: 113132 bytes, checksum: 2dbb738eb27d08559ba1ed0a6ad3c11f (MD5) Nadia Marcia Dumke.pdf.jpg: 3327 bytes, checksum: ea01888a8e3478355c0a38cbe96a336e (MD5) Previous issue date: 2014-08-11 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / A great number of nosocomial infections are associated with the use of hospital medical devices, such as urinary catheter, and biofilm formation mainly caused by fungi of the genus Candida. The treatment results in a high cost hospitalization, thereby increasing the permanence of the patient in the hospital environment and increased morbidity and mortality. This is especially harmful in patients with some immune deficiency, such as those caused by old age or with pre-existing medical conditions and also increasing resistance of microorganisms to conventional treatments. In order to investigate new therapies against this microorganism and combine with nanotechnology, studies with the drug escin and liposomes containing this active ingredient have been performed. The characterization of liposomes was carried out, demonstrating a particle size of liposome containing escin to 224 nm and a polydispersity index of 0.288 and liposome without drug, of 354.2 nm and the polydispersity index 0,215. Therefore methods of formation and adherence of biofilm on urinary catheter in vitro using assays for quantification of the biofilm exopolysaccharides and proteins of Candida albicans have been developed. It was subsequently treated with liposomes containing 0.5% escin, liposome without the drug and free drug. The results demonstrated the occurrence of fungal growth inhibition measured at Calcofluor White Stain method and the minimal inhibitory concentration, at a concentration of 1.56 mg/mL for liposome drug containing escin, achieving g a reduction of biofilm by 75% when compared using the free drug. It was observed that the liposome is containing 0.5% escin at a concentration of 1.56 mg/mL, decreased adherence and biofilm formation on medical hospital material, through the techniques used in the study, highlighting the effectiveness of liposome nanostructures against the microorganism C. albicans / Um número elevado de infecções hospitalares está associado ao uso de material médico hospitalar. Um exemplo é o cateter urinário e, com a formação de biofilme, principalmente causada por fungos do tipo Candida spp. O tratamento hospitalar gera um custo elevado em relação à internação, aumentando assim, a permanência do enfermo em ambiente hospitalar e uma maior morbi-mortalidade. Tal fator se apresenta mais evidente em pacientes com alguma imunodeficiência, tais como aquelas causadas pela idade avançada ou condições clínicas pré-existentes, assim como, também pelo aumento da resistência dos microrganismos aos tratamentos convencionais. Com o intuito de investigar novas terapias contra esse microrganismo e aliar a esse a nanotecnologia, foram realizados estudos com o fármaco escina e com lipossomas contendo esse princípio ativo. A caracterização dos lipossomas foi realizada demonstrando que os mesmos possuem um tamanho de partícula para o lipossoma contendo escina de 224 nm e um índice de polidispersão de 0,288 e para o lipossoma branco, sem o fármaco, de 354,2 nm e índice de polidispersão de 0,215. Deste modo, foram avaliados métodos de formação e aderência de biofilme in vitro em cateter urinário utilizando ensaios para quantificação de proteínas e exopolissacarídeos do biofilme de Candida albicans. Posteriormente, foi realizado um tratamento com lipossomas contendo escina a 0,5%, lipossoma sem o fármaco e o fármaco livre. Os resultados demonstraram a ocorrência de inibição do crescimento fúngico avaliados pelo método de Calcofluor White Stain e a concentração inibitória mínima, na concentração de 1,56 μg/mL para o lipossoma contendo o fármaco escina, obtendo uma redução do biofilme em 75% quando comparado com o uso do fármaco livre. Observou-se que o lipossoma contendo escina a 0,5% na concentração de 1,56 μg/mL, diminuiu a aderência e a formação do biofilme em material médico hospitalar, através das técnicas utilizadas no estudo, salientando a eficiência das nanoestruturas lipossomais contra o microrganismo C. albicans