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Lubricant-infused surfaces (LIS) are created by modifying chemical and physical properties of surfaces with aim of lowering surfaces energy where designed surface will possess liquid-repelling behaviors under low tilting angles. LIS has great potential to be applied on implantable devices due to it is stable anti-biofouling properties under fluidic environment. However, a few studies have reported that the existing research on implant surface uses complicated methods and high cost fabrication to create LIS on titanium implants. Furthermore, current limitation of LIS coatings for titanium implants lies in the lack of tissue integration and cell interaction. As a result, LIS prevents both bacteria and bone cells from adhering to the interface between implant and natural bone. This unselective blocking is problematic for titanium implants used in orthopaedic surgery when devices are required to possess tissue integration properties to facilitate long term fixation in the human body. The overall objective of this thesis is to apply LIS on titanium surfaces via a chemical modification technique and simultaneously integrate bio-functional features onto LIS to promote osteoblasts adhesion. In this project, chitosan and collagen were used to facilitate cell adhesion. To start with, three methods were used to immobilize chitosan on titanium to obtain the desired bio-functional LIS coatings: (1) LIS on top of (3-Glycidyloxypropyl)trimethoxysilane (GPTMS) crosslinked chitosan; (2) LIS on dip-coated chitosan; (3) LIS generated from GPTMS and Trichloro(1H,1H,2H,2H-perfluorooctyl) silane (TPFS) mixed silanes modified titanium surface followed by chitosan functionalization. Among these modification techniques, method (3) showed optimal anti-biofouling and osseointegration properties. Since collagen is well known for increase of cell interactions, it was used via mixed silanes functionalization method. Finally, the properties were compared with chitosan coated surfaces. During tests, surface wettability was measured, anti-biofouling properties and osseointegration was examined with staphylococcus aureus and SAOS-2 cells, respectively. We found that chitosan modified surfaces using method (3) not only significantly increased cell adhesion in comparison with the other two modification methods, but also dramatically decreased bacterial adhesion compared to collagen coated LIS on titanium. Although collagen has better cell adhesion properties than chitosan, collagen coated surface significantly decreased antibiofouling properties. In conclusion, bio-functional lubricant-infused titanium surfaces created by chemical vapor deposition (CVD) method with mixed silanes is a feasible and straightforward method to immobilize biomaterials and stabilize the lubricant layer on titanium substrates. Chitosan coated LIS on titanium prevents bacterial adhesion and simultaneously promotes targeted cell binding. / Thesis / Master of Applied Science (MASc) / Biofouling is a major issue in implantable titanium devices such as coronary stents, plates and nails, and formation of biofilm on implants can lead to infection and failure of the device. Biofilms formed by bacterial adhesion could be resistant to antibiotics and can provoke a series of inflammatory response. Recent advances in anti-biofouling surface treatment has resulted in designing supper slippery lubricant-infused omniphobic surfaces which are inspired from the Nepenthes pitcher plant. Liquid which is tethered on the surface offers a stable liquid interface, repelling both aqueous and organic liquids meanwhile showing excellent bacteria repellency. Lubricant-infused surfaces (LIS) are resistant towards biofilm formation and produce a stable surface that prevent non-specific adhesion. As a result of this repellent properties, LIS also repels the adhesion of desired biomolecules and cells such as osteoblasts, bone cells and growth factors which are essential factors for bone recovery at the implant-bone interface. Our motivation in this thesis is to create a lubricant-infused coating on titanium surfaces that possesses both bio-functional and blocking features. We designed surfaces that decrease implant infection caused by non-specific adhesion and simultaneously promote targeted binding of biomolecules and cells that will increase osseointegration of the implant to enable long-term fixation.

Cochlear implants (CIs) and auditory brainstem implants (ABIs) are prostheses for hearing used in patients with profound hearing impairment. A CI requires an operational cochlear nerve to function in contrast to an ABI. ABIs were initially designed for adult patients with neurofibromatosis type 2 (NF2), suffering from bilateral vestibular schwannomas. Now ABIs are also used for patients, both adults and children, with congenital cochlear malformations, cochlear nerve hypoplasia/aplasia, and cochlear ossification. The aims of this thesis are to evaluate hearing outcome in patients implanted with a CI after long-term deafness. An extended period of deafness has earlier been considered as a contraindication for CI surgery. Further, we analyzed if electrically evoked auditory brainstem responses (eABRs) can predict CI outcome and pinpoint the optimal selection of treatment such as CI or ABI. We also disclose our experiences from ABI surgery in Uppsala, such as implant use, hearing outcome, complications, and satisfaction among the patients. Finally, we evaluated the results and benefits of ABIs in non-NF2 pediatric patients. Results show that patients with an extended deafness period and durations over 20 years can achieve speech understanding and benefit from CIs. Patients with long-term deafness and limited years of hearing before deafness did not perform as well as those with shorter deafness duration and longer hearing experience did. eABR seems to have a definite role in the diagnostic armamentarium, to better consider alternative surgical strategies such as ABI. No eABR waveform predicted a poor CI outcome. There was no correlation between speech perception and eABR waveform latencies or eABR waveform quality. A majority of the ABI patients used their ABIs and benefited from them for at least some period. ABI assisted voice control in a majority of the full-time users and they reported improved understanding of speech with the implant switched on. No severe complications from ABI surgery or ABI stimulation were noted. The patients were generally satisfied, even if their hearing remained very limited. All pediatric patients but one used the implant continuously and benefited from it.

Afirmação do problema. Estudos experimentais em animais são utilizados para avaliar previamente o resultado de pesquisas e sua necessidade de serem realizadas em humanos. Estudos em animais são fundamentais na implantodontia para que haja uma melhor compreensão da osseointegração. Durante o processo de execução de pesquisas nesse tipo de estudo, algumas dificuldades relacionadas ao manuseio, custos de manutenção e bem-estar dos animais tendem a dificultar o seu desenvolvimento. Finalidade. Esse estudo tem como objetivo, testar um novo dispositivo acoplado sobre o implante, para que possa atuar como uma extensão do mesmo, facilitando a realização da Análise de Frequência de Ressonância durante o processo de osseointegração permitindo que implantes instalados em ovelhas em diferentes períodos, possam ser reabertos sem que haja a necessidade de etapas cirúrgicas para a reabertura durante a realização de testes. Material e métodos. Foram utilizadas 4 ovelhas, sendo uma do Grupo Controle (GC) e 3 do Grupo Teste (GT). Cada animal recebeu oito implantes localizados próximos ao ângulo da mandíbula, sendo quatro do lado esquerdo e quatro do lado direito, totalizando, 32 implantes cone-morse Acqua® de 3,5 de diâmetro por 8,5mm de comprimento da empresa Neodent® que foram avaliados pela análise de frequência de ressonância com a medição do ISQ (Quociente de Estabilidade do Implante) utilizando um transdutor (SmartPeg) expressos numa escala de 0 a 100. Para o Grupo Controle (GC) as medições de ISQ foram realizadas pelo método convencional, onde o SmartPeg foi acoplado diretamente sobre a plataforma do implante. Já no Grupo Teste (GT) o dispositivo estudado, foi acoplado ao implante para que pudesse ser realizada a medição. Os períodos estudados foram: imediatamente após a cirurgia e com quatro semanas de osseointegração. Para a análise estatística foram empregados os testes de Wilcoxon e Man-Whitney com a probabilidade de 5% (p<0.05). Resultados. As médias obtidas no GC foram 50,47 imediatamente após cirurgia e 65,68 após 4 semana, enquanto que no GT foram 34,74 e 34,81, respectivamente. Comparando a diferença entre os grupos nas médias de ISQ imediatas e após quatro semanas, houve diferença significativa com p= 0.0321 e p= 0.0027, respectivamente, demonstrando que os resultados no GT nos dois períodos não foram equivalentes quando comparados ao GC. Conclusão. Os resultados demonstraram que o grupo teste, apesar de trazer benefícios em relação ao manuseio dos animais, não apresentou benefícios com relação à eficiência na leitura do ISQ, quando comparado ao método convencional. / Statement of the problem. Experimental studies in animals are used to pre-evaluate the results of research and their need to be performed in humans. Animal studies are fundamental in implantology so that there is a better understanding of osseointegration. During the execution of research in this type of study, some difficulties related to handling, maintenance costs and animal welfare tend to hinder its development. Purpose. This study aims to test a new device coupled on the implant, so that it can act as an extension of the same, facilitating the performance of the Resonance Frequency Analysis during the osseointegration process allowing implants installed in different periods of time, can be reopened without the need for surgical steps for reopening during testing. Material and methods. Four sheep were used, one being from the Control Group (GC) and 3 from the Test Group (GT). Each animal received eight implants located near the angle of the mandible, four on the left side and four on the right side, totaling 32 Acqua® 3.5 mm diameter 8.5 mm long implants of the company Neodent® that were evaluated by the resonance frequency analysis with the ISQ (Implant Stability Ratio) measurement using a transducer (SmartPeg) expressed on a scale of 0 to 100. For the Control Group (GC) the ISQ measurements were performed by the conventional method, where the SmartPeg was attached directly onto the implant platform. In the Test Group (GT) the studied device was attached to the implant so that the measurement could be performed. The periods studied were: immediately after surgery and four weeks of osseointegration. For the statistical analysis Wilcoxon and Man-Whitney tests were used, with a probability of 5% (p <0.05). Results. The averages obtained in the CG were 50.47 immediately after surgery and 65.68 after 4 weeks, while in the GT were 34.74 and 34.81, respectively. Comparing the difference between the groups in the means of immediate SAI and after four weeks, there was a significant difference with p = 0.0321 and p = 0.0027, respectively, demonstrating that the results in the WG in the two periods were not equivalent when compared to the CG. Conclusion. The results showed that the test group, despite having benefits in relation to the handling of the animals, did not present benefits in relation to the efficiency of the ISQ reading when compared to the conventional method.

Introduction : Depuis les premiers implants dentaires Bränemark, les techniques chirurgicales et les matériaux implantaires ont évolué. La référence en terme de matériau implantaire est le Titane. Cependant, d’autres matériaux comme le Zircone ont été proposés pour suppléer le Titane en cas d’allergie au Titane mais aussi pour améliorer la bio-intégration de l’implant dentaire et l’esthétique. Les facteurs de risques d’échec implantaire des implants en Titane incluent, entre autre, l’hygiène orale, la consommation de tabac et la mise en charge immédiate. Objectif : L’étude ZIR-ROC a donc été menée dans le but d’étudier le taux de survie de ces implants zircone après 2 ans de suivi, de recueillir des informations sur l’intégration tissulaire des implants et de rechercher les facteurs de risque d’échec des implants en Zircone. Matériel et méthode : l’étude ZIR-ROC a été menée dans le service de chirurgie orale du CHU de Montpellier sur des implants monobloc en Zircone de la société Paris Implant®. La pose de 43 implants a été déterminée pour permettre l’analyse statistique des résultats. Le forage et l’insertion des implants ont été réalisés à l’aide du système de chirurgie guidée 2ingis®. La variable principale pour évaluer l’ostéo-intégration des implants a été le score délivré par le Periotest®. 22 variables secondaires ont été recueillies tels que les indices gingivaux et de plaque ainsi que l’analyse rétro-alvéolaire. Les données ont été relevées juste avant la chirurgie implantaire, ainsi qu’à 1 semaine, 4 semaines, 5 mois, 1 an et 2 ans. La méthode de Kaplan-Meier, le modèle de Cox et les analyses en composantes principales ont été utilisés pour l’analyse statistique. Résultats : Tous les implants ont présenté une bonne stabilité primaire post-opératoire (valeurs du Periotest comprises entre -8 et +1 ; moyenne à -5,7). Le taux d’échec implantaire a atteint 31% après les 5 premiers mois d’ostéo-intégration. Une mobilité clinique a été observée pour les implants perdus. Les facteurs de risque décrits dans la littérature ont été retrouvés dans le modèle de Cox avec une significativité pour la consommation de tabac et d’alcool et sans significativité statistique pour la densité osseuse ou encore la mise en place d’une couronne provisoire. Par ailleurs, la présence de plaque et d’inflammation gingivale a été observée en faible quantité sur les implants en Zircone. Discussion et conclusion : Le Zircone apparaît comme un matériau biocompatible pour des implants dentaires. Les causes des échecs implantaires précoces observés sont probablement multiples et cette étude n’a pas permis de démontrer l’implication seule de la Zircone dans ces échecs. La recherche des facteurs d’échecs implantaires a conduit à évaluer la technique chirurgicale utilisée pour cette étude mais aussi le dessin de l’implant. De plus, une étude in vitro comparant des implants à base de Zircone et de Titane a été entreprise pour évaluer l’affinité de cellules souches d’origine dentaire pour les 2 matériaux. / Introduction: Since first Bränemark dental implants were implanted, operative surgery and materials for implantation have evolved. Titanium was the gold standard for dental implant material. But others materials like Zirconium were studied in replacement of Titanium due to allergy, bio-integration end aesthetic reasons. Contributing risk factors of Titanium implant failure include oral hygiene, tabacco and early loading among others factors. Objective: The aim of this clinical study was to evaluate survival rate of Zircon implants after 2 years, to collect information for tissue integration of Zirconium implant and to identify risk factors for Zircon implant failure. Material and Methods: ZIR-ROC study, conducted in the Oral Surgery Departement in Montpellier University Hospital, used zircon monobloc (ZIR-ROC®) implants (Paris Implant Society®). 43 implants were required for statistical analysis. Drilling and implantation were conducted with 2ingis® surgical guide system. The Periotest® value was the first endpoint for the implant osseointegration analysis. Gingival and dental plaque indices as well as intraoral X-ray analysis were part of the 22 secondary variables. Data were collected just after implantation surgery, and then, 1 week, 4 weeks, 5 months, 1 year and 2 years after implantation. Kaplan-Meier method, Cox regression model and principal component analysis were used for statistical analysis. Results: All implants showed postoperative optimal primary stability (Periotest® values between -8 and +1; mean: -5,7). Implants failure rate reached 31 percent after the 5 initial months of osseointegration. Clinical mobility was observed for the failed implants. Risk factors published in the scientific literature were observed in the Cox regression model with significant statistical effect for tobacco and alcohol consumption but without significant statistical effect for osseous density or even temporary crown insertion. Furthermore, gingival inflammation and dental plaque presence were low on Zircon implant. Discussion and Conclusion: Zirconium remains a biocompatible material for dental implantation but there were probably many reasons for the observed early implant failures and this study could not demonstrate the only involvement of Zirconium based material. Operative surgery used in this clinical study and the design of the implants were studied for researching other risk factors. In addition, an in vitro study comparing Zirconium versus Titanium as gold standard, was conducted for testing affinity of dental stems cells on Titanium and Zirconium-based dental materials.

Jusqu'à aujourd'hui, le traitement des maladies oculaires postérieures, telles que la dégénérescence maculaire liée à l'âge, la rétinopathie diabétique et l'uvéite, reste difficile. L'œil avec ses différentes barrières oculaires est bien protégé des agressions extérieures. Ces barrières réduisent également la biodisponibilité des médicaments pour le vitré. Après une administration topique, seule une quantité limitée (0,001 - 0,0004 %) permet d'atteindre le vitreux. Ceci est causé par exemple par une dilution des larmes et une faible perméabilité cornéenne du médicament. Après une administration systémique ou orale, les barrières hémato-oculaires empêchent le médicament d'entrer et seulement environ 2 % du médicament administré se trouve dans le vitré. Afin d'atteindre des concentrations thérapeutiques, une dose élevée doit être administrée, ce qui augmente le risque d'effets secondaires. La façon la plus efficace de traiter les maladies postérieures restent l'injection intravitréenne. Cependant, de petites molécules lipophiles comme la dexaméthasone peuvent facilement se diffuser à travers la rétine et les barrières oculaires et ont donc une demi-vie limitée de quelques heures seulement. Étant donné que de nombreuses maladies postérieures sont chroniques, une injection intravitréenne fréquente serait nécessaire. Chaque injection comporte des risques de décollement de la rétine, d'hémorragie et d'autres effets secondaires. Les implants biodégradables pour administration intravitréenne peuvent prolonger la libération du médicament et en diminuer les effets secondaires. PLGA est un polymère largement utilisé qui est biocompatible et biodégradable. Il peut également soutenir la libération du médicament de quelques jours à plusieurs mois. Dans cette étude, les implants de formation in situ (ISFI) et les implants préformés préparés par extrusion à chaude ont été étudié en profondeur. L'objectif de ce travail était (i) d'étudier l'impact du volume du rejet (ii) évaluer le comportement de libération, de gonflement et de dégradation des implants préformés préparés avec différentes charges de médicament et différents types de polymères, (iii) visualiser la libération de médicament et l'absorption d'eau des implants préformés et de l'ISFI en utilisant des médicaments modèles colorés et (iv) étudier l'effet des quantités variables des différents additifs sur les caractéristiques essentielles de l'ISFI. Ces informations peuvent aider à fabriquer des implants avec différents profils de libération. Nos études montrent que l'ISFI est assez robuste en ce qui concerne les différents volumes de l'humeur vitreuse que l'on peut rencontrer in vivo. Cependant, le poids moléculaire et la concentration du polymère ont une forte influence sur la morphologie et le gonflement de l'implant. Par conséquent, la dégradation et la libération du médicament sont affectées. Pour les implants préformés, le gonflement "orchestre" la libération du médicament. Au début, seule une quantité limitée d'eau peut se diffuser dans les implants. Ainsi, seules des quantités insignifiantes du médicament sont dissoutes et peuvent être libérées. Lorsque le PLGA commence à se dégrader, le polymère devient plus hydrophile et de plus grandes quantités d'eau peuvent pénétrer. Ce gonflement du polymère facilite la dissolution et la diffusion du médicament et déclenche la libération du médicament. Les études utilisant des médicaments modèles colorés corroborent le rôle de la pénétration de l'eau et de la dissolution du médicament pour les implants préformés. En ce qui concerne l'ISFI, il a visualisé l'importance de la concentration du polymère sur la structure interne de l'implant qui en résulte et par conséquent l'absorption d'eau et la libération du médicament. Le comportement de gonflement et la morphologie de l'ISFI pourraient également être modifiés de manière significative en utilisant différents additifs. L'effet global sur la libération du médicament a été limité. / Until today, the treatment of posterior eye diseases, such as age-related macular degeneration, diabetic retinopathy and uveitis, remains challenging. The eye with its different ocular barriers is well protected from external factors. Those barriers also reduce the bioavailability of drugs to the vitreous. After a topical administration, only a limited amount (0.001 – 0.0004 %) reaches the vitreous. This is caused by for example reflexive blinking, tear dilution and a low corneal permeability of the drug. After a systemic or oral administration, the blood-aqueous and the blood-retinal barrier hinder the drug from entering and only around 2 % of the administered drug is found in the vitreous. In order to reach therapeutic concentrations, a high dose has to be given which in turn increases the risk for systemic side effects. The most efficient way to treat posterior diseases remains the intravitreal injection. However, small lipophilic molecules like dexamethasone can easily diffuse through the retina and the blood-ocular barriers and, thus, have a limited half-life of just a few hours. Since many of the posterior diseases are chronic, a frequent intravitreal injection would be necessary. Every intravitreal injection bears the risks for retinal detachment, hemorrhage, and other side effects. Biodegradable implants for intravi-treal administration can prolong the drug release and in turn decrease the side effects. Poly(lac-tic-co-glycolic acid) (PLGA) is a widely used polymer that is biocompatible and biodegrada-ble. It can also sustain the drug release from a few days up to several months. In this study, in-situ forming implants (ISFI) and pre-formed implants prepared via hot melt extrusion were studied in depth. The aim of this work was (i) to study the impact of the volume of the release medium, polymer type and concentration as well as drug content of different ISFI, (ii) to eval-uate the drug release, swelling and degradation behavior of pre-formed implants prepared with different drug loadings and polymer types, (iii) to visualize the drug release and water uptake of ISFI and pre-formed implants using colored model drugs and (iv) to investigate the effect of varying amounts of different additives on key features of ISFI. This knowledge can help to manufacture implants with different release profiles. Our studies show that ISFI are rather ro-bust regarding different volumes of the vitreous humor that could be encountered in vivo. How-ever, the polymer molecular weight and polymer concentration have a strong influence on the morphology and swelling behavior of the implants. Consequently, the degradation and drug release are affected. For pre-formed implants the swelling “orchestrates” the drug release. In the beginning only limited amounts of water can diffuse into the implants. Thus, only insignif-icant amounts of the drug are dissolved and can be released. When the PLGA starts to degrade, the polymer becomes more hydrophilic and bigger amounts of water can penetrate. This poly-mer swelling facilitates drug dissolution and diffusion and initiates the drug release. The studies using colored model drugs corroborate the role of water penetration and drug dissolution for pre-formed implants. Concerning ISFI, it visualized the importance of the polymer concentra-tion on the resulting inner implant structure and consequently the water uptake and drug release. The swelling behavior and morphology of ISFI could also be significantly altered using differ-ent additives. The overall effect on the drug release was limited.