Suivi par élastographie ultrasonore après réparation endovasculaire d’anévrisme aorto-iliaque : étude de faisabilité in vivo

Les maladies cardiovasculaires sont la première cause de mortalité dans le monde et les anévrismes de l’aorte abdominale (AAAs) font partie de ce lot déplorable. Un anévrisme est la dilatation d’une artère pouvant conduire à la mort. Une rupture d’AAA s’avère fatale près de 80% du temps. Un moyen de traiter les AAAs est l’insertion d’une endoprothèse (SG) dans l’aorte, communément appelée la réparation endovasculaire (EVAR), afin de réduire la pression exercée par le flux sanguin sur la paroi. L’efficacité de ce traitement est compromise par la survenue d’endofuites (flux sanguins entre la prothèse et le sac anévrismal) pouvant conduire à la rupture de l’anévrisme. Ces flux sanguins peuvent survenir à n’importe quel moment après le traitement EVAR. Une surveillance par tomodensitométrie (CT-scan) annuelle est donc requise, augmentant ainsi le coût du suivi post-EVAR et exposant le patient à la radiation ionisante et aux complications des contrastes iodés. L’endotension est le concept de dilatation de l’anévrisme sans la présence d’une endofuite apparente au CT-scan. Après le traitement EVAR, le sang dans le sac anévrismal coagule pour former un thrombus frais, qui deviendra progressivement un thrombus plus fibreux et plus organisé, donnant lieu à un rétrécissement de l’anévrisme. Il y a très peu de données dans la littérature pour étudier ce processus temporel et la relation entre le thrombus frais et l’endotension. L’étalon d’or du suivi post-EVAR, le CT-scan, ne peut pas détecter la présence de thrombus frais. Il y a donc un besoin d’investir dans une technique sécuritaire et moins coûteuse pour le suivi d’AAAs après EVAR. Une méthode récente, l’élastographie dynamique, mesure l’élasticité des tissus en temps réel. Le principe de cette technique repose sur la génération d’ondes de cisaillement et l’étude de leur propagation afin de remonter aux propriétés mécaniques du milieu étudié. Cette thèse vise l’application de l’élastographie dynamique pour la détection des endofuites ainsi que de la caractérisation mécanique des tissus du sac anévrismal après le traitement EVAR. Ce projet dévoile le potentiel de l’élastographie afin de réduire les dangers de la radiation, de l’utilisation d’agent de contraste ainsi que des coûts du post-EVAR des AAAs. L’élastographie dynamique utilisant le « Shear Wave Imaging » (SWI) est prometteuse. Cette modalité pourrait complémenter l’échographie-Doppler (DUS) déjà utilisée pour le suivi d’examen post-EVAR. Le SWI a le potentiel de fournir des informations sur l’organisation fibreuse du thrombus ainsi que sur la détection d’endofuites. Tout d’abord, le premier objectif de cette thèse consistait à tester le SWI sur des AAAs dans des modèles canins pour la détection d’endofuites et la caractérisation du thrombus. Des SGs furent implantées dans un groupe de 18 chiens avec un anévrisme créé au moyen de la veine jugulaire. 4 anévrismes avaient une endofuite de type I, 13 avaient une endofuite de type II et un anévrisme n’avait pas d’endofuite. Des examens échographiques, DUS et SWI ont été réalisés à l’implantation, puis 1 semaine, 1 mois, 3 mois et 6 mois après le traitement EVAR. Une angiographie, un CT-scan et des coupes macroscopiques ont été produits au sacrifice. Les régions d’endofuites, de thrombus frais et de thrombus organisé furent identifiées et segmentées. Les valeurs de rigidité données par le SWI des différentes régions furent comparées. Celles-ci furent différentes de façon significative (P < 0.001). Également, le SWI a pu détecter la présence d’endofuites où le CT-scan (1) et le DUS (3) ont échoué. Dans la continuité de ces travaux, le deuxième objectif de ce projet fut de caractériser l’évolution du thrombus dans le temps, de même que l’évolution des endofuites après embolisation dans des modèles canins. Dix-huit anévrismes furent créés dans les artères iliaques de neuf modèles canins, suivis d’une endofuite de type I après EVAR. Deux gels embolisants (Chitosan (Chi) ou Chitosan-Sodium-Tetradecyl-Sulfate (Chi-STS)) furent injectés dans le sac anévrismal pour promouvoir la guérison. Des examens échographiques, DUS et SWI ont été effectués à l’implantation et après 1 semaine, 1 mois, 3 mois et 6 mois. Une angiographie, un CT-scan et un examen histologique ont été réalisés au sacrifice afin d’évaluer la présence, le type et la grosseur de l’endofuite. Les valeurs du module d’élasticité des régions d’intérêts ont été identifiées et segmentées sur les données pathologiques. Les régions d’endofuites et de thrombus frais furent différentes de façon significative comparativement aux autres régions (P < 0.001). Les valeurs d’élasticité du thrombus frais à 1 semaine et à 3 mois indiquent que le SWI peut évaluer la maturation du thrombus, de même que caractériser l’évolution et la dégradation des gels embolisants dans le temps. Le SWI a pu détecter des endofuites où le DUS a échoué (2) et, contrairement au CT-scan, détecter la présence de thrombus frais. Finalement, la dernière étape du projet doctoral consistait à appliquer le SWI dans une phase clinique, avec des patients humains ayant déjà un AAA, pour la détection d’endofuite et la caractérisation de l’élasticité des tissus. 25 patients furent sélectionnés pour participer à l’étude. Une comparaison d’imagerie a été produite entre le SWI, le CT-scan et le DUS. Les valeurs de rigidité données par le SWI des différentes régions (endofuite, thrombus) furent identifiées et segmentées. Celles-ci étaient distinctes de façon significative (P < 0.001). Le SWI a détecté 5 endofuites sur 6 (sensibilité de 83.3%) et a eu 6 faux positifs (spécificité de 76%). Le SWI a pu détecter la présence d’endofuites où le CT-scan (2) ainsi que le DUS (2) ont échoué. Il n’y avait pas de différence statistique notable entre la rigidité du thrombus pour un AAA avec endofuite et un AAA sans endofuite. Aucune corrélation n’a pu être établie de façon significative entre les diamètres des AAAs ainsi que leurs variations et l’élasticité du thrombus. Le SWI a le potentiel de détecter les endofuites et caractériser le thrombus selon leurs propriétés mécaniques. Cette technique pourrait être combinée au suivi des AAAs post-EVAR, complémentant ainsi l’imagerie DUS et réduisant le coût et l’exposition à la radiation ionisante et aux agents de contrastes néphrotoxiques.

Relações de cooperação em consórcios públicos de regiões metropolitanas: análises do CONDIAM/PB e consórcio grande Recife

With the disorganized decentralization occurred in Brazil after the 1988 Constitution, municipalities have risen to the level of federal entities. This phenomenon became known as "municipalism" also brought some negative effects such as low capacity financial, economic and political of these entities. In the face of this reality , the municipalities sought in models of collaborative features to address public policy issues ultrarregionais, one of these models are the Public Consortia. Characterized as the organization of all federal entities that aim to solve public policy implementation alone that they could not, or spend great resources for such. This reality of the municipalities have an aggravating factor when looking at the situation in Metropolitan Regions (MRs). This is because the RMs has a historical process of formation that does not encourage cooperation, since that were created top-down during the military regime. Furthermore, the metropolitan municipalities have significant power asymmetries, localist vision, rigidity earmarked revenues, different scenarios conurbation, difficulty standardization of concepts and others that contribute to the vision of low cooperation of these metropolitan areas. Thus, the problem of this work is in the presence of collaborative arrangements, such as the Public Consortia in metropolitan areas, which are seen as areas of low cooperation. To elucidate this research was used for analysis the cases of CONDIAM/PB and Consórcio Grande Recife/PE, because they are apparently antagonistic, but with some points of similarity. The cases has as foundation the Theory of Common Resources, which provides the possibility of collective action through the initiative of individuals. This theory has as its methodology for analyzing the picture IAD Framework, which proposes its analysis based on three axes: external variables, the arena of action and results. The nature of the method of this research was classified as exploratory and descriptive. For the stage of date analysis, was used the method of document analysis and content, Further than of separation of the cases according to theur especificities. At the end of the study, noted that the CONDIAM/PB was a strategy of municipal government of Joao Pessoa to attract funds from the Federal Government for the purpose of to build a landfill, and over the years the ideology of cooperation was left aside, the prevailing view localist municipalities. In the case of Consórcio Grande Recife/PE, members act with some degree of cooperation, especially the collaborative aspect of the region, however, still prevails with greater strength the power of the state of Pernambuco in the decisions and paths of the consortium. Thus, was conclude that the Public Consortia analyzed are an experience of collaborative arrangement, from the initiative of members, as the theory of common resources says, but has not actually signed as a practice of collective action to overcome the dilemmas faced by metropolitan areas

A systems approach to cardiovascular health and disease with a focus on aortic wave dynamics

Cardiovascular diseases (CVDs) have reached an epidemic proportion in the US and worldwide with serious consequences in terms of human suffering and economic impact. More than one third of American adults are suffering from CVDs. The total direct and indirect costs of CVDs are more than $500 billion per year. Therefore, there is an urgent need to develop noninvasive diagnostics methods, to design minimally invasive assist devices, and to develop economical and easy-to-use monitoring systems for cardiovascular diseases. In order to achieve these goals, it is necessary to gain a better understanding of the subsystems that constitute the cardiovascular system. The aorta is one of these subsystems whose role in cardiovascular functioning has been underestimated. Traditionally, the aorta and its branches have been viewed as resistive conduits connected to an active pump (left ventricle of the heart). However, this perception fails to explain many observed physiological results. My goal in this thesis is to demonstrate the subtle but important role of the aorta as a system, with focus on the wave dynamics in the aorta.

The operation of a healthy heart is based on an optimized balance between its pumping characteristics and the hemodynamics of the aorta and vascular branches. The delicate balance between the aorta and heart can be impaired due to aging, smoking, or disease. The heart generates pulsatile flow that produces pressure and flow waves as it enters into the compliant aorta. These aortic waves propagate and reflect from reflection sites (bifurcations and tapering). They can act constructively and assist the blood circulation. However, they may act destructively, promoting diseases or initiating sudden cardiac death. These waves also carry information about the diseases of the heart, vascular disease, and coupling of heart and aorta. In order to elucidate the role of the aorta as a dynamic system, the interplay between the dominant wave dynamic parameters is investigated in this study. These parameters are heart rate, aortic compliance (wave speed), and locations of reflection sites. Both computational and experimental approaches have been used in this research. In some cases, the results are further explained using theoretical models.

The main findings of this study are as follows: (i) developing a physiologically realistic outflow boundary condition for blood flow modeling in a compliant vasculature; (ii) demonstrating that pulse pressure as a single index cannot predict the true level of pulsatile workload on the left ventricle; (iii) proving that there is an optimum heart rate in which the pulsatile workload of the heart is minimized and that the optimum heart rate shifts to a higher value as aortic rigidity increases; (iv) introducing a simple bio-inspired device for correction and optimization of aortic wave reflection that reduces the workload on the heart; (v) deriving a non-dimensional number that can predict the optimum wave dynamic state in a mammalian cardiovascular system; (vi) demonstrating that waves can create a pumping effect in the aorta; (vii) introducing a system parameter and a new medical index, Intrinsic Frequency, that can be used for noninvasive diagnosis of heart and vascular diseases; and (viii) proposing a new medical hypothesis for sudden cardiac death in young athletes.

Induced Damping on Vibrating Circular Plates Submerged in still Fluid

When a structure vibrates immersed in a fluid it is known that the dynamic properties of the system are modified. The surrounding fluid will, in general, contribute to the inertia, the rigidity and the damping coefficient of the coupled fluid-structure system. For light structures, like spacecraft antennas, even when the fluid is air the contribution to the dynamic properties can be important. For not so light structures the ratio of the equivalent fluid/structure mass and rigidity can be very small and the fluid contribution could be neglected. For the ratio of equivalent fluid/structure damping both terms are of the same order and therefore the fluid contribution must be studied. The working life of the spacecraft structure would be on space and so without any surrounding fluid. The response of a spacecraft structure on its operational life would be attenuated by the structural damping alone but when the structure is dynamically tested on the earth the dynamic modal test is performed with the fluid surrounding it. The results thus are contaminated by the effects of the fluid. If the damping added by the fluid is of the same order as the structural damping the response of the structure in space can be quite different to the response predicted on earth. It is therefore desirable to have a method able to determine the amount of damping induced by the fluid and that should be subtracted of the total damping measured on the modal vibration test. In this work, a method for the determination of the effect of the surrounding fluid on the dynamic characteristics of a circular plate has been developed. The plate is assumed to vibrate harmonically with the vacuum modes and the generalized forces matrix due to the fluid is thus computed. For a compressible fluid this matrix is formed by complex numbers including terms of inertia, rigidity and damping. The matrix due to the fluid loading is determined by a boundary element method (BEM). The BEM used is of circular rings on the plate surface so the number of elements to obtain an accurate result is very low. The natural frequencies of the system are computed by an iteration procedure one by one and also the damping fluid contribution. Comparisons of the present method with various experimental data and other theories show the efficiency and accuracy of the method for any support condition of the plate.

Standardized environmental management systems as an internal management tool

In a principal-agent model we analyze the firm’s decision to adopt an informal or a standardized Environmental Management System (EMS). Our results are consistent with empirical evidence in several respects. A standardized EMS increases the internal control at the cost of introducing some degree of rigidity that entails an endogenous setup cost. Standardized systems are more prone to be adopted by big and well established firms and under tougher environmental policies. Firms with standardized EMS tend to devote more effort to abatement although this effort results in lower pollution only if public incentives are strong enough, suggesting a complementarity relationship between standardized EMS and public policies. Emission charges have both a marginal effect on abatement and a qualitative effect on the adoption decision that may induce a conflict between private and public interests. As a result of the combination of these two effects it can be optimal for the government to distort the tax in a specific way in order to push the firm to choose the socially optimal EMS. The introduction of standardized systems can result in win-win situations where firms, society and the environment get better off.

Hybrid materials based on polyethylene and MCM-41 microparticles functionalized with silanes: catalytic aspects of in situ polymerization, crystalline features and mechanical properties

New nanocomposites based on polyethylene have been prepared by in situ polymerization of ethylene in presence of mesoporous MCM-41. The polymerization reactions were performed using a zirconocene catalyst either under homogenous conditions or supported onto mesoporous MCM-41 particles, which are synthesized and decorated post-synthesis with two silanes before polymerization in order to promote an enhanced interfacial adhesion. The existence of polyethylene chains able to crystallize within the mesoporous channels in the resulting nanocomposites is figured out from the small endothermic process, located at around 80 C, on heating calorimetric experiments, in addition to the main melting endotherm. These results indicate that polyethylene macrochains can grow up during polymerization either outside or inside the MCM-41 channels, these keeping their regular hexagonal arrangements. Mechanical response is observed to be dependent on the content in mesoporous MCM-41 and on the crystalline features of polyethylene. Accordingly, stiffness increases and deformability decreases in the nanocomposites as much as MCM-41 content is enlarged and polyethylene amount within channels is raised. Ultimate mechanical performance improves with MCM-41 incorporation without varying the final processing temperature.

Design gráfico alternativo

Dissertação de Mestrado para obtenção do grau de Mestre em Design de Comunicação, apresentada na Universidade de Lisboa - Faculdade de Arquitectura

Fachada flexível para casa padronizada em condomínios

The employment of flexibility in the design of façades makes them adaptable to adverse weather conditions, resulting in both minimization of environmental discomfort and improvement of energy efficiency. The present study highlights the potential of flexible façades as a resource to reduce rigidity and form repetition, which are usually employed in condominiums of standardized houses; as such, the work presented herein contributes to field of study of architectural projects strategies for adapting and integrating buildings within the local climate context. Two façade options were designed using as reference the bionics and the kinetics, as well as their applications to architectural constructions. This resulted in two lightweight and dynamic structures, which cater to constraints of comfort through combinations of movements, which control the impact of solar radiation and of cooling in the environment. The efficacy and technical functionality of the façades were tested with comfort analysis and graphic computation software, as well as with physical models. Thus, the current research contributes to the improvement of architectural solutions aimed at using passive energy strategies in order to offer both better quality for the users and for the sustainability of the planet

Plásticos reforçados a base de tecidos híbridos: efeitos da anisotropia e geometria normativa na caracterização mecânica e da fratura

As most current studies, reinforced plastics have been, in recent years, a viable alternative in building structural elements of medium and large, since the lightness accompanied by high performance possible. The design of hybrid polymer composites (combination of different types of reinforcements) may enable structural applications thereof, facing the most severe service conditions. Within this class of composite materials, reinforced the underlying tissues hybrid high performance are taking space when your application requires high load bearing and high rigidity. The objective of this research work is to study the challenges in designing these fabrics bring these materials as to its mechanical characterization and fracture mechanisms involved. Some parameters associated with the process and / or form of hybridization stand out as influential factors in the final performance of the material such as the presence of anisotropy, so the fabric weave, the process of making the same, normative geometry of the specimens, among others. This sense, four laminates were developed based hybrid reinforcement fabrics involving AS4 carbon fiber, kevlar and glass 49-E as the matrix epoxy vinyl ester resin (DERAKANE 411-350). All laminates were formed each with four layers of reinforcements. Depending on the hybrid fabric, all the influencing factors mentioned above have been studied for laminates. All laminates were manufactured industrially used being the lamination process manual (hand-lay-up). All mechanical characterization and study of the mechanism of fracture (fracture mechanics) was developed for laminates subjected to uniaxial tensile test, bending in three and uniaxial compression. The analysis of fracture mechanisms were held involving the macroscopic, optical microscopy and scanning electron microscopy

Rigidez ou flexibilidade governamental? Discursos anti-corrupção e pró-eficiência sobre contratações com orçamento sigilogo

Dissertação (mestrado)—Universidade de Brasília, Instituto de Ciência Política, Programa de Pós-Graduação em Ciência Política, 2016.

Concurrent transcranial direct current stimulation and progressive resistance training in Parkinson's disease: study protocol for a randomised controlled trial

BACKGROUND: Parkinson's disease (PD) results from a loss of dopamine in the brain, leading to movement dysfunctions such as bradykinesia, postural instability, resting tremor and muscle rigidity. Furthermore, dopamine deficiency in PD has been shown to result in maladaptive plasticity of the primary motor cortex (M1). Progressive resistance training (PRT) is a popular intervention in PD that improves muscular strength and results in clinically significant improvements on the Unified Parkinson's Disease Rating Scale (UPDRS). In separate studies, the application of anodal transcranial direct current stimulation (a-tDCS) to the M1 has been shown to improve motor function in PD; however, the combined use of tDCS and PRT has not been investigated.

METHODS/DESIGN: We propose a 6-week, double-blind randomised controlled trial combining M1 tDCS and PRT of the lower body in participants (n = 42) with moderate PD (Hoehn and Yahr scale score 2-4). Supervised lower body PRT combined with functional balance tasks will be performed three times per week with concurrent a-tDCS delivered at 2 mA for 20 minutes (a-tDCS group) or with sham tDCS (sham group). Control participants will receive standard care (control group). Outcome measures will include functional strength, gait speed and variability, balance, neurophysiological function at rest and during movement execution, and the UPDRS motor subscale, measured at baseline, 3 weeks (during), 6 weeks (post), and 9 weeks (retention). Ethical approval has been granted by the Deakin University Human Research Ethics Committee (project number 2015-014), and the trial has been registered with the Australian New Zealand Clinical Trials Registry (ACTRN12615001241527).

DISCUSSION: This will be the first randomised controlled trial to combine PRT and a-tDCS targeting balance and gait in people with PD. The study will elucidate the functional, clinical and neurophysiological outcomes of combined PRT and a-tDCS. It is hypothesised that combined PRT and a-tDCS will significantly improve lower limb strength, postural sway, gait speed and stride variability compared with PRT with sham tDCS. Further, we hypothesise that pre-frontal cortex activation during dual-task cognitive and gait/balance activities will be reduced, and that M1 excitability and inhibition will be augmented, following the combined PRT and a-tDCS intervention.

Comparative acoustic performance and mechanical properties of silk membranes for the repair of chronic tympanic membrane perforations

The acoustic and mechanical properties of silk membranes of different thicknesses were tested to determine their suitability as a repair material for tympanic membrane perforations. Membranes of different thickness (10-100μm) were tested to determine their frequency response and their resistance to pressure loads in a simulated ear canal model. Their mechanical rigidity to pressure loads was confirmed by tensile testing. These membranes were tested alongside animal cartilage, currently the strongest available myringoplasty graft as well as paper, which is commonly used for simpler procedures. Silk membranes showed resonant frequencies within the human hearing range and a higher vibrational amplitude than cartilage, suggesting that silk may offer good acoustic energy transfer characteristics. Silk membranes were also highly resistant to simulated pressure changes in the middle ear, suggesting they can resist retraction, a common cause of graft failure resulting from chronic negative pressures in the middle ear. Part of this strength can be explained by the substantially higher modulus of silk films compared with cartilage. This allows for the production of films that are much thinner than cartilage, with superior acoustic properties, but that still provide the same level of mechanical support as thicker cartilage. Together, these in vitro results suggest that silk membranes may provide good hearing outcomes while offering similar levels of mechanical support to the reconstructed middle ear.

Fonctionnalisation covalente de monocouches et bicouches de graphène

Le graphène est une nanostructure de carbone hybridé sp2 dont les propriétés électroniques et optiques en font un matériau novateur avec un très large potentiel d’application. Cependant, la production à large échelle de ce matériau reste encore un défi et de nombreuses propriétés physiques et chimiques doivent être étudiées plus en profondeur pour mieux les exploiter. La fonctionnalisation covalente est une réaction chimique qui a un impact important dans l’étude de ces propriétés, car celle-ci a pour conséquence une perte de la structure cristalline des carbones sp2. Néanmoins, la réaction a été très peu explorée pour ce qui est du graphène déposé sur des surfaces, car la réactivité chimique de ce dernier est grandement dépendante de l’environnement chimique. Il est donc important d’étudier la fonctionnalisation de ce type de graphène pour bien comprendre à la fois la réactivité chimique et la modification des propriétés électroniques et optiques pour pouvoir exploiter les retombées. D’un autre côté, les bicouches de graphène sont connues pour avoir des propriétés très différentes comparées à la monocouche à cause d’un empilement des structures électroniques, mais la croissance contrôlée de ceux-ci est encore très difficile, car la cinétique de croissance n’est pas encore maîtrisée. Ainsi, ce mémoire de maîtrise va porter sur l’étude de la réactivité chimique du graphène à la fonctionnalisation covalente et de l’étude des propriétés optiques du graphène. Dans un premier temps, nous avons effectué des croissances de graphène en utilisant la technique de dépôt chimique en phase vapeur. Après avoir réussi à obtenir du graphène monocouche, nous faisons varier les paramètres de croissance et nous nous rendons compte que les bicouches apparaissent lorsque le gaz carboné nécessaire à la croissance reste présent durant l’étape de refroidissement. À partir de cette observation, nous proposons un modèle cinétique de croissance des bicouches. Ensuite, nous effectuons une étude approfondie de la fonctionnalisation du graphène monocouche et bicouche. Tout d’abord, nous démontrons qu’il y a une interaction avec le substrat qui inhibe grandement le greffage covalent sur la surface du graphène. Cet effet peut cependant être contré de plusieurs façons différentes : 1) en dopant chimiquement le graphène avec des molécules réductrices, il est possible de modifier le potentiel électrochimique afin de favoriser la réaction; 2) en utilisant un substrat affectant peu les propriétés électroniques du graphène; 3) en utilisant la méthode d’électrogreffage avec une cellule électrochimique, car elle permet une modulation contrôlée du potentiel électrochimique du graphène. De plus, nous nous rendons compte que la réactivité chimique des bicouches est moindre dû à la rigidité de structure due à l’interaction entre les couches. En dernier lieu, nous démontrons la pertinence de la spectroscopie infrarouge pour étudier l’effet de la fonctionnalisation et l’effet des bicouches sur les propriétés optiques du graphène. Nous réussissons à observer des bandes du graphène bicouche dans la région du moyen infrarouge qui dépendent du dopage. Normalement interdites selon les règles de sélection pour la monocouche, ces bandes apparaissent néanmoins lorsque fonctionnalisée et changent grandement en amplitude dépendamment des niveaux de dopage et de fonctionnalisation.

A BACKING DEVICE BASED ON AN EMBEDDED STIFFENER AND RETRACTABLE INSERTION TOOL FOR THIN-FILM COCHLEAR ARRAYS

Intracochlear trauma from surgical insertion of bulky electrode arrays and inadequate pitch perception are areas of concern with current hand-assembled commercial cochlear implants. Parylene thin-film arrays with higher electrode densities and lower profiles are a potential solution, but lack rigidity and hence depend on manually fabricated permanently attached polyethylene terephthalate (PET) tubing based bulky backing devices. As a solution, we investigated a new backing device with two sub-systems. The first sub-system is a thin poly(lactic acid) (PLA) stiffener that will be embedded in the parylene array. The second sub-system is an attaching and detaching mechanism, utilizing a poly(N-vinylpyrrolidone)-block-poly(d,l-lactide) (PVP-b-PDLLA) copolymer-based biodegradable and water soluble adhesive, that will help to retract the PET insertion tool after implantation. As a proof-of-concept of sub-system one, a microfabrication process for patterning PLA stiffeners embedded in parylene has been developed. Conventional hotembossing, mechanical micromachining, and standard cleanroom processes were integrated for patterning fully released and discrete stiffeners coated with parylene. The released embedded stiffeners were thermoformed to demonstrate that imparting perimodiolar shapes to stiffener-embedded arrays will be possible. The developed process when integrated with the array fabrication process will allow fabrication of stiffener-embedded arrays in a single process. As a proof-of-concept of sub-system two, the feasibility of the attaching and detaching mechanism was demonstrated by adhering 1x and 1.5x scale PET tube-based insertion tools and PLA stiffeners embedded in parylene using the copolymer adhesive. The attached devices survived qualitative adhesion tests, thermoforming, and flexing. The viability of the detaching mechanism was tested by aging the assemblies in-vitro in phosphate buffer solution. The average detachment times, 2.6 minutes and 10 minutes for 1x and 1.5x scale devices respectively, were found to be clinically relevant with respect to the reported array insertion times during surgical implantation. Eventually, the stiffener-embedded arrays would not need to be permanently attached to current insertion tools which are left behind after implantation and congest the cochlear scala tympani chamber. Finally, a simulation-based approach for accelerated failure analysis of PLA stiffeners and characterization of PVP-b-PDLLA copolymer adhesive has been explored. The residual functional life of embedded PLA stiffeners exposed to body-fluid and thereby subjected to degradation and erosion has been estimated by simulating PLA stiffeners with different parylene coating failure types and different PLA types for a given parylene coating failure type. For characterizing the PVP-b-PDLLA copolymer adhesive, several formulations of the copolymer adhesive were simulated and compared based on the insertion tool detachment times that were predicted from the dissolution, degradation, and erosion behavior of the simulated adhesive formulations. Results indicate that the simulation-based approaches could be used to reduce the total number of time consuming and expensive in-vitro tests that must be conducted.

Synthetic approaches to flexible fluorescent conjugated polymers

Conjugated polymers (CPs) are intrinsically fluorescent materials that have been used for various biological applications including imaging, sensing, and delivery of biologically active substances. The synthetic control over flexibility and biodegradability of these materials aids the understanding of the structure-function relationships among the photophysical properties, the self-assembly behaviors of the corresponding conjugated polymer nanoparticles (CPNs), and the cellular behaviors of CPNs, such as toxicity, cellular uptake mechanisms, and sub-cellular localization patterns. ^ Synthetic approaches towards two classes of flexible CPs with well-preserved fluorescent properties are described. The synthesis of flexible poly( p-phenylenebutadiynylene)s (PPBs) uses competing Sonogashira and Glaser coupling reactions and the differences in monomer reactivity to incorporate a small amount (∼10%) of flexible, non-conjugated linkers into the backbone. The reaction conditions provide limited control over the proportion of flexible monomer incorporation. Improved synthetic control was achieved in a series of flexible poly(p-phenyleneethynylene)s (PPEs) using modified Sonogashira conditions. In addition to controlling the degree of flexibility, the linker provides disruption of backbone conjugation that offers control of the length of conjugated segments within the polymer chain. Therefore, such control also results in the modulation of the photophysical properties of the materials. ^ CPNs fabricated from flexible PPBs are non-toxic to cells, and exhibit subcellular localization patterns clearly different from those observed with non-flexible PPE CPNs. The subcellular localization patterns of the flexible PPEs have not yet been determined, due to the toxicity of the materials, most likely related to the side-chain structure used in this series. ^ The study of the effect of CP flexibility on self-assembly reorganization upon polyanion complexation is presented. Owing to its high rigidity and hydrophobicity, the PPB backbone undergoes reorganization more readily than PPE. The effects are enhanced in the presence of the flexible linker, which enables more efficient π-π stacking of the aromatic backbone segments. Flexibility has minimal effects on the self-assembly of PPEs. Understanding the role of flexibility on the biophysical behaviors of CPNs is key to the successful development of novel efficient fluorescent therapeutic delivery vehicles.^