159 research outputs found
Systemic Circular Economy Solutions for Fiber Reinforced Composites
This open access book provides an overview of the work undertaken within the FiberEUse project, which developed solutions enhancing the profitability of composite recycling and reuse in value-added products, with a cross-sectorial approach. Glass and carbon fiber reinforced polymers, or composites, are increasingly used as structural materials in many manufacturing sectors like transport, constructions and energy due to their better lightweight and corrosion resistance compared to metals. However, composite recycling is still a challenge since no significant added value in the recycling and reprocessing of composites is demonstrated. FiberEUse developed innovative solutions and business models towards sustainable Circular Economy solutions for post-use composite-made products. Three strategies are presented, namely mechanical recycling of short fibers, thermal recycling of long fibers and modular car parts design for sustainable disassembly and remanufacturing. The validation of the FiberEUse approach within eight industrial demonstrators shows the potentials towards new Circular Economy value-chains for composite materials
Advanced medical micro-robotics for early diagnosis and therapeutic interventions
Recent technological advances in micro-robotics have demonstrated their immense potential for biomedical applications. Emerging micro-robots have versatile sensing systems, flexible locomotion and dexterous manipulation capabilities that can significantly contribute to the healthcare system. Despite the appreciated and tangible benefits of medical micro-robotics, many challenges still remain. Here, we review the major challenges, current trends and significant achievements for developing versatile and intelligent micro-robotics with a focus on applications in early diagnosis and therapeutic interventions. We also consider some recent emerging micro-robotic technologies that employ synthetic biology to support a new generation of living micro-robots. We expect to inspire future development of micro-robots toward clinical translation by identifying the roadblocks that need to be overcome
Creation and Optimisation of Plasma Etch Processes for the Manufacture of Silicon Microstructures
Microneedles are an area of growing interest for applications in transdermal delivery. Small, minimally invasive medical or cosmetic devices, microneedles are intended to penetrate the skinâs outer protective layer (stratum corneum) to facilitate delivery of active formulations into the skin. Delivery of solution via microneedles has the benefits associated with hypodermic injection, i.e. avoiding the first-pass metabolism systems, with the added advantages of painless delivery and dose sparing from the reduced solution volumes required.Advancements in semiconductor processing technologies and equipment have enabled the creation of devices and structures that could not have been fabricated in the past. This is also true for the fabrication of microneedles, where previous manufacturing methods have relied on hazardous chemicals such as Hydrofluoric Acid and Potassium Hydroxide to create the sharp tip of the needle, required to reduce insertion force.In this thesis, the realisation of a hollow bevelled silicon microneedle fabricated using only plasma processing techniques is presented, providing a route to scalable manufacture of high-performance, sharp-tipped microneedles. The microneedle fabrication process consists of three main etch steps in the process flow to create hollow structures. For each of the Bevel, Bore, and Shaft processes the development and optimisation is detailed. Throughout the process development, several unexpected processing issues were encountered, including depth non-uniformity, ânotchingâ, and âsilicon grassâ. Investigations have been performed to determine the root cause of each issue and fine-tune processes to optimise the final devices. A discussion of the process hardware is also presented, with reference to the benefits for each specific application process.Following development and optimisation of each individual process, the Bevel, Bore, and Shaft processes were integrated in the manufacturing flow to create the final hollow silicon microneedle device. Issues arising from the combination of the three processes have been investigated, resolved, and optimised. This includes the conception and execution of a novel process for the plasma smoothing of an angled silicon surface, which improved the quality of lithography on the non-planar bevel surface and minimised grass formation.Preliminary testing, undertaken to assess the suitability of these devices for transdermal use, included mechanical fracture force, skin penetration, and injection testing. The microneedles were found to be strong enough to remain intact during insertion, and demonstrate successful penetration and injection through the stratum corneum and into the deeper skin layers
Liquid Metal Printing with Scanning Probe Lithography for Printed Electronics
In den letzten Jahren hat das âInternet der Dingeâ (Englisch Internet of Things, abgekĂŒrzt IoT), das auch als Internet of Everything (Deutsch frei âInternet von Allemâ) bezeichnet wird, mit dem Aufkommen der âIndustrie 4.0â einen Strom innovativer und intelligenter sensorgestĂŒtzter Elektronik der neuen Generation in den Alltag gebracht. Dies erfordert auch die Herstellung einer riesigen Anzahl von elektronischen Bauteilen, einschlieĂlich Sensoren, Aktoren und anderen Komponenten. Gleichzeitig ist die herkömmliche Elektronikfertigung zu einem hochkomplexen und investitionsintensiven Prozess geworden. In dem MaĂe, wie die Zahl der elektronischen Bauteile und die Nachfrage nach neuen, fortschrittlicheren elektronischen Bauteilen zunimmt, steigt auch die Notwendigkeit, effizientere und nachhaltigere Wege zur Herstellung dieser Bauteile zu finden. Die gedruckte Elektronik ist ein wachsender Markt, der diese Nachfrage befriedigen und die Zukunft der Herstellung von elektronischen GerĂ€ten neu gestalten könnte. Sie erlaubt eine einfache und kostengĂŒnstige Produktion und ermöglicht die Herstellung von GerĂ€ten auf Papier- oder Kunststoffsubstraten. FĂŒr die Herstellung gibt es dabei eine Vielzahl von Methoden. Techniken auf der Grundlage der Rastersondenlithografie waren dabei schon immer Teil der gedruckten Elektronik und haben zu Innovationen in diesem Bereich gefĂŒhrt. Obwohl die Technologie noch jung ist und der derzeitige Stand der gedruckten Elektronik im industriellen MaĂstab, wie z. B. die Herstellung kompletter integrierter Schaltkreise, stark limitiert ist, sind die potenziellen Anwendungen enorm.
Im Mittelpunkt der Entwicklung gedruckter elektronischer Schaltungen steht der Druck leitfĂ€higer und anderer funktionaler Materialien. Die meisten der derzeit verfĂŒgbaren Arbeiten haben sich dabei auf die Verwendung von Tinten auf Nanopartikelbasis konzentriert. Die Herstellungsschritte auf der Grundlage von Tinten auf Nanopartikelbasis sind komplizierte Prozesse, da sie das AusglĂŒhen (Englisch Annealing) und weitere Nachbearbeitungsschritte umfassen, um die gedruckten Muster leitfĂ€hig zu machen. Die Verwendung von Gallium-basierten, bei/nahe Raumtemperatur flĂŒssigen Metallen und deren direktes Schreiben fĂŒr vollstĂ€ndig gedruckte Elektronik ist immer noch ungewöhnlich, da die Kombination aus dem Vorhandensein einer Oxidschicht, hohen OberflĂ€chenspannungen und ViskositĂ€t ihre Handhabung erschwert.
Zu diesem Zweck zielt diese Arbeit darauf ab, Methoden zum Drucken von Materialien, einschlieĂlich FlĂŒssigmetallen, zu entwickeln, die mit den verfĂŒgbaren Druckmethoden nicht oder nur schwer gedruckt werden können und diese Methoden zur Herstellung vollstĂ€ndig gedruckter elektronischer Bauteile zu verwenden. Weiter werden Lösungen fĂŒr Probleme wĂ€hrend des Druckprozesses untersucht, wie z. B. die Haftung der Tinte auf dem Substrat und andere abscheidungsrelevante Aspekte. Es wird auch versucht, wissenschaftliche Fragen zur StabilitĂ€t von gedruckten elektronischen Bauelementen auf FlĂŒssigmetallbasis zu beantworten.
Im Rahmen der vorliegenden Arbeit wurde eine auf Glaskapillaren basierenden Direktschreibmethode fĂŒr das Drucken von FlĂŒssigmetallen, hier Galinstan, entwickelt. Die Methode wurde auf zwei unterschiedlichen Wegen implementiert: Einmal in einer âHochleistungsversionâ, basierend auf einem angepassten NanolithographiegerĂ€t, aber ebenfalls in einer hochflexiblen, auf Mikromanipulatoren basierenden Version. Dieser Aufbau erlaubt einen on-the-fly (âim Flugeâ) kapillarbasierten Druck auf einer breiten Palette von Geometrien, wie am Beispiel von vertikalen, vertieften OberflĂ€chen sowie gestapelten 3D-GerĂŒsten als schwer zugĂ€ngliche OberflĂ€chen gezeigt wird. Die Arbeit erkundet den potenziellen Einsatz dieser Methode fĂŒr die Herstellung von vollstĂ€ndig gedruckten durch FlĂŒssigmetall ermöglichten Bauteilen, einschlieĂlich WiderstĂ€nden, Mikroheizer, p-n-Dioden und Feldeffekttransistoren. Alle diese elektronischen Bauelemente werden ausfĂŒhrlich charakterisiert. Die hergestellten Mikroheizerstrukturen werden fĂŒr temperaturgeschaltete Mikroventile eingesetzt, um den FlĂŒssigkeitsstrom in einem Mikrokanal zu kontrollieren. Diese Demonstration und die einfache Herstellung zeigt, dass das Konzept auch auf andere Anwendungen, wie z.B. die bedarfsgerechte Herstellung von Mikroheizern fĂŒr in-situ Rasterelektronenmikroskop-Experimente, ausgeweitet werden kann.
DarĂŒber hinaus zeigt diese Arbeit, wie PMMA-Verkapselung als effektive Barriere gegen Sauerstoff und Feuchtigkeit fungiert und zusĂ€tzlich als brauchbarer mechanischer Schutz der auf FlĂŒssigmetall basierenden gedruckten elektronischen Bauteile wirken kann. Insgesamt zeigen der alleinstehende, integrierte Herstellungsablauf und die FunktionalitĂ€t der GerĂ€te, dass das Potenzial des FlĂŒssigmetall-Drucks in der gedruckten Elektronik viel gröĂer ist als einzig die Verwendung zur Verbindung konventioneller elektronischer Bauteile.
Neben der Entwicklung von Druckverfahren und der Herstellung elektronischer Bauteile befasst sich die Arbeit auch mit der Korrosion und der zusĂ€tzlichen Legierung von konventionellen Metallelektroden in Kontakt mit FlĂŒssigmetallen, welche die StabilitĂ€t der Bauteil beintrĂ€chtigen könnten. Zu diesem Zweck wurde eine korrelierte Materialinteraktionsstudie von gedruckten Galinstan- und Goldelektroden durchgefĂŒhrt. Durch die kombinierte Anwendung von optischer Mikroskopie, vertikaler Rasterinterferometrie, Rasterelektronenmikroskopie, Röntgenphotonenspektroskopie und Rasterkraftmikroskopie konnte der Ausbreitungsprozess von FlĂŒssigmetalllinien auf Goldfilmen eingehend charakterisiert werden. Diese Studie zeigt eine unterschiedliche Ausbreitung der verschiedenen Komponenten des FlĂŒssigmetalls sowie die Bildung von intermetallischen Nanostrukturen auf der umgebenden GoldfilmoberflĂ€che. Auf der Grundlage der erhaltenen zeitabhĂ€ngigen, korrelierten Charakterisierungsergebnisse wird ein Modell fĂŒr den Ausbreitungsprozess vorgeschlagen, das auf dem Eindringen des FlĂŒssigmetalls in den Goldfilm basiert. Um eine ergĂ€nzende Perspektive auf die interne Nanostruktur zu erhalten, wurde die Röntgen-Nanotomographie eingesetzt, um die Verteilung von Gold, Galinstan und intermetallischen Phasen in einem in das FlĂŒssigmetall getauchten Golddraht zu untersuchen. Schlussendlich werden Langzeitmessungen des Widerstands an FlĂŒssigmetallleitungen, die Goldelektroden verbinden, durchgefĂŒhrt, was dazu beitrĂ€gt, die Auswirkungen von Materialwechselwirkungen auf elektronische Anwendungen zu bewerten
Contribution du cortex prémoteur à la locomotion entravée chez le chat
La locomotion est une composante fondamentale de la vie animale : elle permet lâaccĂšs continu aux ressources nĂ©cessaires Ă la survie ainsi que lâĂ©vitement de pĂ©rils variĂ©s. Les milieux naturels comme anthropiques regorgent toutefois dâobstacles sâĂ©levant contre notre progression. Pour lâhumain et les autres mammifĂšres terrestres naviguant principalement par la vision, le franchissement efficace de ces obstacles repose critiquement sur la capacitĂ© de modifier proactivement le positionnement et la trajectoire des pas en fonction des informations visuelles extraites durant leur approche.
Au niveau du systĂšme nerveux, cette capacitĂ© implique un processus complexe oĂč le traitement des signaux visuels reflĂ©tant les paramĂštres de lâobstacle spĂ©cifie un cours dâaction sĂ©curisant son franchissement, lequel est ultimement exĂ©cutĂ© par des altĂ©rations prĂ©cises Ă lâactivitĂ© musculaire. Des Ă©tudes approfondies chez le chat, lâun des modĂšles animaux les plus dĂ©veloppĂ©s et investiguĂ©s vis-Ă -vis du contrĂŽle locomoteur, ont prĂ©sentement impliquĂ© deux structures corticales dans ce processus. Le cortex pariĂ©tal postĂ©rieur contribuerait ainsi Ă dĂ©terminer la position relative de lâobstacle et le cortex moteur primaire serait central Ă lâexĂ©cution des modifications de la dĂ©marche. Cependant, notre comprĂ©hension du substrat neural impliquĂ© dans la transformation sensorimotrice joignant ces deux Ă©tapes est extrĂȘmement limitĂ©e. Plusieurs lignes dâĂ©vidences, particuliĂšrement dĂ©rivĂ©es de travaux chez le primate investiguant le contrĂŽle des mouvements volontaires du bras, pointent cependant vers une contribution potentiellement majeure du cortex prĂ©moteur Ă cette fonction.
Cette thĂšse entreprend de dĂ©terminer directement la contribution prĂ©motrice aux modifications de la dĂ©marche. Deux Ă©tudes rapportent ainsi lâactivitĂ© de neurones individuels enregistrĂ©s dans deux larges subdivisions du cortex prĂ©moteur, les aires 6iffu et 4delta, chez le chat Ă©veillĂ© accomplissant librement une tĂąche de nĂ©gociation dâobstacles sur tapis roulant. Ces Ă©tudes font Ă©tat de changements dâactivitĂ© distincts dâune subdivision Ă lâautre et corrĂ©lĂ©s Ă des aspects spĂ©cifiques de la tĂąche, incluant des changements prĂ©paratoires liĂ©s Ă lâapproche finale de lâobstacle et dâautres liĂ©s Ă une ou plusieurs Ă©tapes des ajustements locomoteurs sĂ©quentiels entourant sa nĂ©gociation. Une troisiĂšme Ă©tude investigue par microstimulation intracorticale la capacitĂ© des diffĂ©rentes subdivisions prĂ©motrices du chat Ă modifier la dĂ©marche. Cette Ă©tude expose une variĂ©tĂ© de rĂ©ponses Ă©lectromyographiques complexes sâintĂ©grant en phase avec la marche, oĂč plusieurs subdivisions prĂ©sentent des signatures distinctes dâeffets multi-membres contrastant avec lâinfluence focale du cortex moteur primaire. Chacune de ces trois Ă©tudes est finalement complĂ©mentĂ©e dâinvestigations par traçage rĂ©trograde de connexions anatomiques dĂ©cisives Ă lâinterprĂ©tation fonctionnelle des subdivisions investiguĂ©es.
Ensemble, ces travaux soutiennent et prĂ©cisent une contribution centrale du cortex prĂ©moteur aux modifications de la dĂ©marche sous guidage visuel. Dâune part, ils rapportent pour la premiĂšre fois que lâactivitĂ© neuronale de multiples subdivisions du cortex prĂ©moteur reflĂšte diffĂ©rentes Ă©tapes de la planification locomotrice stipulant les altĂ©rations Ă entreprendre Ă lâapproche dâun obstacle et durant son franchissement. Dâautre part, ils rĂ©vĂšlent complĂ©mentairement que lâactivation de ces subdivisions a le pouvoir dâinfluencer profondĂ©ment la marche. Les donnĂ©es collectĂ©es soulignent finalement plusieurs points de comparaison entre les aires prĂ©motrices du chat et du primate, suggĂ©rant un degrĂ© dâanalogie fonctionnelle extensible Ă la locomotion humaine.Locomotion is a fundamental component of animal life: it provides continuous access to the resources necessary for survival as well as the means to elude potential perils. However, both natural and built environments teem with obstacles impeding oneâs progress. For humans and other terrestrial mammals navigating primarily through vision, efficiently negotiating these obstacles critically requires the capacity to proactively adapt the positioning and trajectory of each step on the basis of visual information extracted during their approach.
In the nervous system, this capacity involves a complex process through which the integration of visual signals reflecting the parameters and location of an obstacle specifies a course of action to ensure its negotiation, Extensive studies in the cat, one of the most common models used to study the neural mechanisms involved in the control of locomotion, have currently implicated two cortical structures to this process. The posterior parietal cortex is suggested to contribute to the determination of the obstacleâs relative position (with respect to the body) while the primary motor cortex is central to the execution of the gait modifications. However, our comprehension of the neural substrate implicated in the sensorimotor transformation linking these defined stages is extremely limited. Several lines of evidence, predominantly derived from work in the primate investigating the voluntary control of arm movements, nonetheless point towards a potentially major contribution of the premotor cortex to this function.
This thesis sets out to directly determine the premotor contribution to the control of gait modifications. Two studies report the activity of individual neurons recorded in two large subdivisions of premotor cortex, areas 6iffu and 4delta, in awake cats freely performing an obstacle negotiation task on treadmill. These studies describe distinct changes in activity across subdivisions that correlate with specific aspects of the task, including preparatory changes related to the final approach of the obstacle and others related to one or more stages of the sequential locomotor adjustments surrounding its negotiation. A third study used intracortical microstimulation to investigate the capacity of different premotor subdivisions of the cat to modify gait. This study reveals a variety of complex electromyographic responses that are integrated into the gait cycle. Moreover, several subdivisions show distinct signatures of multi-limb effects that contrast with the focal influence of the primary motor cortex. Each of these three studies is finally complemented by retrograde tracing investigations of anatomical connections critical to the functional interpretation of the subdivisions examined.
Together, these studies support and clarify a central contribution of the premotor cortex to the modification of gait under visual guidance. We report for the first time that the neural activity of multiple subdivisions of the premotor cortex reflects different stages of the locomotor plan specifying the gait alterations to perform during the approach and crossing of an obstacle. In addition, we reveal that activation of these subdivisions has the power to profoundly influence walking. The data collected finally highlight several points of comparison between the premotor areas of the cat and the primate, suggesting a degree of functional analogy extensible to human locomotion
Studies on the fabrication and contact stiffness of mechanical interfaces with tailored rough and structured surfaces
Contact stiffness is a measure of how interface separation displacement will respond to an applied load. Contact stiffness is most directly affected by interface geometry, material properties, and external factors such as loading, lubrication etc. Surface geometry is often considered in terms of roughness, the asperities that make up a surface and the compliance they introduce to an interface. The compliance or contact stiffness of an interface has an inherent contribution to how mechanical systems operate. This becomes critically important to engineering design where performance is directly linked to interfacial properties, through individual components or a systemic effect â vibrational response machines, biomedical joints, frictional contacts in turbine and engines. If an engineer can control the contact stiffness of an interface, then there is an opportunity to manipulate the performance of a design to suit the needs of the user.
The work in this thesis explores the viability of creating both controlled, tailored, and repeatable pre-defined microstructured and rough surface topographies. The first half of the work involved the development of a novel fabrication technique that combines microfabrication techniques and manufacturing technologies to generate microstructured topographies in functional polymers with the aim of controlling contact stiffness. The designs were initially modelled in finite element software before manufacture and mechanical testing. The microstructured interfaces yielded promising results that indicate high repeatability and tailoring of contact stiffness to the usersâ defined characteristics. The second half introduces the concept of manipulating numerically generated rough surface topographies to be produced in various polymers, again aiming to control contact stiffness. The numerically generated topographies were 3D printed before being replicated in various polymer materials through injection moulding and polymer casting, and finally mechanically tested. The results display a high level of control of surface characteristics which can be translated into the rough surface interfaces. The designs can then be manipulated to achieve the desired contact stiffness properties in a repeatable and tailored fashion. All areas of the work presented in this thesis have the potential to further tribological knowledge and future applications in a wide range of engineering fields
Cell Biomechanical Modeling Based on Membrane Theory with Considering Speed Effect of Microinjection
As an effective method to deliver external materials into biological cells,
microinjection has been widely applied in the biomedical field. However, the
cognition of cell mechanical property is still inadequate, which greatly limits
the efficiency and success rate of injection. Thus, a new rate-dependent
mechanical model based on membrane theory is proposed for the first time. In
this model, an analytical equilibrium equation between the injection force and
cell deformation is established by considering the speed effect of
microinjection. Different from the traditional membrane-theory-based model, the
elastic coefficient of the constitutive material in the proposed model is
modified as a function of the injection velocity and acceleration, effectively
simulating the influence of speeds on the mechanical responses and providing a
more generalized and practical model. Using this model, other mechanical
responses at different speeds can be also accurately predicted, including the
distribution of membrane tension and stress and the deformed shape. To verify
the validity of the model, numerical simulations and experiments are carried
out. The results show that the proposed model can match the real mechanical
responses well at different injection speeds.Comment: 10 pages, 12 figures, submitted to IEEE TMech
Design of antibody-polymer conjugates for immunotherapy: the influence of polymer structure on the antibody's activity.
Antibodies are increasingly useful therapeutics, and examples include the checkpoint inhibitors pembrolizumab1 and ipilimumab2 in cancer immunotherapy, and anti tau therapies in Alzheimerâs disease and dementia.3,4 However, specific applications requiring cytosolic delivery of the antibody, or transport across the blood-brain barrier pose challenges to antibody therapeutics. These issues may reduce the effectiveness of immunotherapy and restrict it to extracellular targets. Conjugating polymers to proteins and enzymes has been very effective at improving their stability and pharmacokinetics,5â8 and similar approaches have been studied for antibody conjugation.9â12 Finding an effective polymeric delivery system for antibodies can greatly improve immunotherapy.
In this work three strategies were explored for the encapsulation and bioconjugation to antibodies. The first approach is the encapsulation via electrostatic interactions between the antibody and a charged block copolymer to form polyion complex (PIC) micelles. Polyphosphonium block copolymers were studied for the first time to encapsulate antibodies, and were compared to their ammonium counterpart. While this approach has the advantage of being reversible, the polymer-antibody electrostatic interactions were too weak for biological applications, and delivery by this means would require a crosslinking strategy. The second approach involves covalent attachment of polymers on the antibodyâs surface via a grafting from polymerisation. An oxygen tolerant technique was employed for the screening of a large number of samples in low volumes (<100 ÎŒL). Successful grafting was demonstrated by AF4 and gel electrophoresis. Enzyme-linked immunosorbent assay (ELISA) showed retention of up to 40% binding activity relative to the native antibody with a marked improvement in stability. The third strategy introduces a novel acid sensitive linker for the reversible covalent attachment of polymers to the antibodyâs surface. This was achieved by using Diels-Alder chemistry to create an activated PEG that forms an amide with a conformational lock similar to citraconic anhydride upon conjugation to the amines on the antibody. The ability of the linker to cleave at pH 5.5 is demonstrated, resulting in almost complete recovery of the original binding activity of the antibody.
Overall, the reversible covalent attachment investigated here seems the most promising, and combining the high throughput method with the cleavable linker approach holds great potential for advancing in immunotherapy.
References
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(4) Castillo-Carranza, D. L.; Sengupta, U.; Guerrero-Munoz, M. J.; Lasagna-Reeves, C. A.; Gerson, J. E.; Singh, G.; Estes, D. M.; Barrett, A. D. T.; Dineley, K. T.; Jackson, G. R.; Kayed, R. Passive Immunization with Tau Oligomer Monoclonal Antibody Reverses Tauopathy Phenotypes without Affecting Hyperphosphorylated Neurofibrillary Tangles. J. Neurosci. 2014, 34 (12), 4260â4272.
(5) Abolmaali, S. S.; Tamaddon, A. M.; Salmanpour, M.; Mohammadi, S.; Dinarvand, R. Block Ionomer Micellar Nanoparticles from Double Hydrophilic Copolymers, Classifications and Promises for Delivery of Cancer Chemotherapeutics. Eur. J. Pharm. Sci. 2017, 104 (January), 393â405.
(6) Kurakhmaeva, K. B.; Djindjikhashvili, I. A.; Petrov, V. E.; Balabanyan, V. U.; Voronina, T. A.; Trofimov, S. S.; Kreuter, J.; Gelperina, S.; Begley, D.; Alyautdin, R. N. Brain Targeting of Nerve Growth Factor Using Poly(Butyl Cyanoacrylate) Nanoparticles. J. Drug Target. 2009, 17 (8), 564â574.
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(8) Klyachko, N. L.; Manickam, D. S.; Brynskikh, A. M.; Uglanova, S. V.; Li, S.; Higginbotham, S. M.; Bronich, T. K.; Batrakova, E. V.; Kabanov, A. V. Cross-Linked Antioxidant Nanozymes for Improved Delivery to CNS. Nanomedicine Nanotechnology, Biol. Med. 2012, 8 (1), 119â129.
(9) Bin Liu, Khushboo Singh , Shuai Gong , Mine Canakci, Barbara A. Osborne, and S. T. Protein Antibody Conjugates PACs A PlugâandâPlay Strategy for Covalent Conjugation and Targeted Intracellular Delivery of Pristine Proteins. Angew. Chemie 2021, 133, 12923â12928.
(10) Chan, L. J.; Bulitta, J. B.; Ascher, D. B.; Haynes, J. M.; Mcleod, V. M.; Porter, C. J. H.; Williams, C. C.; Kaminskas, L. M. PEGylation Does Not Signi Fi Cantly Change the Initial Intravenous or Subcutaneous
Pharmacokinetics or Lymphatic Exposure of Trastuzumab in Rats but Increases Plasma Clearance after Subcutaneous Administration. Mol. Pharm. 2015, 12, 794â809.
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Novel Treatment Strategies for Glioblastoma
This book is a compilation of articles that brings together current knowledge from an international team of contributors who are dedicated investigators exploring novel strategies for the treatment of glioblastoma. These articles describe some of the latest concepts that will provide students, researchers and clinicians with an overview of the therapeutic approaches being developed in the field of neuro-oncology to combat this deadly disease
DĂ©veloppement et validation de sondes en fibre optique miniaturisĂ©es pour le guidage intra-opĂ©ratoire dâinterventions intraoculaires
Les procĂ©dures chirurgicales intraoculaires sont des procĂ©dures difficiles par la prĂ©cision quâelles demandent, on parle de microchirurgie, mais aussi par la difficultĂ© et la faible qualitĂ© de visualisation des tissus Ă traiter. En effet, dans la plupart des procĂ©dures intraoculaires le chirurgien utilise uniquement un microscope ophtalmologique qui ne permet la visualisation des tissus que par la pupille du patient et offre une perception limitĂ©e de la profondeur. La Tomographie en CohĂ©rence Optique (OCT) fournit des images en profondeur des tissus sains de maniĂšre non invasive, elle est utilisĂ©e couramment en diagnostic ophtalmologique et est de plus en plus utilisĂ©e intra-opĂ©rativement. Dans cette thĂšse nous allons prĂ©senter
deux systĂšmes OCT intra-opĂ©ratifs qui visent Ă assister les chirurgiens sur deux procĂ©dures intraoculaires, la vitrectomie et lâinjection sous-rĂ©tinienne. Pour ces deux projets nous avons utilisĂ© le matĂ©riel chirurgical utilisĂ© cliniquement pour
plusieurs raisons : sâassurer dâutiliser des outils adĂ©quats (dimensions, efficacitĂ©, sĂ©curitĂ©) pour la procĂ©dure, garder des outils que les chirurgiens utilisent rĂ©guliĂšrement et avec lesquels ils sont familiers et limiter les coĂ»ts de dĂ©veloppement. Pour le systĂšme OCT nous avons utilisĂ© des sondes OCT en fibre optique car elles sont flexibles, bon marchĂ© et de petit
diamĂštre. Leur focalisation peut Ă©galement ĂȘtre modifiĂ©e dĂ©pendamment de lâapplication avec une fibre optique GRIN Ă leur extrĂ©mitĂ© pour augmenter le signal OCT. Nous avons ainsi attachĂ© Ă ces outils chirurgicaux des sondes OCT en fibre optique. Pour le projet portant sur les injections sous-rĂ©tiniennes il a fallu dans un premier temps dĂ©velopper des sondes
OCT avec des diamĂštres plus petits que ceux existant. Pour ce faire nous avons dĂ©veloppĂ© une mĂ©thode permettant de rĂ©duire le diamĂštre des sondes avec de lâacide fluorhydrique et grĂące Ă un design permettant de conserver les propriĂ©tĂ©s optiques des sondes. Ce travail est prĂ©sentĂ© dans le premier article. Le second article prĂ©sente un systĂšme permettant de guider les injections sous-rĂ©tiniennes. Lâinjection sous-rĂ©tinienne est une intervention chirurgicale de haute prĂ©cision visant Ă restaurer et/ou prĂ©server la vision des patients souffrant de maladies rĂ©tiniennes. NĂ©anmoins, lâinjection sous-rĂ©tinienne reste Ă la limite des capacitĂ©s physiologiques humaines en raison des tremblements de la main et peut ĂȘtre compromise par le reflux du mĂ©dicament si lâinjection nâest pas assez profonde dans la rĂ©tine. Nous avons dĂ©veloppĂ© un systĂšme pour guider lâinjection avec un micromanipulateur et donner des informations prĂ©cises sur la profondeur au chirurgien avec lâOCT intra-opĂ©ratif. AprĂšs avoir miniaturisĂ© une sonde OCT en fibre optique avec la mĂ©thode prĂ©sentĂ©e dans lâarticle 1 nous avons pu lâinsĂ©rer dans une canule utilisĂ©e cliniquement. La sonde couplĂ©e Ă un systĂšme OCT que nous avons dĂ©veloppĂ© acquiert un signal A-scan qui va permettre de connaitre la distance entre la canule et la rĂ©tine mais aussi de sĂ©lectionner la profondeur de lâinjection dans les couches rĂ©tiniennes. La canule est attachĂ©e Ă un micromanipulateur qui assure son dĂ©placement dans lâĆil. Une image M-scan est construite avec le signal OCT et le chirurgien peut directement sĂ©lectionner sur lâimage la profondeur de lâinjection. Nous avons dĂ©veloppĂ© lâinterface sur Labview. AprĂšs avoir sĂ©lectionnĂ© la cible de lâinjection le programme de guidage va dĂ©placer la canule et injecter le volume adĂ©quat grĂące Ă une pompe contrĂŽlable. Nous avons validĂ© notre systĂšme de guidage sur des yeux de porcs ex-vivo. Sur 40 injections 38 prĂ©sentaient un dĂ©collement rĂ©tinien ciblĂ© et localisĂ©, preuve de la rĂ©ussie de lâinjection rĂ©tinienne ce qui reprĂ©sente un taux de succĂšs
de 95% (CI : 83.1 â 99.4). Nous avons aussi grĂące Ă un algorithme de traitement de lâimage calculĂ© le volume prĂ©sent sous la rĂ©tine aprĂšs lâinjection que nous avons comparĂ© au volume injectĂ©. Nous avons ainsi trouvĂ© que 75% du volume initialement injectĂ© se retrouve bien sous la rĂ©tine. Le troisiĂšme article prĂ©sente un systĂšme permettant dâarrĂȘter automatiquement le vitrecteur lors dâune vitrectomie pour rĂ©duire les dommages accidentels sur la rĂ©tine. La survenue
de dĂ©chirures rĂ©tiniennes iatrogĂšniques dans la vitrectomie par la pars plane est une complication qui compromet lâefficacitĂ© globale de la chirurgie. Un certain nombre de dĂ©chirures rĂ©tiniennes iatrogĂšnes se produisent lorsque la rĂ©tine est coupĂ©e accidentellement par le vitrecteur. Nous avons dĂ©veloppĂ© un vitrecteur intelligent capable de dĂ©tecter en temps rĂ©el une
coupure rĂ©tinienne accidentelle et de dĂ©sactiver rapidement la machine de vitrectomie pour les prĂ©venir. Ce vitrecteur intelligent est composĂ© dâune sonde OCT attachĂ©e au vitrecteur et va avoir comme rĂŽle de dĂ©tecter si le vitrecteur aspire la rĂ©tine et va endommager ces tissus sains. La sonde OCT agit comme un dĂ©tecteur de prĂ©sence devant lâouverture du vitrecteur, ceci en comparant un signal de rĂ©fĂ©rence avec le signal en direct. Cette comparaison de signal
OCT va commander un bras robotique pour actionner la pĂ©dale dâarrĂȘt du vitrecteur. Ainsi le chirurgien nâa pas besoin dâinterprĂ©ter un signal, la dĂ©cision dâarrĂȘt du vitrecteur dĂ» Ă la prĂ©sence de la rĂ©tine est prise automatiquement. Ceci va permettre de rĂ©duire grandement, de 300 ms Ă 29 ms, le dĂ©lai de la prise de dĂ©cision dâarrĂȘt du vitrecteur prĂ©cĂ©demment limitĂ© par le temps de rĂ©action du chirurgien. Nous avons dĂ©veloppĂ© les sondes OCT, le systĂšme OCT ainsi que lâalgorithme dâarrĂȘt automatique de ce systĂšme. Nous avons validĂ© sur des yeux porcins in-vivo, deux chirurgiens ont utilisĂ© notre systĂšme en essayant dâendommager les tissus rĂ©tiniens. 70% (CI : 56.39 â 82.02) des tentatives de dommages rĂ©tiniens des chirurgiens furent attĂ©nuĂ©es ou empĂȘchĂ©es par notre systĂšme. Ce projet a abouti au dĂ©pĂŽt dâun
brevet ("Smart Vitrector", Provisional patent application, US 63109040).Intraocular surgical procedures are difficult procedures because of the precision they
require, they are often referred as microsurgery, but also by the little information available to
the surgeon. In most intraocular procedures the surgeon only uses an ophthalmic microscope
which allows visualization of tissue just through the patientâs pupil and offers limited depth
perception. Optical Coherence Tomography (OCT) provides in-depth images of healthy tissue
in a non-invasive manner, is commonly used in ophthalmologic diagnostics, and is increasingly
used intraoperatively. In this thesis we will present two intraoperative OCT systems that aim
to assist surgeons with two intraocular procedures, vitrectomy and subretinal injection. For
these two projects we used the surgical equipment used clinically for several reasons : to make
sure to use adequate tools (dimensions, efficiency, safety) for the procedure, to keep tools
that surgeons use regularly and with which they are familiar and limit development costs.
For the OCT system we used fiber optic OCT probes as they are flexible, cheap and small
in diameter. Their focus can also be modified, depending the application, with a GRIN fiber
at their tip to increase the OCT signal. We have attached optical fiber OCT probes to these
surgical tools. For the subretinal injections project it was first necessary to develop OCT
probes with smaller diameters than existing ones. To do this, we have developed a method
to reduce the diameter of the probes with hydrofluoric acid and a design to maintain the
optical properties of the probes. This work is presented in the first article.
The second article presents a system for guiding subretinal injections. Subretinal injection
of drugs is a challenging surgical intervention aiming to restore and/or preserve the vision of
patients suffering from retinal diseases. Nevertheless, the subretinal injection remains at the
edge of human physiological capacity because of hand tremor and can be mitigated by drug
reflux if the injection is not deep enough in the retina. We developed a system to guide the
injection with a micromanipulator and give precise depth information to the surgeon with
intraoperative OCT. To do so we first miniaturized an optical fiber OCT probe with the
method presented in article 1, we were able to insert it into a cannula used clinically. The
probe coupled to an OCT system that we have developed acquires an A-scan signal which
enables to know the distance between the cannula and the retina but also to select the depth
of the injection into the retinal layers. The cannula is attached to a micromanipulator that moves it inside the eye. An M-scan image is built with the OCT signal and the surgeon
can directly select on the image the depth of the injection. We developed the interface on
Labview. After selecting the injection target, the guidance program will move the cannula
and inject the appropriate volume using a controllable pump.We have validated our guidance
system on pig eyes ex-vivo. Out of 40 injections, 38 presented a retinal detachment, proof of a
successful retinal injection, which represents a success rate of 95% (CI : 83.1 â 99.4). Thanks
to an image processing algorithm, we also calculated the bleb volume under the retina after
the injection, which we compared to the initial injected volume. We have found that 75% of
the injected volume ends in the subretinal space.
The third article presents for automatically stopping the vitrector during a vitrectomy.
The occurrence of iatrogenic retinal breaks in pars plana vitrectomy is a complication that
compromises the overall efficacy of the surgery. A subset of iatrogenic retinal break occurs
when the retina is cut accidentally by the vitrector. We developed a smart vitrector that
can detect in real-time potential accidental retinal cut and activate promptly a vitrectomy
machine to prevent them. To do so an OCT probe is attached to the vitrector and will have
the role of detecting if the vitrector sucks the retina and will damage these healthy tissues.
The OCT probe acts as a presence detector in front of the vitrector opening, by comparing a
reference signal with the live signal. This OCT signal comparison will control a robotic arm
to operate the vitrector stop pedal. Thus, the surgeon does not need to interpret a signal, the
decision to stop the vitrector due to the presence of the retina is taken automatically. This
will greatly reduce, from 300 ms to 29 ms, the delay to stop the vitrector previously limited
by the reaction time of the surgeon. We have developed the OCT probes, the OCT system,
and the automatic shutdown algorithm for this system. We validated our system on in-vivo
porcine eyes, two surgeons used the modified vitrector trying to damage retinal tissue. 70%
(CI : 56.39 â 82.02) of surgeonsâ retinal damage attempts were mitigated or prevented by our
system. This project resulted in a patent ("Smart Vitrector", Provisional patent application,
US 63109040)
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