Rehabilitación visual con implantes o prótesis de visión artificial

En el presente trabajo se realiza una revisión bibliográfica enfocada a entender los implantes o prótesis de visión artificial que existen en el mercado como alternativas para el tratamiento de las personas con ceguera secundaria a un daño en los fotorreceptores o células del epitelio pigmentario de la retina. Se explica la función de los fotorreceptores en el sistema visual humano así como el procesamiento de la información visual normal como base para entender lo que una prótesis que suple los fotorreceptores debe ser capaz de realizar. Se describe brevemente la historia de la estimulación neuronal en las distintas porciones del sistema visual. Se explica la composición general de las prótesis retinianas, se hace mención de las diversas prótesis retinianas que se han desarrollado como prototipos y a nivel investigación y se habla mas a detalle de las únicas dos prótesis retinianas que cuentan con aprobación para su uso en humanos. Finalmente se mencionan los requisitos mínimos para poder hablar de una visión funcional útil y los resultados visuales que se obtienen con las prótesis, así como los candidatos susceptibles a ser implantados y gozar de los beneficios de las prótesis retinianas.Máster en Rehabilitación Visua

Ultra-thin and flexible CMOS technology: ISFET-based microsystem for biomedical applications

A new paradigm of silicon technology is the ultra-thin chip (UTC) technology and the emerging applications. Very thin integrated circuits (ICs) with through-silicon vias (TSVs) will allow the stacking and interconnection of multiple dies in a compact format allowing a migration towards three-dimensional ICs (3D-ICs). Also, extremely thin and therefore mechanically bendable silicon chips in conjunction with the emerging thin-film and organic semiconductor technologies will enhance the performance and functionality of large-area flexible electronic systems. However, UTC technology requires special attention related to the circuit design, fabrication, dicing and handling of ultra-thin chips as they have different physical properties compared to their bulky counterparts. Also, transistors and other active devices on UTCs experiencing variable bending stresses will suffer from the piezoresistive effect of silicon substrate which results in a shift of their operating point and therefore, an additional aspect should be considered during circuit design. This thesis tries to address some of these challenges related to UTC technology by focusing initially on modelling of transistors on mechanically bendable Si-UTCs. The developed behavioural models are a combination of mathematical equations and extracted parameters from BSIM4 and BSIM6 modified by a set of equations describing the bending-induced stresses on silicon. The transistor models are written in Verilog-A and compiled in Cadence Virtuoso environment where they were simulated at different bending conditions. To complement this, the verification of these models through experimental results is also presented. Two chips were designed using a 180 nm CMOS technology. The first chip includes nMOS and pMOS transistors with fixed channel width and two different channel lengths and two different channel orientations (0° and 90°) with respect to the wafer crystal orientation. The second chip includes inverter logic gates with different transistor sizes and orientations, as in the previous chip. Both chips were thinned down to ∼20m using dicing-before-grinding (DBG) prior to electrical characterisation at different bending conditions. Furthermore, this thesis presents the first reported fully integrated CMOS-based ISFET microsystem on UTC technology. The design of the integrated CMOS-based ISFET chip with 512 integrated on-chip ISFET sensors along with their read-out and digitisation scheme is presented. The integrated circuits (ICs) are thinned down to ∼30m and the bulky, as well as thinned ICs, are electrically and electrochemically characterised. Also, the thesis presents the first reported mechanically bendable CMOS-based ISFET device demonstrating that mechanical deformation of the die can result in drift compensation through the exploitation of the piezoresistive nature of silicon. Finally, this thesis presents the studies towards the development of on-chip reference electrodes and biodegradable and ultra-thin biosensors for the detection of neurotransmitters such as dopamine and serotonin

Development of electronics for microultrasound capsule endoscopy

Development of intracorporeal devices has surged in the last decade due to advancements in the semiconductor industry, energy storage and low-power sensing systems. This work aims to present a thorough systematic overview and exploration of the microultrasound (µUS) capsule endoscopy (CE) field as the development of electronic components will be key to a successful applicable µUSCE device. The research focused on investigating and designing high-voltage (HV, < 36 V) generating and driving circuits as well as a low-noise amplifier (LNA) for battery-powered and volume-limited systems. In implantable applications, HV generation with maximum efficiency is required to improve the operational lifetime whilst reducing the cost of the device. A fully integrated hybrid (H) charge pump (CP) comprising a serial-parallel (SP) stage was designed and manufactured for > 20 V and 0 - 100 µA output capabilities. The results were compared to a Dickson (DKCP) occupying the same chip area; further improvements in the SPCP topology were explored and a new switching scheme for SPCPs was introduced. A second regulated CP version was excogitated and manufactured to use with an integrated µUS pulse generator. The CP was manufactured and tested at different output currents and capacitive loads; its operation with an US pulser was evaluated and a novel self-oscillating CP mechanism to eliminate the need of an auxiliary clock generator with a minimum area overhead was devised. A single-output universal US pulser was designed, manufactured and tested with 1.5 MHz, 3 MHz, and 28 MHz arrays to achieve a means of fully-integrated, low-power transducer driving. The circuit was evaluated for power consumption and pulse generation capabilities with different loads. Pulse-echo measurements were carried out and compared with those from a commercial US research system to characterise and understand the quality of the generated pulse. A second pulser version for a 28 MHz array was derived to allow control of individual elements. The work involved its optimisation methodology and design of a novel HV feedback-based level-shifter. A low-noise amplifier (LNA) was designed for a wide bandwidth µUS array with a centre frequency of 28 MHz. The LNA was based on an energy-efficient inverter architecture. The circuit encompassed a full power-down functionality and was investigated for a self-biased operation to achieve lower chip area. The explored concepts enable realisation of low power and high performance LNAs for µUS frequencies

Towards clinical trials of a novel Bionic Eye: Building evidence of safety and efficacy

In the quest for therapeutic solutions for the visually impaired, electrical stimulation of the retina is, and has been, the focus of intense research. Some of these efforts have led to the development of the Phoenix99 Bionic Eye, a device which combines promising technological features with novel stimulation strategies. For medical devices, considerable challenges must be overcome before they’re allowed to be trialled in their target population. The requirements for a study to be performed include the demonstration of a positive risk-benefit ratio of the research. The present dissertation is an attempt to address how pre-clinical trials in animals can be used to understand and minimise risks. A positive risk-benefit ratio means that the potential benefits of the research outweigh the risks of the intervention. In the case of retinal prostheses, the risks include the surgical intervention, the immune response to the device, the safety of the electrical stimuli, and the effects of device ageing. In this work, successful demonstration of the surgical safety and biocompatibility of passive Phoenix99 devices during long-term implantation in sheep called for the evaluation of the chronic effects of the novel stimulation paradigms it can deliver. As preparation for this study, the techniques used to evaluate the safety and efficacy of the stimuli in animals were refined. A systematic approach to minimise the impact of anaesthesia on the experimental results is presented, as well as a novel in vivo retinal recording technique. To maximise the clinical relevance of all animal trials, a computer model for the prediction of thresholds was developed. Finally, in vitro device ageing was performed to deepen our understanding of the design’s potential for long-term implantation. Protocols for a long-term device safety study in sheep and for an acute human trial are also presented, thus taking concrete and sensible steps towards the first clinical use of the Phoenix99 Bionic Eye

Closed-loop approaches for innovative neuroprostheses

The goal of this thesis is to study new ways to interact with the nervous system in case of damage or pathology. In particular, I focused my effort towards the development of innovative, closed-loop stimulation protocols in various scenarios: in vitro, ex vivo, in vivo

Inorganic micro/nanostructures-based high-performance flexible electronics for electronic skin application

Electronics in the future will be printed on diverse substrates, benefiting several emerging applications such as electronic skin (e-skin) for robotics/prosthetics, flexible displays, flexible/conformable biosensors, large area electronics, and implantable devices. For such applications, electronics based on inorganic micro/nanostructures (IMNSs) from high mobility materials such as single crystal silicon and compound semiconductors in the form of ultrathin chips, membranes, nanoribbons (NRs), nanowires (NWs) etc., offer promising high-performance solutions compared to conventional organic materials. This thesis presents an investigation of the various forms of IMNSs for high-performance electronics. Active components (from Silicon) and sensor components (from indium tin oxide (ITO), vanadium pentaoxide (V2O5), and zinc oxide (ZnO)) were realised based on the IMNS for application in artificial tactile skin for prosthetics/robotics. Inspired by human tactile sensing, a capacitive-piezoelectric tandem architecture was realised with indium tin oxide (ITO) on a flexible polymer sheet for achieving static (upto 0.25 kPa-1 sensitivity) and dynamic (2.28 kPa-1 sensitivity) tactile sensing. These passive tactile sensors were interfaced in extended gate mode with flexible high-performance metal oxide semiconductor field effect transistors (MOSFETs) fabricated through a scalable process. The developed process enabled wafer scale transfer of ultrathin chips (UTCs) of silicon with various devices (ultrathin chip resistive samples, metal oxide semiconductor (MOS) capacitors and n‐channel MOSFETs) on flexible substrates up to 4″ diameter. The devices were capable of bending upto 1.437 mm radius of curvature and exhibited surface mobility above 330 cm2/V-s, on-to-off current ratios above 4.32 decades, and a subthreshold slope above 0.98 V/decade, under various bending conditions. While UTCs are useful for realizing high-density high-performance micro-electronics on small areas, high-performance electronics on large area flexible substrates along with low-cost fabrication techniques are also important for realizing e-skin. In this regard, two other IMNS forms are investigated in this thesis, namely, NWs and NRs. The controlled selective source/drain doping needed to obtain transistors from such structure remains a bottleneck during post transfer printing. An attractive solution to address this challenge based on junctionless FETs (JLFETs), is investigated in this thesis via technology computer-aided design (TCAD) simulation and practical fabrication. The TCAD optimization implies a current of 3.36 mA for a 15 μm channel length, 40 μm channel width with an on-to-off ratio of 4.02x 107. Similar to the NRs, NWs are also suitable for realizing high performance e-skin. NWs of various sizes, distribution and length have been fabricated using various nano-patterning methods followed by metal assisted chemical etching (MACE). Synthesis of Si NWs of diameter as low as 10 nm and of aspect ratio more than 200:1 was achieved. Apart from Si NWs, V2O5 and ZnO NWs were also explored for sensor applications. Two approaches were investigated for printing NWs on flexible substrates namely (i) contact printing and (ii) large-area dielectrophoresis (DEP) assisted transfer printing. Both approaches were used to realize electronic layers with high NW density. The former approach resulted in 7 NWs/μm for bottom-up ZnO and 3 NWs/μm for top-down Si NWs while the latter approach resulted in 7 NWs/μm with simultaneous assembly on 30x30 electrode patterns in a 3 cm x 3 cm area. The contact-printing system was used to fabricate ZnO and Si NW-based ultraviolet (UV) photodetectors (PDs) with a Wheatstone bridge (WB) configuration. The assembled V2O5 NWs were used to realize temperature sensors with sensitivity of 0.03% /K. The sensor arrays are suitable for tactile e-skin application. While the above focuses on realizing conventional sensing and addressing elements for e-skin, processing of a large amount of data from e-skin has remained a challenge, especially in the case of large area skin. A Neural NW Field Effect Transistors (υ-NWFETs) based hardware-implementable neural network (HNN) approach for tactile data processing in e-skin is presented in the final part of this thesis. The concept is evaluated by interfacing with a fabricated kirigami-inspired e-skin. Apart from e-skin for prosthetics and robotics, the presented research will also be useful for obtaining high performance flexible circuits needed in many futuristic flexible electronics applications such as smart surgical tools, biosensors, implantable electronics/electroceuticals and flexible mobile phones

Argus® II Retinal Prosthesis System: Clinical & Functional Outcomes

Developing artificial visual systems to restore sight in blind patients has long been the dream of scientists, clinicians and the public at large. After decades of research, the greatest success in the field has been achieved with electronic retinal prostheses. To date, 3 retinal prosthetic systems have made the transition from laboratory / clinical research to entering the commercial market for clinical use, namely the Argus® II Retinal Prosthesis System (Second Sight), the alpha-IMS system (Retinal Implant AG), and the IRIS® II (Pixium Vision). The following body of work describes the Argus® II Retinal Prosthesis system, which obtained regulatory approval in the European Economic Area in 2011 (CE marking) and later on in the USA (FDA approval in February 2013), based on the results of an international multi-centre clinical feasibility trial (Clinical Trial identifier: NCT 00407602). This thesis aims to examine the long-term clinical and functional outcomes in an early cohort of subjects chronically implanted with the Argus® II system, from the original feasibility study. A further aim is to elucidate the characteristics of the artificial vision that is perceived and its long-term repeatability and reproducibility in individual subjects. These two broad aims will assist in understanding the nature of the visual performance provided by this device, as well as to add to the current data that is defining the feasibility of constructing predictable pixelated patterns to achieve useful artificial vision in the future. Finally, we explored the feasibility of real-time imaging of visual cortex activation in response to electrical retinal stimulation with the Argus® II system, using functional near infra-red spectroscopy (fNIRS). Development of this real-time imaging tool will enable future investigations into the differences in the cortical activities in response to different stimulations and in different subjects. This may in turn help us understand the variability in their visual performance, as well as to further explore the extent and effect of cross-modal plasticity at the cortical level, in this cohort of patients who have been deprived of visual inputs for decades. Visual function was assessed in terms of: a) form recognition and b) spatial localisation under both 2-dimensional (2D) screen-based laboratory settings and 3-dimensional (3D) paradigms simulating real-life settings. A prospective study of 11 Argus® II subjects showed that the subjects could identify distinct geometric shapes presented in high contrast better with the prosthetic system switched on (median % of correct identification = 20.0%, IQR = 18.8), versus off (median = 12.5%, IQR = 5.0). The accuracy of shapes identification could be further improved by enhancing the outlines of the geometric shape (median = 33.1%, IQR = 21.6). A further prospective study from a subset of 7 subjects showed that this 2D shape identification could be translated into improved identification of 3D objects. These subjects could identify 8 common daily-life objects presented in high contrast with the prosthetic system switched on (median = 31.3%, IQR = 20.3) versus off (median = 12.5%, IQR = 12.5). Scrambling of the transmission signals within the prosthetic system in order to separate light information from form information (i.e. “scrambled mode”) hindered the identification in some but not all subjects (median = 25.0%, IQR = 12.5). The accuracy of object identification could also be improved by enhancing the edges of objects (median = 43.8%, IQR = 15.6). Previously published data showed that Argus® II subjects were able to locate and point to white squares presented on touch screens against a black background more accurately with the prosthetic system switched on versus off. We demonstrated with a prospective study of 5 subjects that they could localise an object on the table, reach out and grasp the object (prehension) with great accuracy (66.7 – 100%) when the prosthetic system was switched on, versus no object prehension (0%) with the system switched off. A prospective study of 6 Argus® II subjects illustrated that while there was a wide variation in the shape and size of the phosphenes perceived by individual subjects, the elicited phosphenes were consistently reproducible in each subject using fixed stimulating parameters, with inter-stimuli intervals ranging from 20 minutes apart, down to 1 second. The perceived location of the phosphenes grossly matched retinotopic agreement, with 4 subjects drawing phosphenes in the same visual field quadrant as predicted by the relative stimulus-fovea position, and 2 subjects depicting phosphenes in the same hemi-field as the expected locations. A retrospective study of 3 Argus® II subjects who underwent MRI brain scan (for unrelated medical reasons) showed that MRI brain scans of up to 1.5 Tesla field strength appeared to have no detrimental effect on the subjects and their implant function. The Argus® II implant produced an artefact of around 50mm x 50mm in size which would prevent visualisation of structures within the orbit, but visualisation of surrounding tissues outside this areas are unaffected. The use of functional MRI as a tool of exploring visual cortex activation in Argus® II subjects was discounted, due to concerns of signal interference from the radiofrequency telemetry of Argus® II system with that of MRI. Subsequently, we have demonstrated in a prospective study that an alternative neuro-imaging technique, functional near infra-red spectroscopy (fNIRS), was capable of capturing real-time cortical activation in 5 out of 6 Argus® II subjects, and maybe a feasible tool for future investigation into cortical function and interactions. The work in this thesis has shown that the Argus® II retinal prosthesis system could improve visual function both in terms of form recognition, as well as object localisation in 3D in situations simulating real-life settings, in a cohort of patients with end-stage retinitis pigmentosa or other outer retinal diseases such as choroideremia. The wide variation in the visual performance level observed could in part be attributable to the diversity in the phosphene features perceived by these subjects. Nevertheless, the consistency and reproducibility with which these phosphenes could be elicited, with fixed stimulating parameters within each subject, provides an encouraging basis for the construction of more complicated pixelated images. Future work to determine the underlying factors influencing the perceived phosphene characteristics, may allow for better prediction of functional outcome, which could in turn be useful for patient selection and tailored preoperative counselling. For those subjects already implanted with the Argus® II system, future work into determining the suitable stimulating parameters for each electrode / quad stimulation may be required for individual subjects, to achieve the construction of optimised and useful, pixelated prosthetic vision

Wireless power and communication system for medical implants

This thesis aims to examine the hypothesis that “Power of more than 1 mW can be received by the microsystem inside a human body through a wireless magnetic coupling link with a receiver of a diameter less than 2mm from a transfer distance as much as 20 cm” and “Data can be transmitted wirelessly from the microsystem to an external reader using the same magnetic coupling link as the wireless power system”. A 3-coil weakly coupled magnetic resonance wireless power transfer system has been built based on solenoid coils. The design of the transmitter of the system includes the designs of a single-turn coupling coil and a multi-turn primary coil. To maximise the magnetic field generated by the transmitter, the relative position of the two coils is optimised to match the impedances of the coils. Design flow is reported for the optimum dimensional parameters (coil diameter, gap interval, number of turns) of the primary coil after a detailed analysis of the co-dependencies of the parameters. The design of the receiver of the system includes the designs of the receiver coil and the rectifier. Two kinds of solenoid receiver coils have been analysed, the air-core coil and the ferrite-core coil. Due to the size limitation (2 mm-diameter) of the receiver, only the ferrite-core solenoid coil is able to meet the power demand. Design flow of the ferrite-core coil is reported. In terms of the rectifier, a novel static gate-control bootstrapping rectifier (static BSR) and a novel opto-coupled dynamic gate-control (OCDGC) bootstrapping rectifier are reported, which have low power consumption and high power conversion efficiency compared with junction-diode rectifiers and comparator-based rectifiers. The power delivered to load (PDL) of the whole WPT system is tested in air and human conductive tissue at transfer distances within 20 cm with consideration of rectifier power conversion efficiencies and different load conditions (500 Ω and 5 kΩ). Results show that, at 20 cm transfer distance, the system will be able to meet the 1 mW power demand for light load condition (5 kΩ) both in air and in human conductive tissue; But in heavy load condition (500 Ω), a high number of receiver coil turns will be needed to meet the power demand. The sensitivity of the data transfer of the whole WPT system is also analysed based on load shift keying (LSK) modulation. The S-parameter S11 ratio is the Figure of Merit (FOM) of the data transfer analysis. It can be concluded that the hypotheses of the thesis are feasible, which is an inspiration of multiple deep-tissue micro-implants for medical purposes

Políticas de Copyright de Publicações Científicas em Repositórios Institucionais: O Caso do INESC TEC

A progressiva transformação das práticas científicas, impulsionada pelo desenvolvimento das novas Tecnologias de Informação e Comunicação (TIC), têm possibilitado aumentar o acesso à informação, caminhando gradualmente para uma abertura do ciclo de pesquisa. Isto permitirá resolver a longo prazo uma adversidade que se tem colocado aos investigadores, que passa pela existência de barreiras que limitam as condições de acesso, sejam estas geográficas ou financeiras. Apesar da produção científica ser dominada, maioritariamente, por grandes editoras comerciais, estando sujeita às regras por estas impostas, o Movimento do Acesso Aberto cuja primeira declaração pública, a Declaração de Budapeste (BOAI), é de 2002, vem propor alterações significativas que beneficiam os autores e os leitores. Este Movimento vem a ganhar importância em Portugal desde 2003, com a constituição do primeiro repositório institucional a nível nacional. Os repositórios institucionais surgiram como uma ferramenta de divulgação da produção científica de uma instituição, com o intuito de permitir abrir aos resultados da investigação, quer antes da publicação e do próprio processo de arbitragem (preprint), quer depois (postprint), e, consequentemente, aumentar a visibilidade do trabalho desenvolvido por um investigador e a respetiva instituição. O estudo apresentado, que passou por uma análise das políticas de copyright das publicações científicas mais relevantes do INESC TEC, permitiu não só perceber que as editoras adotam cada vez mais políticas que possibilitam o auto-arquivo das publicações em repositórios institucionais, como também que existe todo um trabalho de sensibilização a percorrer, não só para os investigadores, como para a instituição e toda a sociedade. A produção de um conjunto de recomendações, que passam pela implementação de uma política institucional que incentive o auto-arquivo das publicações desenvolvidas no âmbito institucional no repositório, serve como mote para uma maior valorização da produção científica do INESC TEC.The progressive transformation of scientific practices, driven by the development of new Information and Communication Technologies (ICT), which made it possible to increase access to information, gradually moving towards an opening of the research cycle. This opening makes it possible to resolve, in the long term, the adversity that has been placed on researchers, which involves the existence of barriers that limit access conditions, whether geographical or financial. Although large commercial publishers predominantly dominate scientific production and subject it to the rules imposed by them, the Open Access movement whose first public declaration, the Budapest Declaration (BOAI), was in 2002, proposes significant changes that benefit the authors and the readers. This Movement has gained importance in Portugal since 2003, with the constitution of the first institutional repository at the national level. Institutional repositories have emerged as a tool for disseminating the scientific production of an institution to open the results of the research, both before publication and the preprint process and postprint, increase the visibility of work done by an investigator and his or her institution. The present study, which underwent an analysis of the copyright policies of INESC TEC most relevant scientific publications, allowed not only to realize that publishers are increasingly adopting policies that make it possible to self-archive publications in institutional repositories, all the work of raising awareness, not only for researchers but also for the institution and the whole society. The production of a set of recommendations, which go through the implementation of an institutional policy that encourages the self-archiving of the publications developed in the institutional scope in the repository, serves as a motto for a greater appreciation of the scientific production of INESC TEC