Hardware design of a portable medical device to measure the quadriceps muscle group after a total knee arthroplasty by EMG, LBIA and clinical score methods

El propòsit d'aquest projecte és el disseny del hardware d'un dispositiu mèdic portàtil per a mesurar senyals d'electromiografia (EMG) i bioimpedància localitzada (LBIA), que s'utilitzarà per avaluar la progressió de dues pròtesis de genoll (Medial-Pivot i Ultra- Congruent) en pacients operats d'una artroplàstia total de genoll per a l'hospital Germans Trias i Pujol de Badalona. Per això, s'ha realitzat un estudi complet sobre els senyals d'EMG i LBIA, per tal de definir les característiques necessàries de l'equip mèdic i poder optimitzar el disseny electrònic. Per l'adquisició de senyals EMG, s'ha dissenyat i simulat un sistema compost per diferents fases, que treballen independentment per adquirir, amplificar, filtrar i adaptar el senyal EMG pel seu futur processament digital. D'altra banda, per obtenir valors de la bioimpedància localitzada dels diferents músculs que conformen el quàdriceps, s'ha dissenyat un sistema compost per dos grans blocs; el primer bloc és l'etapa d'injecció, on es genera i s'injecta un senyal feble de corrent altern a la zona a mesurar, mentre que el segon bloc, és l'etapa d'adquisició de senyals. Aquest últim s'encarrega d'adquirir la diferència de voltatge produïda per la injecció de corrent al múscul (anteriorment mencionat) per després calcular la bioimpedància a partir de la llei d'ohm. Tots els senyals són digitalitzats mitjançant el microcontrolador STM32F407VG, que s'encarregarà de processar i aconseguir les dades claus per determinar quina de les deus pròtesis desenvolupa una millor funció mecànica i una millor adaptació biològica. És important remarcar que tot el disseny, sigui per a EMG o LBIA s'ha dut a terme de manera discreta sense fer servir Front-Ends comercials o integrats complexos més que l'amplificador d'instrumentació o ADC. En addició, el present treball inclou una primera estimació dels costos de producció i fabricació per a una sola unitat, càlculs de consums i funcionament (sorolls, CMRR del sistema i amplada de banda) i una simulació completa d'EMG i LBIA per observar com funciona i es du a terme cada etapa del circuit. Finalment, en tractar-se d'un equip mèdic, també s'ha revisat la normativa aplicable i se n'ha analitzat l'impacte ambiental, s'ha proposat i definit diferents punts per a futurs treballs, com podria ser la validació i testatge de l'equip, càlculs més aproximats de consums i perfilar la bill of materials (BOM) per a grans demandes de components.The purpose of this project is the hardware design of a portable medical device to measure electromyography (EMG) and localized bioimpedance (LBIA) signals, which will be used to evaluate the adaptability and progression of two knee prostheses (medial-pivot and ultra-congruent) in patients undergoing total knee arthroplasty at the Germans Trias i Pujol Hospital in Badalona. For this, the present work undercovers the relevant properties of the EMG and LBIA signals in order to define the characteristics of the medical equipment and thus optimize its electronic design. For the EMG measurements, a system made up of different stages has been designed and simulated. These phases work independently to acquire, amplify, filter, and adapt the EMG signal for its further digital processing. On the other hand, to obtain the bioimpedance values of different quadriceps muscles, a system composed of two large blocks has been designed; the first is the injection block, where a weak alternating current signal is generated and injected into the area to be measured, while the second block is the signal acquisition stage. The purpose of the latter is to acquire the voltage difference produced by the injection of current (mentioned above) and then obtain the bioimpedance from Ohm's law. All the signals are digitized from the STM32F407VG microcontroller, which will be in charge of processing and obtaining the key data to determine which of the two prostheses performs a better mechanical function and biological adaptation. It is important to note that the entire design, whether for EMG or LBIA, has been developed discreetly without using commercial Front-Ends or complex ICs other than the instrumentation amplifier or ADC. In addition, the thesis includes a first estimation of the production and manufacturing costs for a single unit, calculations of consumption and work operation (noise, CMRR of the system and bandwidth) and a complete simulation of EMG and LBIA to observe how it works on each stage for both circuits. Finally, as it is a medical device, the applicable regulations have also been reviewed and its environmental impact has been analysed. Additionally, different points have been proposed and defined for future work, such as the construction of the PCB and its respective validation, improving both the consumption calculations and the list of materials (BOM) for large component demands.El propósito de este proyecto es el diseño del Hardware de un dispositivo médico portátil para mediciones de electromiografía (EMG) y bioimpedancia localizada (LBIA), que se utilizará para estudiar la evolución de la adaptabilidad y funcionamiento de dos prótesis de rodilla (medial-pívot y ultracongruente) en pacientes operados de artroplastia total de rodilla en el Hospital Germans Trias i Pujol de Badalona. Para ello, se ha realizado un estudio exhaustivo sobre las propiedades de las señales de EMG y LBIA con la finalidad de definir las características del equipo médico y de esta forma, optimizar el diseño electrónico del mismo. Para la lectura de mediciones EMG, se ha diseñado y simulado un sistema constituido por distintas etapas, que trabajan independientemente para adquirir, amplificar, filtrar, y adaptarla señal EMG para su posterior procesado digital. Por otro lado, para obtener los valores de bioimpedancia de distintos músculos del cuádriceps, se ha diseñado un sistema compuesto por dos grandes bloques; el primero es el bloque de inyección, donde se genera y se inyecta una señal débil de corriente alterna en la zona a medir, mientras que el segundo bloque es la etapa de adquisición de señales. Esta última tiene como finalidad adquirir la diferencia de voltaje producido por la inyección de corriente (anteriormente mencionada) para después obtener la bioimpedancia a partir de la ley de ohm. Todas las señales son digitalizadas a partir del microcontrolador STM32F407VG, que se encargará de procesar y obtener los datos claves para determinar cuál de las dos prótesis desempeña una mejor función mecánica y adaptación biológica. Es importante remarcar que todo el diseño, ya sea para EMG o LBIA, se ha desarrollado de manera discreta sin usar Front-Ends comerciales o integrados complejos más que el amplificador de instrumentación o ADC. En adición, la tesis incluye una primera estimación de los costes de producción y fabricación para una sola unidad, cálculos de consumos y funcionamiento (ruidos, CMRR del sistema y ancho de banda) y una simulación completa de EMG y LBIA para observar cómo funciona y se desarrolla cada etapa de los distintos circuitos. Finalmente, al tratarse de un equipo médico, también se ha revisado la normativa aplicable y se ha analizado el impacto ambiental del mismo. Por último, se han propuesto y definido distintos puntos para futuros trabajos, como es la construcción de la PCB y su respectiva validación, realizar cálculos más aproximados de consumos y perfilar la lista de materiales (BOM) para grandes demandas de componentes

Firmware design of a portable medical device to measure the quadriceps muscle group after a total knee arthroplasty by EMG, LBIA and clinical score methods

El objetivo de este proyecto es el diseño del firmware de un dispositivo médico portátil para mediciones de EMG y LBIA, que se utilizará para la evaluación de pacientes de artroplastia total de rodilla, para estudiar la progresión de diferentes prótesis de rodilla (Medial-Pivot y Ultra-Congruente). En la tesis, se expone el conocimiento actual de los estudios y aplicaciones de EMG y LBIA, junto con los dispositivos comerciales utilizados actualmente. Además, se han estudiado e implementado las diferentes técnicas de filtrado y procesamiento digital para señales de EMG y LBIAs. Adicionalmente, se ha realizado un estudio estadístico preliminar con datos LBIA de 12 pacientes de artroplastia total de rodilla. El diseño del firmware de esta tesis incluye: los procesos de adquisición de datos con el uso de diferentes ADCs (Conversor Analógico a Digital) (de la propia placa y externos, utilizando la interfaz SPI) y un DAC (Conversor Digital a Analógico), el correspondiente procesamiento de la señal y la extracción de sus características, la comunicación con un dispositivo externo utilizando un módulo BLE externo con interfaz UART, el proceso de encriptación de los datos médicos, la funcionalidad de manejo de errores y la aproximación del nivel de batería. En esta tesis, todos los flujos de trabajo de los procesos se exponen y explican mediante diagramas de flujo, mientras que se justifica cada cálculo y configuración. Además, todo el código correspondiente se ha programado en lenguaje C y se expone en los anexos. También se ha revisado la normativa aplicable y se ha analizado tanto el impacto ambiental como el coste económico del producto. Por último, se proponen mejoras para futuros trabajos.The aim of this project is the firmware design for a portable medical device for EMG and LBIA measurements which will be used for the assessment of total knee arthroplasty patients to study the progression of different knee prostheses (Medial-Pivot and Ultra-Congruent). For its realization, the state of the art of the EMG and LBIA studies and applications are exposed, along with the currently used medical devices. In addition, the different digital filtering and processing techniques for these studies have been studied and implemented. Furthermore, a preliminary statistical study has been performed with LBIA data from 12 patients with total knee arthroplasty. The firmware design of this thesis includes: the acquiring data processes with the use of different ADCs (from the actual board and external, using the SPI interface) and a DAC, the corresponding signal processing and feature abstraction, the communication with an external device using an external BLE module with UART interface, the medical data encrypting process, the error handling functionality, and the battery level approximation. In this work, all the process workflows are exposed and explained using flowcharts, while every calculation and configuration is justified. In addition, all the corresponding code has been programmed using C language and exposed in the Annexes. Moreover, the applicable regulation has been reviewed, and both the environmental impact and economic cost of the product have been analyzed. Finally, improvements are proposed for future work.L'objectiu d'aquest projecte és el disseny del microprogramari d'un dispositiu mèdic portàtil per a mesures d'EMG i LBIA. L’aparell mèdic s'utilitzarà per a l'avaluació de pacients d'artroplàstia total de genoll per estudiar la progressió de dues pròtesis de genoll (Medial-Pivot i Ultra- Congruent). En el treball, s'exposa el coneixement actual dels estudis i aplicacions d'EMG i LBIA, juntament amb els dispositius comercials utilitzats actualment. A més, s'han estudiat i implementat les diferents tècniques de filtrat i processament digital dels senyals de EMG i LBIA. Addicionalment, s'ha fet un estudi estadístic preliminar amb dades de LBIA de 12 pacients amb artroplàstia total de genoll. El disseny del microprogramari d'aquesta tesi inclou: els processos d'adquisició de dades fent ús de diferents ADCs (de la pròpia placa i externs, utilitzant la interfície SPI) i un DAC, el processament dels senyals i l'abstracció de les seves característiques, la comunicació amb un dispositiu extern utilitzant un mòdul BLE extern amb interfície UART, el procés d'encriptació de les dades mèdiques, la funcionalitat de l’avaluació d'errors i l'aproximació del nivell de bateria. En aquest treball, totes les funcionalitats del dispositiu s'exposen i s'expliquen mitjançant diagrames de flux i es justifiquen els càlculs i configuracions corresponents. Tot el codi desenvolupat s'ha programat en llenguatge C i s'exposa als annexos. A més, s'ha revisat la normativa aplicable i s'ha analitzat tant l'impacte ambiental com el cost econòmic de l’aparell. Finalment, es proposen millores per a futurs desenvolupaments

Organic electrochemical transistors for neurotechnology

The organic electrochemical transistor is a device that has proven to provide a comprehensive insight into physiological activity. The burden of brain-related illnesses and the potential societal impact of enhancing human interaction and communication with computers motivates the advancement of technologies to provide greater insights into neural activity. This research focuses on the intersection of these fields through developing organic electrochemical transistors for neurotechnology. As such, this research reports the fabrication, characterisation, and operation of the devices to demonstrate their applicability in providing an accurate description of neural activity. In turn, pathways are offered on the optimisation and enhancement of transistor performance, informing the field on methods to maximise the efficacy of biosensing devices. This thesis opens with the motivations to develop neurotechnology in society by considering the burden of neurological disorders and the enhancement of human-machine communication. The roles that bioelectronics and organic electrochemical transistors could take in achieving such goals are then described. The literature on organic electrochemical transistors and their applications in neurotechnology is then examined. Foundational to this research was the design and fabrication of novel transistor architectures. As such, fabrication methods are then described which provide micrometre-scale resolutions, facilitating the production of biocompatible, high-performance devices. The thesis then describes an investigation with the aim to optimise the performance of organic electrochemical transistors for the maximisation of the range of electrophysiological signals that the devices can resolve and amplify. Devices are demonstrated with high amplification factors and bandwidths sufficient for transducing the full bioelectric spectrum. The devices efficaciously resolve electrophysiological inputs with a wide range of voltage and frequency characteristics, demonstrated through measuring the device response to pre-recorded signals and supported through noise quantification. Research is then presented with aims to employ organic electrochemical transistors in a linear amplifier topology that provides precise amplification control. Circuit parameters are identified for stable amplifier operation, and the transistors are physically implemented into amplifier circuits. An equation is then formulated which models the transistor current in the linear, non-linear and saturation regimes, and this equation is used to simulate the amplifier response. Through experimentation and simulation, the amplifier is extensively characterised, providing quantitative measures on amplifier gain, linearity, bandwidth, and noise. The amplifier is then inputted with pre-recorded bioelectric signals and the linear gain of the amplifier is experimentally demonstrated. The thesis then presents an investigation with the aim to determine the effect of electrode architecture on organic electrochemical transistor characteristics and bioelectric performance. The impacts of varying the interconnect resistance on the steady-state and transient characteristics are examined. Then, arrays of devices are fabricated, and the effects of varying the interconnect resistance and the interdigitated electrode geometry on bioelectric performance are quantified. The electrode architecture at the measurement site is then varied for a fixed site area to determine an optimal configuration for resolving bioelectric inputs. The investigation presents a pathway for the optimisation of electrode architecture for a given application. Finally, the thesis describes research that aims to determine the relationships between the morphological properties of the organic layer and the electrical characteristics relevant to biosensing performance. Electrical characterisations and resonant Raman spectroscopy are carried out on organic electrochemical transistors that are immersed in an aqueous solution over a period of 50 days, and the temporal changes in the derived parameters are presented. Then, the effects of varying the applied voltages on the active layer morphology and the device noise are investigated, providing an insight into how the structural changes of organic polymers correlate to variations in noise.Open Acces

Design and Optimisation of Extracellular Microelectrodes

The work described in this thesis concerns the development and application of design methods for the optimisation of thin film metal microelectrodes, to be used for recording the electrical signals generated by neurons in culture

Limb-state information encoded by peripheral and central somatosensory neurons:Implications for an afferent interface

A major issue to be addressed in the development of neural interfaces for prosthetic control is the need for somatosensory feedback. Here, we investigate two possible strategies: electrical stimulation of either dorsal root ganglia (DRG) or primary somatosensory cortex (S1). In each approach, we must determine a model that reflects the representation of limb state in terms of neural discharge. This model can then be used to design stimuli that artificially activate the nervous system to convey information about limb state to the subject. Electrically activating DRG neurons using naturalistic stimulus patterns, modeled on recordings made during passive limb movement, evoked activity in S1 that was similar to that of the original movement. We also found that S1 neural populations could accurately discriminate different patterns of DRG stimulation across a wide range of stimulus pulse-rates. In studying the neural coding in S1, we also decoded the kinematics of active limb movement using multi-electrode recordings in the monkey. Neurons having both proprioceptive and cutaneous receptive fields contributed equally to this decoding. Some neurons were most informative of limb state in the recent past, but many others appeared to signal upcoming movements suggesting that they also were modulated by an efference copy signal. Finally, we show that a monkey was able to detect stimulation through a large percentage of electrodes implanted in area 2. We discuss the design of appropriate stimulus paradigms for conveying time-varying limb state information, and the relative merits and limitations of central and peripheral approaches

Biomedical Engineering

Biomedical engineering is currently relatively wide scientific area which has been constantly bringing innovations with an objective to support and improve all areas of medicine such as therapy, diagnostics and rehabilitation. It holds a strong position also in natural and biological sciences. In the terms of application, biomedical engineering is present at almost all technical universities where some of them are targeted for the research and development in this area. The presented book brings chosen outputs and results of research and development tasks, often supported by important world or European framework programs or grant agencies. The knowledge and findings from the area of biomaterials, bioelectronics, bioinformatics, biomedical devices and tools or computer support in the processes of diagnostics and therapy are defined in a way that they bring both basic information to a reader and also specific outputs with a possible further use in research and development

Novel flexible multielectrode arrays for neuronal stimulation and recording

This thesis will focus on developments in coupling the multidisciplinary research interests of Physics, Micro-engineering and neurobiology towards the development of a proof of concept retinal prosthetic device. With recent developments in low-power electronics and semiconductor fabrication techniques many applications in the life sciences have emerged. One such application is in the development of a retinal prosthetic device which relies on the ability to record information from and feed information directly to small retinal neuronal cells which are approximately 5mum diameter. Where successful, we achieve the possibility of restoring sight to people affected by degenerative visual diseases such as Age Related Macular Degeneration and Retinitis Pigmentosa. Both these conditions affect the photosensitive elements of the eye yet leave the remaining pathways to the visual cortex, the area of the brain responsible for our visual precept, intact. High-density electrode arrays axe becoming well established as tools for the measurement of neuronal signals. The fabrication of arrays on flexible materials allows for 2D position sensitive recording of cellular activity in vivo and for the possibility of direct in vivo stimulus. Using flexible polymer materials (Pryalin PI2545), compliant with semiconductor fabrication techniques, a process allowing the fabrication of flexible multi-site microelectrode neuronal recording and stimulating arrays is presented. The development of both 8 and 74 electrode arrays on polyimide substrates with 50mum and 5mum minimum linewidths respectively is described. Implementing low noise amplification, 8muV rms (bandpass typically 80-2000 Hz), the polyimide 8-electrode arrays have been used to stimulate and record electroretinogram and ganglion cell action potentials in vivo from the frog retina (Rana lemporaria). Such arrays coupled to our application specific pixellated CMOS sensors, the IPIX, incorporating an ability to apply neural network algorithms should allow for the recovery of basic functionality in the human retina. The IPIX detector is an Active Pixel Sensor which responds to incident light in the visible region. It responds to the varying intensity of light over 3 log units and outputs varying frequency voltage pulses of similar form to that of a healthy retina. Stimulation studies for electro-deposited platinum electrodes of 4 nA/mum2 indicate upper breakdown limits for charge density approaching 100 muCm-2. Investigations of lifetime stimulation of a 50 mum diameter electrode, of typical impedance less than 20 kO at 1 kHz, suggest operational limits over lifetime in the order of 10 muCm-2. These charge densities are adequate for neuronal cell stimulation. It is believed that the system described in this thesis can form the basis on which to deploy a retinal prosthetic device. Moreover, in the short term, the information provided by this system will allow for investigations into deciphering the 'wiring diagram' of the retina

Developing an In Vitro Assay for Detection and Characterization of Functional Connectivity within Transplantation Candidate Embryonic Stem Cell-Derived V2a Interneuron Networks

Facilitating plasticity after spinal cord injury tends to be the focus of most modern interventions for this condition. In particular, stem cell therapies attempt to both modulate and mimic some of the native plasticity after injury through multiple mechanisms. One such mechanism, the creation of new exogenous relay circuits bridging the injury, has been explored extensively, revealing serious impediments to its optimization and adoption for clinical settings. Our collaborator, the Sakiyama-Elbert group, has spent years addressing the first limitation, the variability of cellular graft composition, by perfecting protocols to generate embryonic stem cell (ESC)-derived populations of neurons with pre-determined genetic identity. Recently, they developed a protocol to develop highly-enriched populations of Chx10-expressing V2a interneurons (INs), a ventral interneuron population that has garnered recent interest due to its role in central pattern generating function and favorable phenotypic properties. This predominantly glutamatergic and long, ipsilaterally projecting population appears to be a prime candidate for transplantation therapies for SCI, especially for the creation of relay circuits that can potentially circumnavigate injuries. The research documented in this thesis attempts to begin to address the second limitation of stem cell transplantation therapy, our minimal understanding of intra-graft network connectivity after transplantation. Due to the limitations of current techniques for evaluating the connectivity of populations like ESC-derived V2a INs, the relationship between functional recovery and the functional properties of the novel circuits formed within the graft still eludes researchers. This thesis focuses on the development of an assay capable of rapidly detecting connectivity within ESC-derived candidate populations. By extending previous work in the stem cell field, we combine in vitro multi-electrode arrays (MEAs) with an extensively studied metric of functional connectivity, cross-correlation, to detect and characterize individual functional connections between ESC-derived neurons. We first validated this assay by culturing ESC-derived populations differentiated for increased expression of Chx10 on MEAs. We found that both dissociated and aggregated cultures formed functional busting networks with significant functional connectivity detected with the use of Between-Sample Analysis of Connectivity, a methodology originally developed for in vitro circadian networks. Aggregated networks, however, had much more consistent electrode coverage and individual neuron detection that dissociated networks. After this validation study, we characterized the functional connectivity within highly-enriched populations of ESC-V2a INs, comparing their connectivity to populations of ESC-MN/glia and mixed populations of ESC-V2a/MN/glia. We found that ESC-MN/glia aggregates formed active networks with a variety of activity and functional connectivity that was dependent on the transmission of glutamate. ESC-V2a INs could only survive out to the 4-week time point if they were grown in media conditioned with glial factors, but these cultures still lacked spontaneous extracellular activity. Mixed ESC-V2a/MN/glia populations formed the most active networks and had thousands of detectable connections which were also dependent on glutamate transmission. Application of glycine antagonist modulated network activity but the underlying cause is fairly inconclusive due to possible secondary effects. High growth factor concentrations in the growth media actually decreased network activity and detectable functional connections in the mixed populations. All of these findings in this proof of concept study collectively suggest that a mixture of ESC-V2a INs and ESC-MN/glia may be the most viable candidate for transplantation and sets the stage for future investigations into the manipulability of their connectivity with electrical stimulation, as well as scaled versions of this assay performed in combination with animal studies