Prototype d’une micropompe dédiée à l’injection des médicaments anti-épileptiques

RÉSUMÉ L’épilepsie est une des maladies du système nerveux central qui demeure sans solution efficace malgré les progrès technologiques impressionnants dans le domaine biomédical. En effet, environ 15% des patients souffrants de cette maladie sont réfractaires à tout médicament ou autre solution médicale. De nos jours, le traitement d’épilepsie, chez les patients réfractaires, consiste à stimuler électriquement la région du cerveau provoquant les foyers épileptiques. De plus, des travaux de recherche sont en cours pour examiner les résultats d’injection des médicaments ou de refroidissement de régions épileptiques. Nous proposons dans ce mémoire une solution basée sur une micropompe automatisée et miniaturisée permettant d’empêcher le foyer épileptique de se déclarer et se propager en injectant des débits précis des médicaments à l’endroit de détection du foyer juste au moment de sa naissance. La micropompe choisie est basée sur un mécanisme qui génère un champ magnétique à l’aide d’une microbobine intégrée. Cette micropompe sert à manipuler un diaphragme intégré pour déplacer les médicaments à injecter. La membrane de la micropompe en question est fabriquée par polydiméthylsiloxane (PDMS) qui vibre à une fréquence variant entre 85 et 175 Hz. La micropompe permet de livrer un débit de 2.9 ml/min et est activée par un circuit de détection de crises épileptiques. Quant à l’interface électronique, elle regroupe un microcontrôleur, quelques circuits logiques simples et un convertisseur numérique – analogique (CNA) qui servent à contrôler et commander le courant alimentant la microbobine faisant partie de la micropompe. Le déclenchement de la micropompe proposée a été validé, en partie, à l'aide d'enregistrements d’électroencéphalogrammes intracorticaux (icEEG) des patients atteints d'épilepsies. Les résultats obtenus ont confirmé l’opération de l’injection précise des médicaments. Notre système, destiné à être implantable, se caractérise également par la réduction de la consommation d’énergie dans sa mise en oeuvre. Nous avons réalisé à ce sujet des circuits donnant lieu à des bonnes performances en terme d’économie d’énergie, comparé à un autre type de micropompes piézoélectriques du commerce que nous avons examiné dans ce projet dont la consommation est de l’ordre de 70 mA au lieu de 40 mA obtenue dans la micropompe proposée.----------ABSTRACT Approximately 15% of patients with partial epilepsy are neither drug responsive nor good candidate for surgery. There has been growing interest in neuro-responsive intracerebral local treatment of seizures such as focal drug delivery, focal cooling, or electrical stimulation. The latter requires an effective seizure-detection system and an intracortical stimulator. In this project, we present an automated miniaturized micropump that provides precise drug flow rate in order to control epileptic seizure. The implantable responsive drug delivery system proposed by Polystim team was validated using intracortical Electroencephalogram (icEEG) recordings from patients with refractory epilepsy. In this project, the proposed micropump is based on electromagnetic mechanism that is generated through microcoil and deflects a diaphragm fabricated using a polydimethysiloxane (PDMS), by supplying precise amount of current using a digital-to-analog convertor (DAC). The device delivers simultaneous focal drug to suppress the seizure following its onset detection by a dedicated microelectronic interface. The PDMS based membrane is driven under a range of an actuating frequency between 85 and 175 Hz. It provides a flow rate of 2.9 ml/min when all the inputs of the DAC are high and the operation frequency is 143 Hz. The feedback controller and the micropump are activated for a given duration (2, 4, 8, 16 seconds) on response to seizure detections, but they remain in sleep mode for the rest of time. The experimental results demonstrated the detection accuracy of proposed implantable responsive drug delivery systems. The implemented control circuit provides a good performance in term of power consumption, comparing with another piezoelectric micropump we previously used in our experiments. The later requires about 70 mA instead of 40 mA for the proposed micropump

Applications of Wireless Power Transfer in Medicine : State-of-the-Art Reviews

Magnetic resonance within the field of wireless power transfer has seen an increase in popularity over the past decades. This rise can be attributed to the technological advances of electronics and the increased efficiency of popular battery technologies. The same principles of electromagnetic theory can be applied to the medical field. Several medical devices intended for use inside the body use batteries and electrical circuits that could be powered wirelessly. Other medical devices limit the mobility or make patients uncomfortable while in use. The fundamental theory of electromagnetics can improve the field by solving some of these problems. This survey paper summarizes the recent uses and discoveries of wireless power in the medical field. A comprehensive search for papers was conducted using engineering search engines and included papers from related conferences. During the initial search, 247 papers were found then non-relevant papers were eliminated to leave only suitable material. Seventeen relevant journal papers and/or conference papers were found, then separated into defined categories: Implants, Pumps, Ultrasound Imaging, and Gastrointestinal (GI) Endoscopy. The approach and methods for each paper were analyzed and compared yielding a comprehensive review of these state of the art technologies

Implantable Micro-Device for Epilepsy Seizure Detection and Subsequent Treatment

RÉSUMÉ L’émergence des micro-dispositifs implantables est une voie prometteuse pour le traitement de troubles neurologiques. Ces systèmes biomédicaux ont été exploités comme traitements non-conventionnels sur des patients chez qui les remèdes habituels sont inefficaces. Les récents progrès qui ont été faits sur les interfaces neuronales directes ont permis aux chercheurs d’analyser l’activité EEG intracérébrale (icEEG) en temps réel pour des fins de traitements. Cette thèse présente un dispositif implantable à base de microsystèmes pouvant capter efficacement des signaux neuronaux, détecter des crises d’épilepsie et y apporter un traitement afin de l’arrêter. Les contributions principales présentées ici ont été rapportées dans cinq articles scientifiques, publiés ou acceptés pour publication dans les revues IEEE, et plusieurs autres tels que «Low Power Electronics» et «Emerging Technologies in Computing». Le microsystème proposé inclus un circuit intégré (CI) à faible consommation énergétique permettant la détection de crises d’épilepsie en temps réel. Cet CI comporte une pré-amplification initiale et un détecteur de crises d’épilepsie. Le pré-amplificateur est constitué d’une nouvelle topologie de stabilisateur d’hacheur réduisant le bruit et la puissance dissipée. Les CI fabriqués ont été testés sur des enregistrements d’icEEG provenant de sept patients épileptiques réfractaires au traitement antiépileptique. Le délai moyen de la détection d’une crise est de 13,5 secondes, soit avant le début des manifestations cliniques évidentes. La consommation totale d’énergie mesurée de cette puce est de 51 μW. Un neurostimulateur à boucle fermée (NSBF), quant à lui, détecte automatiquement les crises en se basant sur les signaux icEEG captés par des électrodes intracrâniennes et permet une rétroaction par une stimulation électrique au même endroit afin d’interrompre ces crises. La puce de détection de crises et le stimulateur électrique à base sur FPGA ont été assemblés à des électrodes afin de compléter la prothèse proposée. Ce NSBF a été validé en utilisant des enregistrements d’icEEG de dix patients souffrant d’épilepsie réfractaire. Les résultats révèlent une performance excellente pour la détection précoce de crises et pour l’auto-déclenchement subséquent d’une stimulation électrique. La consommation énergétique totale du NSBF est de 16 mW. Une autre alternative à la stimulation électrique est l’injection locale de médicaments, un traitement prometteur de l’épilepsie. Un système local de livraison de médicament basé sur un nouveau détecteur asynchrone des crises est présenté.----------ABSTRACT Emerging implantable microdevices hold great promise for the treatment of patients with neurological conditions. These biomedical systems have been exploited as unconventional treatment for the conventionally untreatable patients. Recent progress in brain-machine-interface activities has led the researchers to analyze the intracerebral EEG (icEEG) recording in real-time and deliver subsequent treatments. We present in this thesis a long-term safe and reliable low-power microsystem-based implantable device to perform efficient neural signal recording, seizure detection and subsequent treatment for epilepsy. The main contributions presented in this thesis are reported in five journal manuscripts, published or accepted for publication in IEEE Journals, and many others such as Low Power Electronics, and Emerging Technologies in Computing. The proposed microsystem includes a low-power integrated circuit (IC) intended for real-time epileptic seizure detection. This IC integrates a front-end preamplifier and epileptic seizure detector. The preamplifier is based on a new chopper stabilizer topology that reduces noise and power dissipation. The fabricated IC was tested using icEEG recordings from seven patients with drug-resistant epilepsy. The average seizure detection delay was 13.5 sec, well before the onset of clinical manifestations. The measured total power consumption of this chip is 51 µW. A closed-loop neurostimulator (CLNS) is next introduced, which is dedicated to automatically detect seizure based on icEEG recordings from intracranial electrode contacts and provide an electrical stimulation feedback to the same contacts in order to disrupt these seizures. The seizure detector chip and a dedicated FPGA-based electrical stimulator were assembled together with common recording electrodes to complete the proposed prosthesis. This CLNS was validated offline using recording from ten patients with refractory epilepsy, and showed excellent performance for early detection of seizures and subsequent self-triggering electrical stimulation. Total power consumption of the CLNS is 16 mW. Alternatively, focal drug injection is the promising treatment for epilepsy. A responsive focal drug delivery system based on a new asynchronous seizure detector is also presented. The later system with data-dependent computation reduces up to 49% power consumption compared to the previous synchronous neurostimulator

Towards rapid 3D direct manufacture of biomechanical microstructures

The field of stereolithography has developed rapidly over the last 20 years, and commercially available systems currently have sufficient resolution for use in microengineering applications. However, they have not as yet been fully exploited in this field. This thesis investigates the possible microengineering applications of microstereolithography systems, specifically in the areas of active microfluidic devices and microneedles. The fields of micropumps and microvalves, stereolithography and microneedles are reviewed, and a variety of test builds were fabricated using the EnvisionTEC Perfactory Mini Multi-Lens stereolithography system in order to define its capabilities. A number of microneedle geometries were considered. This number was narrowed down using finite element modelling, before another simulation was used to optimise these structures. 9 × 9 arrays of 400 μm tall, 300 μm base diameter microneedles were subjected to mechanical testing. Per needle failure forces of 0.263 and 0.243 N were recorded for the selected geometries, stepped cone and inverted trumpet. The 90 μm needle tips were subjected to between 30 and 32 MPa of pressure at their failure point - more than 10 times the required pressure to puncture average human skin. A range of monolithic micropumps were produced with integrated 4 mm diameter single-layer 70 μm-thick membranes used as the basis for a reciprocating displacement operating principle. The membranes were tested using an oscillating pneumatic actuation, and were found reliable (>1,000,000 cycles) up to 2.0 PSIG. Pneumatic single-membrane nozzle/diffuser rectified devices produced flow rates of up to 1,000 μl/min with backpressures of up to 375 Pa. Another device rectified using active membrane valves was found to self-prime, and produced backpressures of up to 4.9 kPa. These devices and structures show great promise for inclusion in complex, fully integrated and active microfluidic systems fabricated using microstereolithography alone, with implications for both cost of manufacture and lead time

Ultra-violet lithography of thick photoresist for the applications in BioMEMS and micro optics

UV lithography of thick photoresist is widely used in microelectromechanical systems (MEMS) and micro-optoelectromechanical systems (MOEMS). SU-8 is a typical negative tone thick photoresist for micro systems, and can be used for both structural material and pattern transfer. This dissertation presents an effort to comprehensively study these important subjects. The first part, and the most fundamental part of this dissertation concentrated on the numerical analysis and experimental study of the wavelength dependent absorbance of SU-8 and the diffraction effects on the sidewall profiles of the microstructures made using UV lithography of SU-8. This study has laid the foundation for all the designs and analysis for the BioMEMS and Micro-optic components and systems using UV lithography of SU-8 in the following chapters of the dissertation. After a full discussion of UV lithography of SU-8, the applications of SU-8 in BioMEMS and micro optics were presented in the following areas: 1) design, analysis, and molding fabrication of biodegradable PLGA microstructures for implanted drug delivery application; 2) design, fabrication, and test of a novel three-dimensional micro mixer/reactor based on arrays of spatially impinging micro-jets; 3) design, analysis, fabrication, and test of a novel new type of truly three-dimensional hydro-focusing unit for flow cytometry applications based on SU-8; 4) Study on a new technology to fabricate out-of-plane pre-aligned microlens and microlens array, and the application of the microlens in a fiber bundle coupler. Finally, a new negative tone thick photoresist based on the composition of EPON resins 165 and 154 were introduced. The synthesis, physical properties, and UV-lithography properties of this new photoresist have been completed. The experimental results have proved it can be a better alternative to SU-8 and can be used in various MEMS and MOEMS applications. Most of the contents have been published or accepted for publications in technical journals or international conferences. Two US patent applications are pending and two more disclosures have been filed for the new technologies presented in this dissertation. There are obviously more work to be done in this promising area and these are presented in the section for future work

A fluorescent oil detection device

On April 20th 2010, the largest offshore oil spill in U.S. history happened in the Gulf of Mexico. It is estimated total more than 4 million barrels oil spilled to Gulf of Mexico. More than two million gallons had been used. This had made the threat to coastal and sea ecosystem even greater and long term. Real-time monitoring is also a critical topic for oil spill response. In-situ monitoring devices are needed for rapid collection of real-time data. A new generation of instruments for spilled oil detection is reported in this paper. The main hypothesis in this research is that the sensitivity of the new instrument based on a micro-fluidic-optic chip can be higher than its conventional sized counterparts. The adoption of the micro-fluidic-optic chip helped to miniaturize the sample extraction unit and also to integrate the optical detection on the same chip substrate. Only the monitoring and displaying unit and the power supply were external to the micro-fluidic-optic chip. In this way, the micro-fluidic-optic chip is replaceable and can be disposable. This also helps to eliminate the need for cleaning the fluidic components, which may be very difficult in micro-scales because of surface tension and flow resistances. Liquid-Liquid extraction unit for sample pre-concentration and micro-optic components for fluorescence detection are the key microfluidic components and have been designed and fabricated on a single disposable chip. In the Liquid-Liquid extraction system, different designs are compared and electromagnetically actuated micro-valves and peristaltic pumps have been designed and fabricated to control the aqueous sample fluid and the organic phase solution. In the micro-optic detection system, different designs are compared and an out-of-plane lens was designed, fabricated, and integrated to enhance the measurement sensitivity. The experimental results of the integrated system have proved that the liquid-liquid extraction functioned very well and the overall measurement sensitivity of the system has been increased more than six hundred percent. An overall oil detection sensitivity blow 1ppm has been achieved. The research work presented in this dissertation has proved the feasibility of this novel oil detection instrument based on micro-fluidic-optic chip. This detection system may also be used for detection of other samples that can be measured based on fluoresce principles

Microfabricated All-Around-Electrode AC Electro-osmotic Micropump

This thesis presents the fabrication and characterisation of AC electro-osmotic micropumps with a simple design and velocity generation enhanced by about four times with respect to devices with simpler designs. Electro-osmosis is a convenient and effective method to pump liquids without the need for moving components. The implementation of valveless micropumps is important for the realisation of safe and robust biomedical devices, which require long-term reliability. AC electro-osmosis has the advantage, over other kinds of pumping strategies, of being implementable with relatively simple geometries and fabrication processes. Moreover, it uses low voltages and avoids undesired phenomena such as electrolysis, thus being suitable for the implementation in implantable devices that should operate in a closed environment. Whereas AC electro-osmotic pumps presented in the literature exploit planar electrode designs and fail to generate good values of velocity and pressure, the prototypes presented in this work have electrodes patterned all around the pumping channel and can generate much larger values. Moreover, with respect to other improved prototypes based on 3D electrode geometries, our devices are simpler to fabricate and give comparable enhancements of the performances. In this work, we present the development of the all-around-electrode devices and give a theoretical explanation for the measured improvements in velocity generation. The fabrication process is carried out in the cleanroom by depositing Ti/Pt electrodes on pre-structured Pyrex substrates and requires only three lithographic steps. The performances of the fabricated devices are characterised as a function of the applied voltage and frequency, and the dynamic behaviour of the prototypes is studied using the Fourier transform. In order to evaluate the suitability of the pumps for biomedical fluids, the dependence of velocity generation on the concentration of the pumped solution is also addressed. Finally, we show that the fabrication process can be adapted to an industrial batch manufacture requiring lower costs by substituting the Pyrex substrates with thin plastic foils. All-around-electrode micropumps can be successfully fabricated by patterning metal electrodes onto 12-µm-thick plastic foils and the costs might be further reduced by substituting the metal structures with inkjet-printed conductive-polymer electrodes

Towards rapid 3D direct manufacture of biomechanical microstructures

The field of stereolithography has developed rapidly over the last 20 years, and commercially available systems currently have sufficient resolution for use in microengineering applications. However, they have not as yet been fully exploited in this field. This thesis investigates the possible microengineering applications of microstereolithography systems, specifically in the areas of active microfluidic devices and microneedles. The fields of micropumps and microvalves, stereolithography and microneedles are reviewed, and a variety of test builds were fabricated using the EnvisionTEC Perfactory Mini Multi-Lens stereolithography system in order to define its capabilities. A number of microneedle geometries were considered. This number was narrowed down using finite element modelling, before another simulation was used to optimise these structures. 9 × 9 arrays of 400 μm tall, 300 μm base diameter microneedles were subjected to mechanical testing. Per needle failure forces of 0.263 and 0.243 N were recorded for the selected geometries, stepped cone and inverted trumpet. The 90 μm needle tips were subjected to between 30 and 32 MPa of pressure at their failure point - more than 10 times the required pressure to puncture average human skin. A range of monolithic micropumps were produced with integrated 4 mm diameter single-layer 70 μm-thick membranes used as the basis for a reciprocating displacement operating principle. The membranes were tested using an oscillating pneumatic actuation, and were found reliable (>1,000,000 cycles) up to 2.0 PSIG. Pneumatic single-membrane nozzle/diffuser rectified devices produced flow rates of up to 1,000 μl/min with backpressures of up to 375 Pa. Another device rectified using active membrane valves was found to self-prime, and produced backpressures of up to 4.9 kPa. These devices and structures show great promise for inclusion in complex, fully integrated and active microfluidic systems fabricated using microstereolithography alone, with implications for both cost of manufacture and lead time.EThOS - Electronic Theses Online ServiceEngineering and Physical Sciences Research Council (EPSRC)GBUnited Kingdo

Valve Regulated Implantable Intrathecal Drug Deliver for Chronic Pain Management.

Chronic pain afflicts an estimated 100 million people in the United States with annual costs exceeding $100 billion. Treatment modalities for severe chronic pain include implantation of an intrathecal drug delivery device (IDDD). Conventionally, these devices are of two types: passive, permitting the delivery of a single analgesic mixture at a fixed rate; or active, permitting variable delivery by virtue of a peristaltic pump. This thesis presents an implantable system for medication delivery from multiple reservoirs with micromachined components. These components permit the use of an architecture that can provide superior volume efficiency and permit complex multi-drug delivery protocols. The system comprises three main components: regulatory valves, pressurized reservoirs, and control electronics. Important design considerations for each of these components are emphasized. Piezoelectric microvalves were designed and tested for use with aqueous flows. Two types of spring pressurized reservoirs were also designed and tested for feasibility in an IDDD. Reservoirs were pressurized using springs fabricated from silicon and generated up to 80kPa of pressure. Alternative reservoirs were pressurized using compressive metal springs and generated up to 18kPa of pressure. A first-generation system was developed that demonstrated controlled diffusion into agar gel. Water flow was regulated from 0.2-5mL/day, and bolus delivery was demonstrated. A second-generation system utilizing a two-valve manifold with embedded sensors was used to independently regulate isopropyl alcohol flow at set rates between 0.05-1mL/hr. Both systems demonstrated liquid delivery at intrathecal flow rates using continuous and duty-cycle flow regulation. Outlet pressure sensors were used to detect acute catheter occlusions and disconnects. A smart refill port was developed to allow for power transfer rates necessary to recharge batteries during a reservoir refill session. Recharging at current rates up to 500mA was demonstrated. The proposed valve-regulated architecture and two preliminary prototypes allowed evaluation of potential solutions to challenges for application of the architecture in an IDDD. Recommendations for future systems and plans for bench-top and in vitro testing are detailed. The proposed work may lead to a system that provides the functionality of commercially available implantable drug delivery devices with high volume efficiency, and the ability to independently regulate multiple medications.Ph.D.Electrical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/75815/1/evansall_1.pd