EUROSENSORS XVII : book of abstracts

Fundação Calouste Gulbenkien (FCG).Fundação para a Ciência e a Tecnologia (FCT)

A Label Free CMOS-Based Smart Petri Dish for Cellular Analysis

RÉSUMÉ Le dépistage de culture cellulaire à haut débit est le principal défi pour une variété d’applications des sciences de la vie, y compris la découverte de nouveaux médicaments et le suivi de la cytotoxicité. L’analyse classique de culture cellulaire est généralement réalisée à l’aide de techniques microscopiques non-intégrées avec le système de culture cellulaire. Celles-ci sont laborieuses spécialement dans le cas des données recueillies en temps réel ou à des fins de surveillance continue. Récemment, les micro-réseaux cellulaires in-vitro ont prouvé de nombreux avantages dans le domaine de surveillance des cellules en réduisant les coûts, le temps et la nécessité d’études sur des modèles animaux. Les microtechniques, y compris la microélectronique et la microfluidique,ont été récemment utilisé dans la biotechnologie pour la miniaturisation des systèmes biologiques et analytiques. Malgré les nombreux efforts consacrés au développement de dispositifs microfluidiques basés sur les techniques de microscopie optique, le développement de capteurs intégrés couplés à des micropuits pour le suivi des paramètres cellulaires tel que la viabilité, le taux de croissance et cytotoxicité a été limité. Parmi les différentes méthodes de détection disponibles, les techniques capacitives offrent une plateforme de faible complexité. Celles-ci ont été considérablement utilisées afin d’étudier l’interaction cellule-surface. Ce type d’interaction est le plus considéré dans la majorité des études biologiques. L’objectif de cette thèse est de trouver des nouvelles approches pour le suivi de la croissance cellulaire et la surveillance de la cytotoxicité à l’aide d’un réseau de capteurs capacitifs entièrement intégré. Une plateforme hybride combinant un circuit microélectronique et une structure microfluidique est proposée pour des applications de détection de cellules et de découverte de nouveaux médicaments. Les techniques biologiques et chimiques nécessaires au fonctionnement de cette plateforme sont aussi proposées. La technologie submicroniques Standard complementary metal-oxide-Semiconductor (CMOS) (TSMC 0.35 μm) est utilisée pour la conception du circuit microélectronique de cette plateforme. En outre, les électrodes sont fabriquées selon le processus CMOS standard sans la nécessité d’étapes de post-traitement supplémentaires. Ceci rend la plateforme proposée unique par rapport aux plateformes de dépistage de culture cellulaire à haut débit existantes. Plusieurs défis ont été identifiés durant le développement de cette plateforme comme la sensibilité, la bio-compatibilité et la stabilité et les solutions correspondantes sont fournies.----------ABSTRACT High throughput cell culture screening is a key challenge for a variety of life science applications, including drug discovery and cytotoxicity monitoring. Conventional cell culture analysis is widely performed using microscopic techniques that are not integrated into the target cell culture system. Additionally, these techniques are too laborious in particular to be used for real-time and continuous monitoring purposes. Recently, it has been proved that invitro cell microarrays offer great advantages for cell monitoring applications by reducing cost, time, and the need for animal model studies. Microtechnologies, including microelectronics and microfluidics, have been recently used in biotechnology for miniaturization of biological and analytical systems. Despite many efforts in developing microfluidic devices using optical microscopy techniques, less attention have been paid on developing fully integrated sensors for monitoring cell parameters such as viability, growth rate, and cytotoxicity. Among various available sensing methods, capacitive techniques offer low complexity platforms. This technique has significantly attracted attentions for the study of cell-surface interaction which is widely considered in biological studies. This thesis focuses on new approaches for cell growth and cytotoxicity monitoring using a fully integrated capacitive sensor array. A hybrid platform combining microelectronic circuitry and microfluidic structure is proposed along with other required biological and chemical techniques for single cell detection and drug discovery applications. Standard submicron complementary metal–oxide–semiconductor (CMOS) technology (TSMC 0.35 μm) is used to develop the microelectronic part of this platform. Also, the sensing electrodes are fabricated in standard CMOS process without the need for any additional post processing step, which makes the proposed platform unique compared to other state of the art high throughput cell assays. Several challenges in implementing this platform such as sensitivity, bio-compatibility, and stability are discussed and corresponding solutions are provided. Specifically, a new surface functionalization method based on polyelectrolyte multilayers deposition is proposed to enhance cell-electrode adherence and to increase sensing electrodes’ life time. In addition, a novel technique for microwell fabrication and its integration with the CMOS chip is proposed to allow parallel screening of cells. With the potential to perform inexpensive, fast, and real-time cell analyses, the proposed platform opens up the possibility to transform from passive traditional cell assays to a smart on-line monitoring system

Design and fabrication of a multipurpose compliant nanopositioning architecture

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering, 2013.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.Cataloged from student-submitted PDF version of thesis.Includes bibliographical references (p. 227-241).This research focused on generating the knowledge required to design and fabricate a high-speed application flexible, low average cost multipurpose compliant nanopositioner architecture with high performance integrated sensing. Customized nanopositioner designs can be created in ~~1 week, for 30x increase in sensing dynamic range over comparable state-of-the-art compliant nanopositioners. These improvements will remove one of the main hurdles to practical non-IC nanomanufacturing, which could enable advances in a range of fields including personalized medication, computing and data storage, and energy generation/storage through the manufacture of metamaterials. Advances were made in two avenues: flexibility and affordability. The fundamental advance in flexibility is the use of a new approach to modeling the nanopositioner and sensors as combined mechanical/electronic systems. This enabled the discovery of the operational regimes and design rules needed to maximize performance, making it possible to rapidly redesign nanopositioner architecture for varying functional requirements such as range, resolution and force. The fundamental advance to increase affordability is the invention of Non-Lithographically-Based Microfabrication (NLBM), a hybrid macro-/micro-fabrication process chain that can produce MEMS with integrated sensing in a flexible manner, at small volumes and with low per-device costs. This will allow for low-cost customizable nanopositioning architectures with integrated position sensing to be created for a range of micro-/nano- manufacturing and metrology applications. A Hexflex 6DOF nanopositioner with titanium flexures and integrated siliconpiezoresistive sensing was fabricated using NLBM. This device was designed with a metal mechanical structure in order to improve its robustness for general handling and operation. Single crystalline silicon piezoresistors were patterned from bulk silicon wafers and transferred to the mechanical structure via thin-film patterning and transfer. This work demonstrates that it is now feasible to design and create a customized positioner for each nanomanufacturing/metrology application. The Hexflex architecture can be significantly varied to adjust range, resolution, force scale, stiffness, and DOF all as needed. The NLBM process was shown to enable alignment of device components on the scale of 10's of microns. 150μm piezoresistor arm widths were demonstrated, with suggestions made for how to reach the expected lower bound of 25[mu]m. Flexures of 150[mu]m and 600[mu]m were demonstrated on 4 the mechanical structure, with a lower bound of ~~50[mu]m expected for the process. Electrical traces of 800[mu]m width were used to ensure low resistance, with a lower bound of ~~100[mu]m expected for the process. The integrated piezoresistive sensing was designed to have a gage factor of about 125, but was reduced to about 70 due to lower substrate temperatures during soldering, as predicted by design theory. The sensors were measured to have a full noise dynamic range of about 59dB over a 10kHz sensor bandwidth, limited by the Schottky barrier noise. Several simple methods are suggested for boosting the performance to ~~135dB over a 10kHz sensor bandwidth, about a <1Å resolution over the 200[mu]m range of the case study device. This sensor performance is generally in excess of presently available kHz-bandwidth analog-to-digital converters.by Robert M. Panas.Ph.D

Development of piezoresistive sensors for biomedical applications

Tese de doutoramento em Engenharia Electrónica Industrial e de ComputadoresIn the last decades there has been an increase in sensing systems applied in a variety of situations with a large variety of sensor ranges. This represents a growing area with high potential. One of the areas of sensor development that require a great deal of attention is the area of sensor for biomedical applications and biosensors. These sensors have to overcome a number of challenges and limitations inherent to the environment where they are introduced. These difficulties lead to the necessity of using new materials and new techniques for their construction together with the more traditional materials, e.g. silicon based, which have already proven their potential in this area. Among the various materials, polymers have proven to be a good choice, due to a set of advantages such as simple processing, flexibility and facility of being obtained in different shapes. Therefore it is interesting to fabricate polymer based piezoresistive sensors for functional coatings of implantable hip prosthesis. These sensors will allow coating the prosthesis and provide new functionalities to the implants such as the possibility to measure forces and deformations between the prosthesis and the bone and therefore improving the postoperative diagnostic. In this works, a model of hip prosthesis with coated sensors was developed. For this purpose, flexible piezoresistive sensors have been developed that allow being implanted. Strain sensors were fabricated based on thin films of n+-nc-si.H by the technique of hot-wire chemical vapor deposition at a temperature of 150 ºC on a polymeric substrate, using the lithographic technique to construct the various layers of the sensors. The sensor has a gauge factor of -28 for low frequency deformation cycles. In the last decades there has been an increase in sensing systems applied in a variety of situations with a large variety of sensor ranges. This represents a growing area with high potential. One of the areas of sensor development that require a great deal of attention is the area of sensor for biomedical applications and biosensors. These sensors have to overcome a number of challenges and limitations inherent to the environment where they are introduced. These difficulties lead to the necessity of using new materials and new techniques for their construction together with the more traditional materials, e.g. silicon based, which have already proven their potential in this area. Among the various materials, polymers have proven to be a good choice, due to a set of advantages such as simple processing, flexibility and facility of being obtained in different shapes. Therefore it is interesting to fabricate polymer based piezoresistive sensors for functional coatings of implantable hip prosthesis. These sensors will allow coating the prosthesis and provide new functionalities to the implants such as the possibility to measure forces and deformations between the prosthesis and the bone and therefore improving the postoperative diagnostic. In this works, a model of hip prosthesis with coated sensors was developed. For this purpose, flexible piezoresistive sensors have been developed that allow being implanted. Strain sensors were fabricated based on thin films of n+-nc-si.H by the technique of hot-wire chemical vapor deposition at a temperature of 150 ºC on a polymeric substrate, using the lithographic technique to construct the various layers of the sensors. The sensor has a gauge factor of -28 for low frequency deformation cycles.In the last decades there has been an increase in sensing systems applied in a variety of situations with a large variety of sensor ranges. This represents a growing area with high potential. One of the areas of sensor development that require a great deal of attention is the area of sensor for biomedical applications and biosensors. These sensors have to overcome a number of challenges and limitations inherent to the environment where they are introduced. These difficulties lead to the necessity of using new materials and new techniques for their construction together with the more traditional materials, e.g. silicon based, which have already proven their potential in this area. Among the various materials, polymers have proven to be a good choice, due to a set of advantages such as simple processing, flexibility and facility of being obtained in different shapes. Therefore it is interesting to fabricate polymer based piezoresistive sensors for functional coatings of implantable hip prosthesis. These sensors will allow coating the prosthesis and provide new functionalities to the implants such as the possibility to measure forces and deformations between the prosthesis and the bone and therefore improving the postoperative diagnostic. In this works, a model of hip prosthesis with coated sensors was developed. For this purpose, flexible piezoresistive sensors have been developed that allow being implanted. Strain sensors were fabricated based on thin films of n+-nc-si.H by the technique of hot-wire chemical vapor deposition at a temperature of 150 ºC on a polymeric substrate, using the lithographic technique to construct the various layers of the sensors. The sensor has a gauge factor of -28 for low frequency deformation cycles. Sensors with larger flexibility were also developed though inkjet printing technique. Various configurations and materials were used to evaluate which materials are most appropriate for these types of sensors. Sensors with a gauge factor of approximately 2.5 for an active layer of PeDOT were obtained. A sensor matrix of 4 x 5 sensors was fabricated with an active area of 1.8 x 1.5 mm2 per sensor. These sensors were subjected to a set of electromechanical tests to evaluate its performance in situations close to end use. So the prosthesis was coated with the various sensors, cemented and subjected to deformation cycles for three levels of force according to standard ISO7206. An adaptive system read-out electronic circuit was developed and built that allows reading piezoresistive sensors with different characteristics. This system allows measuring a matrix of 8x8 sensors, but can be scaled to a large number of sensors. The readable range of the system is between 50 Ω and 100 kΩ according to the needs of the sensors being implanted. The total area of the circuit is 135 mm2, according to the requirements of a circuit to be used in in-vivo applications. An energy management system was also implemented that allows to activate and deactivate parts of the circuit when they are not needed, reducing the energy consumption. The system was validated by measuring a matrix of sensors with different characteristics. Finally, simulations were performed in order to evaluate the best options for the development of a wireless communications system. Three possible operation frequency ranges were used for three types of standard antennas. The communication system was introduced into a model simulating the characteristics of the various layers that constitute the human body. These simulations allow evaluate the frequency range most appropriate for implantable devices, the most appropriate antenna and the best location within the body. So the frequency chosen for the implementation was 868 Mhz for a Inverted- F antenna (IFA). In conclusion, the key elements for the implementations of an instrumented hip prosthesis were development and validated. The developed and/or simulated elements, including sensors, circuits for reading and communication system can also be used in other applications due to characteristics.These simulations allow evaluate the frequency range most appropriate for implantable devices, the most appropriate antenna and the best location within the body. So the frequency chosen for the implementation was 868 Mhz for a Inverted- F antenna (IFA). In conclusion, the key elements for the implementations of an instrumented hip prosthesis were development and validated. The developed and/or simulated elements, including sensors, circuits for reading and communication system can also be used in other applications due to characteristics. Neste trabalho foi desenvolvido um modelo de prótese de anca com implementação de sensores. Para atingir esse objectivo, foram desenvolvidos sensores piezoresitivos flexíveis que permitam ser implantados. Assim foram fabricados sensores de deformação baseados em filmes finos de n+-nc-si.H pela técnica de hot-wire chemical vapor deposition a uma temperatura de 150ºC sobre um substrato polimérico. Recorreu-se a técnica de litografia para construir as várias camadas do sensor. Os sensores apresentam um gauge factor de -28, para ciclos de baixa frequência em testes de four-point-bending. Foram ainda desenvolvidos sensores com uma maior flexibilidade através da técnica de inkjet printing. Para esse desenvolvimento foram usadas várias configurações e materiais, para avaliar quais os materiais mais adequados para este tipo de sensores. Na caracterização destes sensores obteve-se um gauge factor de aproximadamente 2.5 para uma camada ativa de PeDOT. Com os melhores sensores obtidos foram construídas matrizes de 4 x 5 sensores que apresentam uma área ativa de 1.8 x 1.5mm2 por sensor. Estes sensores foram sujeitos a um conjunto de ensaios electromecânicos, para avaliar o seu desempenho em situações próximas da utilização final. Desta forma foi revestida uma prótese com os diferentes sensores, cimentada e sujeita a ciclos de deformação para três níveis de força, segundo a norma ISO7206. Foi desenvolvido e construído um sistema de leitura adaptável que permite medir sensores piezoresistivos com diferentes características entre eles. Este sistema permite medir uma matriz de 8x8 sensores, mas pode ser escalada para um número maior de sensores. A gama de leitura do sistema varia entre 50 Ω e 100 kΩ, de acordo com as necessidades dos sensores a serem implementados. A área total deste circuito é de 135 mm2, de acordo com as necessidades de um circuito a ser utilizado em aplicações in-vivo. Foi também implementado um sistema de gestão de energia que permite ativar e desativar partes do circuito quando estas não são necessárias, permitindo, desta forma, reduzir os consumos de energia. O sistema foi validado através da medição de uma matriz de sensores com diferentes características. foram realizadas simulações de forma a avaliar as melhores opções para o desenvolvimento do sistema de comunicação sem fios. Foram usadas três possíveis gamas de frequência de operação para três tipos de antenas standard. O sistema de comunicação foi introduzido num modelo simulando as características das várias camadas que constituem o corpo humano. Estas simulações permitem aferir a gama de frequências mais adequadas para os dispositivos implantáveis, a antena mais adequada e a sua melhor localização, pois foi verificado como as várias camadas que constituem o corpo humano influenciam a comunicação. Assim, a frequência escolhida para a implementação foi de 868 MHz e a antena foi a IFA. Em conclusão, os elementos principais para a implementação de uma prótese de anca instrumentada, foram desenvolvidos e validados. Os elementos desenvolvidos e/ou simulados, incluindo os sensores, circuitos de leitura e sistema de comunicação, poderão igualmente ser utilizados em outras aplicações devido às suas boas características

Optical fibre based cantilever for sensing applications

The project investigated in this thesis is concerned with application of using optical fibre cantilever sensors for various applications where traditional electrical sensors cannot survive or work. These applications include micro-machined optical fibre-top cantilever sensor for high temperature and pH measurement, ferrule-top measurement to monitor real-time biomolecule binding process and optical fibre side cantilever sensor for acceleration measurement. In addition, a further investigation of optical fibre diaphragm sensor used for prostate stiffness measurement is also presented based on the same interrogation technique. First of all, interferometry to monitor the cantilever deflection will be investigated to avoid issues associated with intensity based systems while retaining high measurement resolution. Secondly, different manufacture techniques of cantilevers compatible with silica optical fibres (laser machining with ns/ps laser, FIB machining) is proposed for deflection measurement. This includes temperature/pH sensing, biological binding monitoring multicore fibres for multi-measurand sensors and optically activated sensors for acceleration measurements. The use of optical fibre offers a route to miniaturise sensor configuration to allow measurement of real-time bending of micro-cantilevers which can be transferred to cantilever surface energy change by Stoney’s equation. By investigating this small energy change, behaviour of real-time biomolecule binding can be monitored. A number of techniques and applications are investigated in the thesis