Trends of biosensing: plasmonics through miniaturization and quantum sensing

Despite being extremely old concepts, plasmonics and surface plasmon resonance-based biosensors have been increasingly popular in the recent two decades due to the growing interest in nanooptics and are now of relevant significance in regards to applications associated with human health. Plasmonics integration into point-of-care devices for health surveillance has enabled significant levels of sensitivity and limit of detection to be achieved and has encouraged the expansion of the fields of study and market niches devoted to the creation of quick and incredibly sensitive label-free detection. The trend reflects in wearable plasmonic sensor development as well as point-of-care applications for widespread applications, demonstrating the potential impact of the new generation of plasmonic biosensors on human well-being through the concepts of personalized medicine and global health. In this context, the aim here is to discuss the potential, limitations, and opportunities for improvement that have arisen as a result of the integration of plasmonics into microsystems and lab-on-chip over the past five years. Recent applications of plasmonic biosensors in microsystems and sensor performance are analyzed. The final analysis focuses on the integration of microfluidics and lab-on-a-chip with quantum plasmonics technology prospecting it as a promising solution for chemical and biological sensing. Here it is underlined how the research in the field of quantum plasmonic sensing for biological applications has flourished over the past decade with the aim to overcome the limits given by quantum fluctuations and noise. The significant advances in nanophotonics, plasmonics and microsystems used to create increasingly effective biosensors would continue to benefit this field if harnessed properly

A Spectral-Scanning Nuclear Magnetic Resonance Imaging (MRI) Transceiver

An integrated spectral-scanning nuclear magnetic resonance imaging (MRI) transceiver is implemented in a 0.12 mum SiGe BiCMOS process. The MRI transmitter and receiver circuitry is designed specifically for small-scale surface MRI diagnostics applications where creating low (below 1 T) and inhomogeneous magnetic field is more practical. The operation frequency for magnetic resonance detection and analysis is tunable from 1 kHz to 37 MHz, corresponding to 0-0.9 T magnetization for ^1H (hydrogen). The concurrent measurement bandwidth is approximately one frequency octave. The chip can also be used for conventional narrowband nuclear magnetic resonance (NMR) spectroscopy from 1 kHz up to 250 MHz. This integrated transceiver consists of both the magnetic resonance transmitter which generates the required excitation pulses for the magnetic dipole excitation, and the receiver which recovers the responses of the dipoles

Implantable Microsystem Technologies For Nanoliter-Resolution Inner Ear Drug Delivery

Advances in protective and restorative biotherapies have created new opportunities to use site-directed, programmable drug delivery systems to treat auditory and vestibular disorders. Successful therapy development that leverages the transgenic, knock-in, and knock-out variants of mouse models of human disease requires advanced microsystems specifically designed to function with nanoliter precision and with system volumes suitable for implantation. The present work demonstrates a novel biocompatible, implantable, and scalable microsystem consisted of a thermal phase-change peristaltic micropump with wireless control and a refillable reservoir. The micropump is fabricated around a catheter microtubing (250 μm OD, 125 μm ID) that provided a biocompatible leak-free flow path while avoiding complicated microfluidic interconnects. Direct-write micro-scale printing technology was used to build the mechanical components of the pump around the microtubing directly on the back of a printed circuit board assembly. In vitro characterization results indicated nanoliter resolution control over the desired flow rates of 10–100 nL/min by changing the actuation frequency, with negligible deviations in presence of up to 10× greater than physiological backpressures and ±3°C ambient temperature variation. A biocompatibility study was performed to evaluate material suitability for chronic subcutaneous implantation and clinical translational development. A stand-alone, refillable, in-plane, scalable, and fully implantable microreservoir platform was designed and fabricated to be integrated with the micropump. The microreservoir consists two main components: a cavity for storing the drug and a septum for refilling. The cavity membrane is fabricated with thin Parylene-C layers, using a polyethylene glycol (PEG) sacrificial layer. The septum thickness is minimized by pre-compression down to 1 mm. The results of in vitro characterization indicated negligible restoring force for the optimized cavity membrane and thousands of punctures through the septum without leakage. The micropump and microreservoir were integrated into microsystems which were implanted in mice. The microtubing was implanted into the round window membrane niche for infusion of a known ototoxic compound (sodium salicylate) at 50 nL/min for 20 min. Real-time shifts in distortion product otoacoustic emission thresholds and amplitudes were measured during the infusion. The results match with syringe pump gold standard. For the first time a miniature and yet scalable microsystem for inner ear drug delivery was developed, enabling drug discovery opportunities and translation to human

Integration of virus-like particle macromolecular bioreceptors in electrochemical biosensors

Rapid, sensitive and selective detection of chemical hazards and biological pathogens has shown growing importance in the fields of homeland security, public safety and personal health. In the past two decades, efforts have been focusing on performing point-of-care chemical and biological detections using miniaturized biosensors. These sensors convert target molecule binding events into measurable electrical signals for quantifying target molecule concentration. However, the low receptor density and the use of complex surface chemistry in receptors immobilization on transducers are common bottlenecks in the current biosensor development, adding to the cost, complexity and time. This dissertation presents the development of selective macromolecular Tobacco mosaic virus-like particle (TMV VLP) biosensing receptor, and the microsystem integration of VLPs in microfabricated electrochemical biosensors for rapid and performance-enhanced chemical and biological sensing. Two constructs of VLPs carrying different receptor peptides targeting at 2,4,6-trinitrotoluene (TNT) explosive or anti-FLAG antibody are successfully bioengineered. The VLP-based TNT electrochemical sensor utilizes unique diffusion modulation method enabled by biological binding between target TNT and receptor VLP. The method avoids the influence from any interfering species and environmental background signals, making it extremely suitable for directly quantifying the TNT level in a sample. It is also a rapid method that does not need any sensor surface functionalization process. For antibody sensing, the VLPs carrying both antibody binding peptides and cysteine residues are assembled onto the gold electrodes of an impedance microsensor. With two-phase immunoassays, the VLP-based impedance sensor is able to quantify antibody concentrations down to 9.1 ng/mL. A capillary microfluidics and impedance sensor integrated microsystem is developed to further accelerate the process of VLP assembly on sensors and improve the sensitivity. Open channel capillary micropumps and stop-valves facilitate localized and evaporation-assisted VLP assembly on sensor electrodes within 6 minutes. The VLP-functionalized impedance sensor is capable of label-free sensing of antibodies with the detection limit of 8.8 ng/mL within 5 minutes after sensor functionalization, demonstrating great potential of VLP-based sensors for rapid and on-demand chemical and biological sensing

MRI-Based Communication with Untethered Intelligent Medical Microrobots

RESUME Les champs magnétiques présent dans un système clinique d’Imagerie par Résonance Magnétique (IRM) peuvent être exploités non seulement, afin d’induire une force de déplacement sur des microrobots magnétiques tout en permettant l’asservissement de leur position - une technique connue sous le nom de Navigation par Résonance Magnétique (NRM), mais aussi pour mettre en œuvre un procédé de communication. Pour des microrobots autonomes équipés de senseurs ayant un certain niveau d'intelligence et opérant à l'intérieur du corps humain, la puissance de transmission nécessaire pour communiquer des informations à un ordinateur externe par des méthodes présentement connues est insuffisante. Dans ce travail, une technique est décrite où une telle perte de puissance d'émission en raison de la mise à l'échelle de ces microrobots peut être compensée par le scanner IRM agissant aussi comme un récepteur très sensible. La technique de communication prend la forme d'une modification de la fréquence du courant électrique circulant le long d'une bobine miniature incorporé dans un microrobot. La fréquence du courant électrique peut être réglée à partir d'une entrée de seuil prédéterminée du senseur mis en place sur le microrobot. La fréquence devient alors corrélée à l’information de l’état du senseur recueilli par le microrobot et elle est déterminée en utilisant l'IRM. La méthode proposée est indépendante de la position et l'orientation du microrobot et peut être étendue à un grand nombre de microrobots pour surveiller et cartographier les conditions physiologiques spécifiques dans une région plus vaste à n’importe quelle profondeur à l'intérieur du corps.----------ABSTRACT The magnetic environment provided by a clinical Magnetic Resonance Imaging (MRI) scanner can be exploited to not only induce a displacement force on magnetic microrobots while allowing MR-tracking for serving control purpose or positional assessment - a technique known as Magnetic Resonance Navigation (MRN), but also for implementing a method of communication with intelligent microrobots. For untethered sensory microrobots having some level of intelligence and operating inside the body, the transmission power necessary to communicate information to an external computer via known methods is insufficient. In this work, a technique is described where such loss of transmission power due to the scaling of these microrobots can be compensated by the same MRI scanner acting as a more sensitive receiver. A communication scheme is implemented in the form of a frequency alteration in the electrical current circulating along a miniature coil embedded in a microrobot. The frequency of the electrical current could be regulated from a predetermined sensory threshold input implemented on the microrobot. Such a frequency provides information on the level of sensory information gathered by the microrobot, and it is determined using MR imaging. The proposed method is independent of the microrobot's position and orientation and can be extended to a larger number of microrobots for monitoring and mapping specific physiological conditions inside a larger region at any depths within the body

Roadmap for optofluidics

Optofluidics, nominally the research area where optics and fluidics merge, is a relatively new research field and it is only in the last decade that there has been a large increase in the number of optofluidic. applications, as well as in the number of research groups, devoted to the topic. Nowadays optofluidics applications include, without being limited to, lab-on-a-chip devices, fluid-based and controlled lenses, optical sensors for fluids and for suspended particles, biosensors, imaging tools, etc. The long list of potential optofluidics applications, which have been recently demonstrated, suggests that optofluidic technologies will become more and more common in everyday life in the future, causing a significant impact on many aspects of our society. A characteristic of this research field, deriving from both its interdisciplinary origin and applications, is that in order to develop suitable solutions a. combination of a deep knowledge in different fields, ranging from materials science to photonics, from microfluidics to molecular biology and biophysics,. is often required. As a direct consequence, also being able to understand the long-term evolution of optofluidics research is not. easy. In this article, we report several expert contributions on different topics. so as to provide guidance for young scientists. At the same time, we hope that this document will also prove useful for funding institutions and stakeholders. to better understand the perspectives and opportunities offered by this research field

Optical microsystem for spectroscopy signals extraction applied to gastrointestinal dysplasia detection

Tese de Doutoramento em Engenharia BiomédicaThe early detection of gastrointestinal cancer, in the dysplastic stage, is essential to increase the patient survival rate. Spectroscopic techniques, particularly diffuse reflectance and fluorescence, can improve the gastrointestinal dysplasia detection, since these techniques can be used to extract biochemical and morphologic information related with the status of a gastrointestinal tissue. Several research groups have developed prototypes for the extraction of diffuse reflectance and fluorescence signals applied to gastrointestinal cancer detection. Despite their advantages associated with the gastrointestinal cancer identification, they have several disadvantages related with the use of complex, high-cost and sophisticate components such as xenon lamps, lasers, monochromators, optical fibers and high quantum efficiency detectors, which may hamper their wide use as well as their huge clinical value. Therefore, it is of utmost importance to develop a low-cost, miniaturized and minimal invasive microsystem for spectroscopic signals extraction. As a result, in this work it is proposed the implementation of a microsystem, which comprises in a single chip, an optical filter system for selection and extraction of the diffuse reflectance and fluorescence signals in relevant spectral bands, a silicon photodiodes matrix (4×4) and its readout electronics, and miniaturized light emitting diodes. The main applications of this microsystem are: its use as a portable device in a surgery room for inspection of total removing of the cancerous or dysplastic tissue; and its integration with the standard endoscopes and colonoscopes using it as an auxiliary, to the physician, in early gastrointestinal cancer detection. Along this thesis, important steps towards that microsystem implementation were achieved. In a first step experimental measurements were performed, with phantoms representative of the main absorbing, scattering and fluorescence properties of gastrointestinal tissues (containing hemoglobin, polystyrene microspheres to represent collagen fibers, and the fluorophores NADH and Carbostyril 124, the latter representing collagen), in order to study the diffuse reflectance and fluorescence typical spectra and their temperature dependence. Moreover, the viability of using only 16 spectral bands (between 350 and 750 nm) for signals extraction was discussed, proving the feasibility of an optical filter system implementation in the final microsystem. Therefore, it were designed, fabricated and characterized 16 MgO/TiO2 and SiO2/TiO2 based thin-film optical filters. Their characterization performed through optical transmittance, selectivity, profilometry and scanning electron microscopy, allowed understanding the deviations between the simulated characteristics and the ones experimentally obtained. Moreover, the optical filters results showed transmittances ranging from 50% to 90% approximately, and a full width half maximum (FWHM) averaging from 11 nm to 20 nm, which fits the required application. The fabricated optical filters had some deviations considering their simulated characteristics, which can be explained by the complexity of the optical filters design, for example, the materials refractive index dependence with wavelength and thin-film thickness. The diffuse reflectance and fluorescence signals that pass through the optical filters can be measured with an on-chip silicon photodetectors matrix (4×4), based on n+/p-epilayer junction photodiodes with an active area of 100 × 100 µm2, and a light-to-frequency converter, per each photodiode, that enables producing a digital signal with a frequency proportional to the photodiode current. As a result, the design and implementation of a CMOS microsystem comprising these components were performed. The photodiodes characterization showed a responsivity of 200 mA/W at 550 nm, approximately, and the light-to-frequency converter connected to the photodiode showed a linear response (R2>0.99) with a sensitivity of 25 Hz/nA at 550 nm, approximately. The behavior of the current-to-frequency converter, with an external current source directly injected in its input, was also studied allowing to confirm its linearity in the range of currents produced in this application, its power consumption of 1 mW, and its maximum input current, approximately 300 µA. This CMOS approach avoids the need of an expensive readout optical microsystem, since it is possible to integrate the photodiodes and the readout electronics in a small silicon area (275 × 100 µm2 per photodiode and its respective converter). The performance of the implemented microsystem and the fabricated optical filters was evaluated, using phantoms (also containing hemoglobin, polystyrene microspheres, NADH and Carbostyril 124). The obtained results have shown the viability of the microsystem (including the optical filter system) to extract diffuse reflectance and fluorescence signals. Some issues were noted on the sensitivity of the implemented optical setups for the on-chip measurements. However, some solutions were proposed for the remaining problems, specifically the future use of miniaturized light emitting diodes and the direct deposition of the optical filters on the top of the photodetection system. Finally, the direct integration of optical filters on top of the photodiodes was discussed and a new approach was tested.The author, Sara Filomena Ribeiro Pimenta, was supported by the Portuguese Foundation for Science and Technology (in portuguese FCT – Fundação para a Ciência e a Tecnologia) with the PhD grant SFRH/BD/87605/2012. This work is also funded by FEDER funds through the “Eixo I do Programa Operacional Fatores de Competitividade” (POFC) QREN, project reference COMPETE: FCOMP-01-0124-FEDER- 020241 and by FCT, project reference PTDC/EBB-EBI/120334/2010. Finally, the author thanks to the PEst-C/FIS/UI0607/2013, UID/FIS/04650/2013, UID/EEA/04436/2013 and POCI-01- 0145-FEDER-006941 for the use of equipment.A deteção precoce do cancro gastrointestinal, na fase de displasia, é essencial para o aumento da taxa de sobrevivência do paciente. As técnicas de espetroscopia, particularmente a refletância difusa e a fluorescência, permitem melhorar a deteção de displasia gastrointestinal, ao poderem ser utilizadas para a extração de informação bioquímica e morfológica associada ao estado do tecido gastrointestinal. Diversos grupos de investigação têm desenvolvido protótipos para a extração de sinais de refletância difusa e de fluorescência, para aplicação na deteção do cancro gastrointestinal. Apesar das vantagens associadas com a identificação do cancro gastrointestinal, esses sistemas apresentam várias desvantagens relacionadas com a utilização de componentes complexos, de elevado custo e sofisticados, como por exemplo, lâmpadas de xénon, lasers, monocromadores, fibras óticas e detetores de elevada eficiência, que podem dificultar a sua ampla utilização, bem como o seu elevado valor clínico. Portanto, é de extrema importância o desenvolvimento de um microssistema de baixo custo, miniaturizado e minimamente invasivo para a extração de sinais de espetroscopia. Assim, neste trabalho é proposta a implementação de um microssistema, num único chip, compreendendo: um sistema de filtros óticos para a seleção dos sinais de refletância difusa e de fluorescência em bandas espetrais relevantes; uma matriz de fotodíodos de silício (4×4) e a respetiva eletrónica de leitura; e díodos emissores de luz miniaturizados. As principais aplicações deste microssistema são: a sua utilização como sistema portátil numa sala de cirurgia para inspeção da remoção total do tecido maligno ou displásico; ou a sua integração com os sistemas de endoscopia e colonoscopia, servindo como auxiliar de diagnóstico, na deteção precoce de cancro gastrointestinal. Com a realização desta tese foram dados passos importantes para a implementação desse microssistema. Numa primeira fase, foram realizados testes experimentais, com um grupo de fantomas representativos das propriedades de absorção, difusão e de fluorescência dos tecidos gastrointestinais (contendo hemoglobina, microesferas de polistireno representando as fibras de colagénio, e os fluoróforos NADH e Carbostyril 124, este último para representar o colagénio), de forma a obter os espetros típicos de refletância difusa e de fluorescência e a influência da temperatura do fantoma nos mesmos. Para além disso, a viabilidade de usar apenas 16 bandas espetrais (entre 350 e 750 nm) para a extração dos sinais espetroscópicos foi discutida, provando a exequibilidade da implementação de um sistema de filtros óticos no microssistema final. Assim, foram desenhados, fabricados e caracterizados 16 filtros óticos baseados em filmes finos de MgO/TiO2 e SiO2/TiO2. A sua caracterização do ponto de vista da transmitância ótica, seletividade, profilometria e microscopia eletrónica de varrimento, permitiu perceber os desvios verificados entre as características simuladas e as obtidas experimentalmente. Para além disso, os resultados da caracterização dos filtros óticos mostraram transmitâncias óticas que variam entre 50% e 90%, aproximadamente, e uma largura a meia-altura (FWHM) média entre 11 nm e 20 nm, o que é adequado para a aplicação pretendida. Os filtros óticos fabricados possuem alguns desvios das suas características simuladas, o que pode ser explicado pela complexidade no projeto de filtros óticos, por exemplo, a dependência dos índices de refração com o comprimento de onda e espessura do filme fino. Os sinais de refletância difusa e fluorescência que atravessam os filtros óticos podem ser medidos através de uma matriz de fotodetetores de silício (4×4), baseada em fotodíodos do tipo n+/p-epilayer com uma área ativa de 100 × 100 µm2, e um conversor luz-frequência, um por cada fotodíodo, que permite produzir um sinal digital com uma frequência proporcional à corrente gerada pelo fotodíodo. Assim, o projeto e a implementação de um microssistema CMOS incluindo esses componentes foram executados. A caracterização dos fotodíodos da matriz resultou num valor de responsividade de 200 mA/W a 550 nm, aproximadamente, e a do conversor luz-frequência, quando ligado a um fotodíodo, resultou numa resposta linear (R2>0.99) com uma sensibilidade de 25 Hz/nA a 550 nm, aproximadamente. O comportamento do conversor corrente-frequência, com uma fonte de corrente externa diretamente injetada na sua entrada, foi também estudado, permitindo confirmar a sua linearidade na gama de correntes envolvidas nesta aplicação, a sua potência de consumo de 1 mW, e a sua corrente de entrada máxima, aproximadamente 300 µA. Esta abordagem em tecnologia CMOS evita a utilização de um microssistema ótico de leitura de elevado custo, uma vez que torna possível a integração dos fotodíodos e respetiva eletrónica de leitura numa área de silício pequena (275 × 100 µm2 por fotodíodo e respetivo conversor). Foi avaliado o desempenho do microssistema implementado e dos filtros óticos fabricados usando fantomas (mais uma vez contendo hemoglobina, microesferas de polistireno, NADH e Carbostyril 124). Os resultados obtidos provaram a viabilidade do microssistema (incluindo o sistema de filtros óticos) para a extração de sinais de refletância difusa e de fluorescência. Foram notados alguns problemas na sensibilidade dos setups óticos implementados para as medições on-chip. No entanto, foram também propostas algumas soluções para os respetivos problemas, especificamente o uso futuro de díodos emissores de luz miniaturizados e a deposição direta dos filtros óticos no sistema de fotodeteção. Finalmente, a integração dos filtros óticos depositados diretamente em cima dos fotodíodos foi discutida e uma nova abordagem foi testada

CMOS and MEMS Based Microsystems for Manipulation and Detection of Magnetic Beads for Biomedical Applications

RÉSUMÉ Les micro et nano billes magnétiques dédiées à l'étiquetage des bio-particules attirent de plus en plus d'intérêt dans de nombreuses applications environnementales et sanitaires, tels que l'analyse de gènes, le transport des médicaments, la purification et l'immunologie. Les dimensions réduites et la haute sensibilité des billes magnétiques rendent leurs manipulations à haute précision possibles. Leur simplicité de suivi dans le milieu biologique et leur biocompatibilité permettent d’effectuer des détections rapides et à haute sensibilité pour des applications in vivo et in vitro. L'utilisation traditionnelle des billes magnétiques prend place dans un laboratoire se servant du matériel encombrant et dispendieux. Avec le développement de la technologie de microfabrication, des billes magnétiques peuvent être traitées dans un microsystème, plus précisément, dans une structure laboratoire sur puce (LoC). La combinaison microfluidique et microélectronique offre des possibilités d’autoévaluation, ce qui peut augmenter l'efficacité du travail. Cette thèse est orientée vers de nouvelles approches pour la manipulation et la détection de bio-particules se servant de la technologie de microsystèmes basées sur des structures microelectroniques et microfluidiques et en utilisant des marqueurs de billes magnétiques. Basé sur un réseau de microbobines à la fois comme une source de champ magnétique et un capteur inductif, le microsystème proposé est réalisé grâce à l'efficacité de fabrication de structures CMOS-MEMS, ainsi que des circuits intégrés dédiés CMOS de haute performance afin d'obtenir un rendement élevé de manipulation et de détection de billes magnétiques. Plusieurs défis ont été analysés dans la mise en œuvre de ces microsystèmes et des solutions correspondantes fournies. Plus précisément, la conception et la mise en œuvre d'une plate-forme contrôlée en température en format portable sont d'abord présentées, dans un effort réalisé pour résoudre la question de la chaleur par effet Joule lors de l'application du réseau de microbobines comme une source de champ magnétique dédié à la manipulation de billes magnétiques. Une plateforme similaire à cette dernière a été améliorée pour effectuer une analyse magnétique immunologique, en ajoutant des circuits de détection par des billes magnétiques. De plus, des IgG et anti-IgG de souris ont été utilisés dans des expériences pour vérifier les performances de détection de la plateforme de microsystème proposé.----------ABSTRACT Magnetic micro/nano beads as labels of bio-particles have been attracting more and more interest in many environmental and health applications, such as gene and drug delivery, purification, and immunoassay. The miniature size and high sensitivity of magnetic bead allow accurate manipulation, whereas its high distinguishability from biological background and biocompatibility make fast and high sensitivity detection possible for in vitro and in vivo applications. Traditional employment of magnetic beads is done in laboratory environment with the assist of bulky and expensive equipment. Thanks to the development of microfabrication technology, magnetic beads therefore can be handled on a microsystem, more specifically, a Lab-on-Chip (LoC). The combination of microfluidics with microelectronics offers the possibility of automatic analyses, which can liberate the labor and increase the efficiency.This thesis focuses on new approaches for bio-particles manipulation and detection on microelectronic/microfluidic hybrid microsystems using magnetic beads as labels. Based on planar microcoil array as both magnetic field source and the front-end inductive sensor, the proposed microsystems can take advantage of the massive producible CMOS/MEMS fabrication process, as well as the customized high performance CMOS circuits, to achieve a high efficient magnetic beads manipulation and a quantitative detection. Several challenges in implementing such microsystems are analyzed and corresponding solutions are provided. Specifically, the design and implementation of a temperature controllable LoC platform in portable format is firstly presented, for the sake of resolving the Joule heat issue when applying microcoil array as magnetic field source in magnetic beads manipulation. The similar platform is then improved to be used for magnetic immunoassay, by adding magnetic beads sensing circuits. Mouse IgG and anti-mouse IgG are employed in experiments to verify the detection performance of the proposed microsystem platform. Additionally, a fully integrated silicon substrate MEMS chip which integrates both microfluidic channel and microcoil array on a single chip is designed and fabricated following the Finite Element Analysis (FEA) simulation results and tested using bio-particles attached magnetic beads. This monolithic chip has the potential to be applied for in vivo applications