685 research outputs found

    On-chip biosensing platforms based on gold and silicon optical nano-resonators

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    Point-of-care (POC) devices are compact, mobile and fast detection platforms expected to advance early diagnosis, treatment monitoring and personalized healthcare, and revolutionize today’s healthcare system, especially in remote areas. The need for POC devices strongly drives the development of novel biosensor technology. Building a small, fast, simple, and sensitive platform for biomolecule detection is a challenge that relies on the integration of multiple fields of expertise and engineering. Optical nanoresonators have shown great promise as label-free biosensors because of direct light coupling and sub-wavelength sensing modes. Metallic nanoresonators with localized surface plasmon resonances (LSPR) are already well studied and were proven a solid alternative to the commercialized surface plasmon resonance (SPR) sensors. More recently, dielectric nanoresonators have also gained traction due to the reduced losses and the ability to manipulate both the electric and magnetic components of the incident light. In this thesis, we advance the field of biosensing and use optical nanoresonators as operative platforms relevant for disease diagnosis and treatment monitoring. By combining different optimized optical nanoresonators, both metallic and dielectric, with state-of-the-art microfluidics and surface chemistry, we have developed and tested several detection platforms. We first focused on developing a microfluidic lab-on-chip device for multiplexed biosensing utilizing the LSPR of gold nanoresonator arrays. By simultaneously tracking the extinction of 32 sensor arrays, we demonstrated multiplexed quantitative detection of four breast cancer markers in human serum. We showed that with well-optimized immunoassays, a low limit of detection (LOD) can be reached, paving the way towards clinically-relevant POC devices. Additionally, we implemented silicon nanoresonators supporting Mie resonances into functional and clinically-relevant applications. By integrating several arrays of Si nanoresonators with state-of-the-art microfluidics, we demonstrated their ability to detect cancer markers in human serum with high sensitivity and high specificity. Furthermore, we showed that the fabrication of Si nanoresonator array using low cost and scalable projection lithography leads to sufficiently low limits of detection, while enabling cheaper and faster sensor production for future POC applications. We also investigated the respective role of electric and magnetic dipole resonances and showed that they are associated with two different transduction mechanisms: resonance redshift and extinction decrease. Our work advances the development of future point-of-care sensing platforms for fast and low cost health monitoring at the molecular scale.La instrumentación Point-of-care (POC) es compacta, móvil y permite una detección rápida, razón por la que se prevé que sean de gran ayuda en áreas como el diagnostico precoz, la monitorización de tratamientos y la medicina personalizada, revolucionando los modelos sanitarios, especialmente en las zonas de difícil acceso y con menos recursos. La necesidad de este tipo de dispositivos impulsa el desarrollo de novedosas tecnologías en el campo de los bio-sensores. Diseñar equipos para la detección de bio-moléculas que sean rápidos, pequeños y sencillos es un reto que requiere la integración de múltiples campos de la ciencia y la ingeniería. Los nano-resonadores ópticos muestran un gran potencial como bio-sensores sin necesidad de marcaje, gracias a su capacidad de acoplase directamente con la luz en modos menores que la longitud de onda. Los nano-resonadores metálicos basados en resonancias plasmónicas superficiales localizadas (LSPR) han sido estudiados y han demostrado ser una firme alternativa a los ya comerciales basados en resonancias plasmónicas superficiales (SPR). Los nano-resonadores dieléctricos han sido recientemente objeto de atención debido a sus bajas perdidas y la capacidad de manipular los componentes eléctricos y magnéticos de la luz. En esta tesis presentamos avances en el campo de la bio-detección y en el uso de los nano-resonadores ópticos como potenciales herramientas para la detección de enfermedades y monitorización de los tratamientos. Hemos desarrollado y evaluado distintas plataformas de detección combinando los nano-resonadores ópticos, tanto metálicos como dieléctricos, con las más avanzadas técnicas de microfluídica y química de superficies. En primer lugar, nos centramos en el desarrollo de un dispositivo microfluídico basado en sensores LSPR de oro que permite multiplexar 32 canales. Los 32 sensores se monitorizan en tiempo real para demostrar la cuantificación de 4 marcadores de cáncer de mama en suero sanguíneo humano. Demostramos que mediante la optimización de los ensayos se pueden alcanzar bajos límites de detección (LOD), lo que allana el camino hacia dispositivos POC de uso clínico. Por otro lado, hemos utilizado los nano-resonadores de silicio integrados con la microfluídica para también detectar marcadores de cáncer en suero. Estos sensores, cuyo principio de funcionamiento se basa en resonancias de MIE, han demostrado ser una alternativa razonable a los sensores de oro. Además, demostramos que un proceso de fabricación de nano-resonadores de silicio rápido, escalable y de bajo coste da lugar a límites de detección suficientes para la producción de futuras POC. También realizamos un minucioso estudio del rol de las resonancias eléctricas y magnéticas en dichos sensores y su relación con el desplazamiento y el cambio magnitud de la resonancia del sensor global. Nuestro trabajo es un avance en el desarrollo de futuros instrumentos POC rápidos y baratos en el ámbito de la salud a escala molecular.Postprint (published version

    Giant Magnetoresistive Biosensors for Time-Domain Magnetorelaxometry: A Theoretical Investigation and Progress Toward an Immunoassay.

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    Magnetorelaxometry (MRX) is a promising new biosensing technique for point-of-care diagnostics. Historically, magnetic sensors have been primarily used to monitor the stray field of magnetic nanoparticles bound to analytes of interest for immunoassays and flow cytometers. In MRX, the magnetic nanoparticles (MNPs) are first magnetized and then the temporal response is monitored after removing the magnetic field. This new sensing modality is insensitive to the magnetic field homogeneity making it more amenable to low-power portable applications. In this work, we systematically investigated time-domain MRX by measuring the signal dependence on the applied field, magnetization time, and magnetic core size. The extracted characteristic times varied for different magnetic MNPs, exhibiting unique magnetic signatures. We also measured the signal contribution based on the MNP location and correlated the coverage with measured signal amplitude. Lastly, we demonstrated, for the first time, a GMR-based time-domain MRX bioassay. This approach validates the feasibility of immunoassays using GMR-based MRX and provides an alternative platform for point-of-care diagnostics

    Optical Quartz Crystal Microbalance (OQCM) for Dual-Mode Analysis

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    Label-free biosensors allow for real-time measurements of the target molecule, providing valuable kinetic data about the unperturbed biological system. Yet, they generally rely on a single transduction mechanism that reflects a single aspect of a system. In order to have a more complete understanding of the system, many aspects of the system need to be examined simultaneously. An integrated multi-mode label-free sensor capable of providing consistent and complementary information about multiple aspects of a system is highly desirable for biomedical research. Currently there are some hybrid sensors utilizing the optical and quartz crystal microbalance (QCM) techniques to measure both the optical and mechanical properties of a system. However, those hybrid sensors have some shortcomings in implementation and performance that limit their applicability. In this research, we developed Optical Quartz Crystal Microbalance (OQCM) sensors - hybrid sensors utilizing the same techniques for simultaneously measuring both optical and mechanical properties, which also address these shortcomings. Two OQCM structures were designed, fabricated and explored. The first structure is an interferometric OQCM sensor (I-OQCM) with a multilayer planar optical structure. The interference between reflections at the interfaces between layers generates an interference pattern in the optical spectrum that shifts upon accumulation of additional films on the structure. The second structure is a plasmonically-enhanced grating OQCM sensor (PEG-OQCM). The theory and simulation analyses indicate that the PEG-OQCM can achieve near zero bulk refractive index sensitivity by optimizing the incidence angle. Simulation results show that at an incident angle of 47 degrees, the bulk RI sensitivity becomes near zero around bulk RI = 1.33. Experimental results for vapor deposition, water and biosensing (solution of streptavidin) match well with the simulation results. With this PEG-OQCM structure, an optical linewidth of 25 nm was obtained in air, 15 nm in water – up to 6 times narrower than that of SPR/LSPR (50-100 nm in water). The OQCMs were characterized separately to demonstrate the operation in each mode for each structure, and tests were performed to show biosensing capability. Dual-mode tests were conducted for both the I-OQCM and PEG-OQCM to show the capability of simultaneous measurement of both optical and mechanical properties and responses of a system. The test results validate the simulation analyses and correlation between the optical and mechanical responses that would provide corroborating information for more reliable, robust cross-examination/confirmation for the evaluation of test systems. The OQCM-A sensor with 3 single I-OQCM sensors on a single wafer was also designed, fabricated. Each I-OQCM sensor can be characterized independently of the others. Mechanical response tests performed on the OQCM-A indicate that each sensor responds independently of the other sensors and the cross-talk between on adjacent sensors is negligible.PHDElectrical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/143989/1/zvzhang_1.pd

    Electromagnetic Field Manipulation: Biosensing to Antennas

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    We will explore how understanding and controlling electromagnetic fields can provide significant impact across a multitude of applications throughout the whole frequency spectrum from DC to daylight. Starting from the DC end of the electromagnetic spectrum, we motivate the design of a new integrated magnetic biosensing design as well as various improvements to the initial design based on spatial and temporal manipulations of the magnetic fields. Next, we look into the RF domain and develop maximal performance bounds for antennas and other electromagnetic structures. We develop rapid simulation techniques which when coupled with heuristic optimization algorithms can quickly and effectively produce new antenna structures with little to no manual intervention. We demonstrate the efficacy of these techniques in the context of on-chip antenna designs and a 3D printed coupling antenna for a dielectric waveguide communication link. We present the design of a 120GHz dual-channel 100Gbps QPSK/64QAM transceiver IC developed in a standard 28nm bulk CMOS process. Finally, we explore the higher THz regime in the context of photonic device optimization. We optimize compact photonic multiplexer devices which are fabricated in a standard foundry process and evaluate their performance against simulation results

    Ultrafast Microfluidic Immunoassays Towards Real-time Intervention of Cytokine Storms

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    Biomarker-guided precision medicine holds great promise to provide personalized therapy with a good understanding of the molecular or cellular data of an individual patient. However, implementing this approach in critical care uniquely faces enormous challenges as it requires obtaining “real-time” data with high sensitivity, reliability, and multiplex capacity near the patient’s bedside in the quickly evolving illness. Current immunodiagnostic platforms generally compromise assay sensitivity and specificity for speed or face significantly increased complexity and cost for highly multiplexed detection with low sample volume. This thesis introduces two novel ultrafast immunoassay platforms: one is a machine learning-based digital molecular counting assay, and the other is a label-free nano-plasmonic sensor integrated with an electrokinetic mixer. Both of them incorporate microfluidic approaches to pave the way for near-real-time interventions of cytokine storms. In the first part of the thesis, we present an innovative concept and the theoretical study that enables ultrafast measurement of multiple protein biomarkers (<1 min assay incubation) with comparable sensitivity to the gold standard ELISA method. The approach, which we term “pre-equilibrium digital enzyme-linked immunosorbent assay” (PEdELISA) incorporates the single-molecular counting of proteins at the early, pre-equilibrium state to achieve the combination of high speed and sensitivity. We experimentally demonstrated the assay’s application in near-real-time monitoring of patients receiving chimeric antigen receptor (CAR) T-cell therapy and for longitudinal serum cytokine measurements in a mouse sepsis model. In the second part, we report the further development of a machine learning-based PEdELISA microarray data analysis approach with a significantly extended multiplex capacity using the spatial-spectral microfluidic encoding technique. This unique approach, together with a convolutional neural network-based image analysis algorithm, remarkably reduced errors faced by the highly multiplexed digital immunoassay at low analyte concentrations. As a result, we demonstrated the longitudinal data collection of 14 serum cytokines in human patients receiving CAR-T cell therapy at concentrations < 10pg/mL with a sample volume < 10 µL and 5-min assay incubation. In the third part, we demonstrate the clinical application of a machine learning-based digital protein microarray platform for rapid multiplex quantification of cytokines from critically ill COVID-19 patients admitted to the intensive care unit. The platform comprises two low-cost modules: (i) a semi-automated fluidic dispensing module that can be operated inside a biosafety cabinet to minimize the exposure of technician to the virus infection and (ii) a compact fluorescence optical scanner for the potential near-bedside readout. The automated system has achieved high interassay precision (~10% CV) with high sensitivity (<0.4pg/mL). Our data revealed large subject-to-subject variability in patient responses to anti-inflammatory treatment for COVID-19, reaffirming the need for a personalized strategy guided by rapid cytokine assays. Lastly, an AC electroosmosis-enhanced localized surface plasmon resonance (ACE-LSPR) biosensing device was presented for rapid analysis of cytokine IL-1β among sepsis patients. The ACE-LSPR device is constructed using both bottom-up and top-down sensor fabrication methods, allowing the seamless integration of antibody-conjugated gold nanorod (AuNR) biosensor arrays with microelectrodes on the same microfluidic platform. Applying an AC voltage to microelectrodes while scanning the scattering light intensity variation of the AuNR biosensors results in significantly enhanced biosensing performance. The technologies developed have enabled new capabilities with broad application to advance precision medicine of life-threatening acute illnesses in critical care, which potentially will allow the clinical team to make individualized treatment decisions based on a set of time-resolved biomarker signatures.PHDMechanical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/163129/1/yujing_1.pd

    On-chip biosensing platforms based on gold and silicon optical nano-resonators

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    Point-of-care (POC) devices are compact, mobile and fast detection platforms expected to advance early diagnosis, treatment monitoring and personalized healthcare, and revolutionize today’s healthcare system, especially in remote areas. The need for POC devices strongly drives the development of novel biosensor technology. Building a small, fast, simple, and sensitive platform for biomolecule detection is a challenge that relies on the integration of multiple fields of expertise and engineering. Optical nanoresonators have shown great promise as label-free biosensors because of direct light coupling and sub-wavelength sensing modes. Metallic nanoresonators with localized surface plasmon resonances (LSPR) are already well studied and were proven a solid alternative to the commercialized surface plasmon resonance (SPR) sensors. More recently, dielectric nanoresonators have also gained traction due to the reduced losses and the ability to manipulate both the electric and magnetic components of the incident light. In this thesis, we advance the field of biosensing and use optical nanoresonators as operative platforms relevant for disease diagnosis and treatment monitoring. By combining different optimized optical nanoresonators, both metallic and dielectric, with state-of-the-art microfluidics and surface chemistry, we have developed and tested several detection platforms. We first focused on developing a microfluidic lab-on-chip device for multiplexed biosensing utilizing the LSPR of gold nanoresonator arrays. By simultaneously tracking the extinction of 32 sensor arrays, we demonstrated multiplexed quantitative detection of four breast cancer markers in human serum. We showed that with well-optimized immunoassays, a low limit of detection (LOD) can be reached, paving the way towards clinically-relevant POC devices. Additionally, we implemented silicon nanoresonators supporting Mie resonances into functional and clinically-relevant applications. By integrating several arrays of Si nanoresonators with state-of-the-art microfluidics, we demonstrated their ability to detect cancer markers in human serum with high sensitivity and high specificity. Furthermore, we showed that the fabrication of Si nanoresonator array using low cost and scalable projection lithography leads to sufficiently low limits of detection, while enabling cheaper and faster sensor production for future POC applications. We also investigated the respective role of electric and magnetic dipole resonances and showed that they are associated with two different transduction mechanisms: resonance redshift and extinction decrease. Our work advances the development of future point-of-care sensing platforms for fast and low cost health monitoring at the molecular scale.La instrumentación Point-of-care (POC) es compacta, móvil y permite una detección rápida, razón por la que se prevé que sean de gran ayuda en áreas como el diagnostico precoz, la monitorización de tratamientos y la medicina personalizada, revolucionando los modelos sanitarios, especialmente en las zonas de difícil acceso y con menos recursos. La necesidad de este tipo de dispositivos impulsa el desarrollo de novedosas tecnologías en el campo de los bio-sensores. Diseñar equipos para la detección de bio-moléculas que sean rápidos, pequeños y sencillos es un reto que requiere la integración de múltiples campos de la ciencia y la ingeniería. Los nano-resonadores ópticos muestran un gran potencial como bio-sensores sin necesidad de marcaje, gracias a su capacidad de acoplase directamente con la luz en modos menores que la longitud de onda. Los nano-resonadores metálicos basados en resonancias plasmónicas superficiales localizadas (LSPR) han sido estudiados y han demostrado ser una firme alternativa a los ya comerciales basados en resonancias plasmónicas superficiales (SPR). Los nano-resonadores dieléctricos han sido recientemente objeto de atención debido a sus bajas perdidas y la capacidad de manipular los componentes eléctricos y magnéticos de la luz. En esta tesis presentamos avances en el campo de la bio-detección y en el uso de los nano-resonadores ópticos como potenciales herramientas para la detección de enfermedades y monitorización de los tratamientos. Hemos desarrollado y evaluado distintas plataformas de detección combinando los nano-resonadores ópticos, tanto metálicos como dieléctricos, con las más avanzadas técnicas de microfluídica y química de superficies. En primer lugar, nos centramos en el desarrollo de un dispositivo microfluídico basado en sensores LSPR de oro que permite multiplexar 32 canales. Los 32 sensores se monitorizan en tiempo real para demostrar la cuantificación de 4 marcadores de cáncer de mama en suero sanguíneo humano. Demostramos que mediante la optimización de los ensayos se pueden alcanzar bajos límites de detección (LOD), lo que allana el camino hacia dispositivos POC de uso clínico. Por otro lado, hemos utilizado los nano-resonadores de silicio integrados con la microfluídica para también detectar marcadores de cáncer en suero. Estos sensores, cuyo principio de funcionamiento se basa en resonancias de MIE, han demostrado ser una alternativa razonable a los sensores de oro. Además, demostramos que un proceso de fabricación de nano-resonadores de silicio rápido, escalable y de bajo coste da lugar a límites de detección suficientes para la producción de futuras POC. También realizamos un minucioso estudio del rol de las resonancias eléctricas y magnéticas en dichos sensores y su relación con el desplazamiento y el cambio magnitud de la resonancia del sensor global. Nuestro trabajo es un avance en el desarrollo de futuros instrumentos POC rápidos y baratos en el ámbito de la salud a escala molecular

    Optofluidic plasmonic onchip nanosensor array for biodetection

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    Thesis (Ph.D.)--Boston UniversitySurface plasmon resonance (SPR) sensing has been demonstrated in the past decade to be the gold standard technique for biochemical interaction analysis, and plays an important role in drug discovery and biomedical research. The technique circumvents the need of fluorescence/radioactive tagging or enzymatic detection, enables ultrasensitive remote sensing, and quantitatively monitors bio-interaction in real time. Although SPR has these attractive features that can satisfy most research/clinic requirements, there still exist problems that limit its applications. First, the reflection geometry of the prism coupling scheme adds limitations for high throughput screening application. Additionally, SPR instrumentations are bulky and not suitable for point-of-care settings. Moreover, the SPR sensor is embedded in conventional micro-fluidic cells, in which the sensor performance is limited by inefficient analyte transport. Suspended plasmonic nanohole array (PNA) offers an opportunity to overcome these limitations. A collinear excitation/collection coupling scheme combined with the small footprint of PNA provides unique platform for multiplexing and system minimization. The suspended nanohole structure also offers a unique configuration to integrate nano-photonics with nano-fluidics. This thesis focuses on developing a lab-on-a-chip PNA platform for point-of-care bio-detection. To achieve this, we first demonstrate that the figure-of-merit of our PNA sensor surpasses that of the prism coupled SPR. We also show that the ultrasensitive label-free PNA sensor is able to directly detect intact viruses from biological media at clinically relevant concentrations with little sample preparation. We then present a plasmonic microarray with over one million PNA sensors on a microscope slide for high throughput screening applications. A dual-color filter imaging method is introduced to increase the accuracy, reliability, and signal-to-noise ratio in a highly multiplexed manner. Finally, we present a nanoplasmonic-nanofluidic platform enabling active delivery of analyte to the sensor. Sensor response time is reduced by an order of magnitude compared to the conventional flow scheme. A dynamic range spanning 5 orders of magnitude from 10^3 to 10^7 particles/mL is shown on this platform corresponding to analyte concentration sufficient for clinical applications. The proposed approach opens up opportunities of a lab-on-a-chip bio-detection system for drug screening, disease diagnostic as well as clinic studies
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