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

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

Engineering of plasmonic excitations for hand-held and ultra-sensitive biosensors

Thesis (Ph.D.)--Boston UniversityEarly detection and effective diagnosis are important for disease screening and preventing epidemics. Recently, optical biosensors have attracted significant attention, as they are very powerful detection and analysis tools that have variety of applications in homeland security, public and global healthcare, biomedical research and pharmacology. However, most of these biosensors are time-consuming, require costly chemical procedures and bulky instrumentation, and need advanced medical infrastructures with trained laboratory professionals. In order to address these needs, recently lensfree computational on-chip imaging techniques have been introduced to eliminate the need for bulky and costly optical components. However, this technology is limited by the size of the analytes as it uses a lensfree computational technique insufficient for detecting biomolecules down to nm-scale. In order to provide highly sensitive and massively multiplexed detection of biomolecular binding events, fluorescent imaging and surface plasmon resonance (SPR) based platforms are the most favored. However, SPR sensors are limited due to the alignment sensitive prism coupling scheme and bulky instrumentation while the fluorescence imaging suffers from quantitative and qualitative drawbacks of the labeling steps. This thesis focuses on the unique integration of lensfree telemedicine technology and nanostructured plasmonic chip technology to realize ultra-sensitive and label-free biosensing in a high-throughput and massively multiplexed manner for field-settings. Toward this aim, we introduce a handheld on-chip biosensing technology that employs plasmonic microarrays coupled with a lensfree computational imaging system. Employing a sensitive plasmonic array design that is combined with lensfree computational imaging, we demonstrate label-free and quantitative detection of biomolecules with a protein layer thickness down to 3 nm. Integrating large-scale plasmonic microarrays, our platform enables the simultaneous detection of protein mono- and bilayers on the same platform over a wide range of biomolecule concentrations. In this plasmonic device, we also monitor binding dynamics of protein complexes as a function of time by integrating it with microfluidics. Plasmonic antennas utilized in our lensfree platform, supporting very sharp and sensitive spectral feature as well as easily accessible large local electromagnetic fields, are highly advantageous for biosensing applications as they enable stronger interaction between surface waves and biological molecules on the sensing chip

Silicon-Based Integrated Label-Free Optofluidic Biosensors: Latest Advances and Roadmap

By virtue of the well-developed micro- and nanofabrication technologies and rapidly progressing surface functionalization strategies, silicon-based devices have been widely recognized as a highly promising platform for the next-generation lab-on-a-chip bioanalytical systems with a great potential for point-of-care medical diagnostics. Herein, an overview of the latest advances in silicon-based integrated optofluidic label-free biosensing technologies relying on the efficient interactions between the evanescent light field at the functionalized surface and specifically bound analytes is presented. State-of-the-art technologies demonstrating label-free evanescent wave-based biomarker detection mainly encompass three device configurations, including on-chip waveguide-based interferometers, microring resonators, and photonic-crystal-based cavities. Moreover, up-to-date strategies for elevating the sensitivities and also simplifying the sensing processes are discussed. Emerging laboratory prototypes with advanced integration and packaging schemes incorporating automatic microfluidic components or on-chip optoelectronic devices lead to one significant step forward in real applications of decentralized diagnostics. Besides, particular attention is paid to currently commercialized label-free optical bioanalytical models on the market. Finally, the prospects are elaborated with several research routes toward chip-scale, low-cost, highly sensitive, multi-functional, and user-friendly bioanalytical systems benefiting to global healthcare. © 2020 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinhei

The Boston University Photonics Center annual report 2015-2016

This repository item contains an annual report that summarizes activities of the Boston University Photonics Center in the 2015-2016 academic year. The report provides quantitative and descriptive information regarding photonics programs in education, interdisciplinary research, business innovation, and technology development. The Boston University Photonics Center (BUPC) is an interdisciplinary hub for education, research, scholarship, innovation, and technology development associated with practical uses of light.This has been a good year for the Photonics Center. In the following pages, you will see that this year the Center’s faculty received prodigious honors and awards, generated more than 100 notable scholarly publications in the leading journals in our field, and attracted $18.9M in new research grants/contracts. Faculty and staff also expanded their efforts in education and training, and cooperated in supporting National Science Foundation sponsored Sites for Research Experiences for Undergraduates and for Research Experiences for Teachers. As a community, we emphasized the theme of “Frontiers in Plasmonics as Enabling Science in Photonics and Beyond” at our annual symposium, hosted by Bjoern Reinhard. We continued to support the National Photonics Initiative, and contributed as a cooperating site in the American Institute for Manufacturing Integrated Photonics (AIM Photonics) which began this year as a new photonics-themed node in the National Network of Manufacturing Institutes. Highlights of our research achievements for the year include an ambitious new DoD-sponsored grant for Development of Less Toxic Treatment Strategies for Metastatic and Drug Resistant Breast Cancer Using Noninvasive Optical Monitoring led by Professor Darren Roblyer, continued support of our NIH-sponsored, Center for Innovation in Point of Care Technologies for the Future of Cancer Care led by Professor Cathy Klapperich, and an exciting confluence of new grant awards in the area of Neurophotonics led by Professors Christopher Gabel, Timothy Gardner, Xue Han, Jerome Mertz, Siddharth Ramachandran, Jason Ritt, and John White. Neurophotonics is fast becoming a leading area of strength of the Photonics Center. The Industry/University Collaborative Research Center, which has become the centerpiece of our translational biophotonics program, continues to focus onadvancing the health care and medical device industries, and has entered its sixth year of operation with a strong record of achievement and with the support of an enthusiastic industrial membership base

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

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

Dual-Mode Electro-Optical Techniques for Biosensing Applications : A Review

The monitoring of biomolecular interactions is a key requirement for the study of complex biological processes and the diagnosis of disease. Technologies that are capable of providing label-free, real-time insight into these interactions are of great value for the scientific and clinical communities. Greater understanding of biomolecular interactions alongside increased detection accuracy can be achieved using technology that can provide parallel information about multiple parameters of a single biomolecular process. For example, electro-optical techniques combine optical and electrochemical information to provide more accurate and detailed measurements that provide unique insights into molecular structure and function. Here, we present a comparison of the main methods for electro-optical biosensing, namely, electrochemical surface plasmon resonance (EC-SPR), electrochemical optical waveguide lightmode spectroscopy (EC-OWLS), and the recently reported silicon-based electrophotonic approach. The comparison considers different application spaces, such as the detection of low concentrations of biomolecules, integration, the tailoring of light-matter interaction for the understanding of biomolecular processes, and 2D imaging of biointeractions on a surface

Phase-sensitive plasmonic biosensor using a portable and large field-of-view interferometric microarray imager

Nanophotonics, and more specifically plasmonics, provides a rich toolbox for biomolecular sensing, since the engineered metasurfaces can enhance light–matter interactions to unprecedented levels. So far, biosensing associated with high-quality factor plasmonic resonances has almost exclusively relied on detection of spectral shifts and their associated intensity changes. However, the phase response of the plasmonic resonances have rarely been exploited, mainly because this requires a more sophisticated optical arrangement. Here we present a new phase-sensitive platform for high-throughput and label-free biosensing enhanced by plasmonics. It employs specifically designed Au nanohole arrays and a large field-of-view interferometric lens-free imaging reader operating in a collinear optical path configuration. This unique combination allows the detection of atomically thin (angstrom-level) topographical features over large areas, enabling simultaneous reading of thousands of microarray elements. As the plasmonic chips are fabricated using scalable techniques and the imaging reader is built with low-cost off-the-shelf consumer electronic and optical components, the proposed platform is ideal for point-of-care ultrasensitive biomarker detection from small sample volumes. Our research opens new horizons for on-site disease diagnostics and remote health monitoring.Peer ReviewedPostprint (published version