Optical Microresonators for Sensing and Transduction: A Materials Perspective

Optical microresonators confine light to a particular microscale trajectory, are exquisitely sensitive to their microenvironment, and offer convenient readout of their optical properties. Taken together, this is an immensely attractive combination that makes optical microresonators highly effective as sensors and transducers. Meanwhile, advances in material science, fabrication techniques, and photonic sensing strategies endow optical microresonators with new functionalities, unique transduction mechanisms, and in some cases, unparalleled sensitivities. In this progress report, the operating principles of these sensors are reviewed, and different methods of signal transduction are evaluated. Examples are shown of how choice of materials must be suited to the analyte, and how innovations in fabrication and sensing are coupled together in a mutually reinforcing cycle. A tremendously broad range of capabilities of microresonator sensors is described, from electric and magnetic field sensing to mechanical sensing, from single‐molecule detection to imaging and spectroscopy, from operation at high vacuum to in live cells. Emerging sensing capabilities are highlighted and put into context in the field. Future directions are imagined, where the diverse capabilities laid out are combined and advances in scalability and integration are implemented, leading to the creation of a sensor unparalleled in sensitivity and information content.     

Label‐Free Optofluidic Nanobiosensor Enables Real‐Time Analysis of Single‐Cell Cytokine Secretion

Single‐cell analysis of cytokine secretion is essential to understand the heterogeneity of cellular functionalities and develop novel therapies for multiple diseases. Unraveling the dynamic secretion process at single‐cell resolution reveals the real‐time functional status of individual cells. Fluorescent and colorimetric‐based methodologies require tedious molecular labeling that brings inevitable interferences with cell integrity and compromises the temporal resolution. An innovative label‐free optofluidic nanoplasmonic biosensor is introduced for single‐cell analysis in real time. The nanobiosensor incorporates a novel design of a multifunctional microfluidic system with small volume microchamber and regulation channels for reliable monitoring of cytokine secretion from individual cells for hours. Different interleukin‐2 secretion profiles are detected and distinguished from single lymphoma cells. The sensor configuration combined with optical spectroscopic imaging further allows us to determine the spatial single‐cell secretion fingerprints in real time. This new biosensor system is anticipated to be a powerful tool to characterize single‐cell signaling for basic and clinical research.     

Reduced Graphene Oxide‐Functionalized High Electron Mobility Transistors for Novel Recognition Pattern Label‐Free DNA Sensors

We designed and constructed reduced graphene oxide (rGO) functionalized high electron mobility transistor (HEMT) for rapid and ultra‐sensitive detection of label‐free DNA in real time. The micrometer sized rGO sheets with structural defects helped absorb DNA molecules providing a facile and robust approach to functionalization. DNA was immobilized onto the surface of HEMT gate through rGO functionalization, and changed the conductivity of HEMT. The real time monitor and detection of DNA hybridization by rGO functionalized HEMT presented interesting current responses: a “two steps” signal enhancement in the presence of target DNA; and a “one step” signaling with random DNA. These two different recognition patterns made the HEMT capable of specifically detecting target DNA sequence. The working principle of the rGO functionalized HEMT can be demonstrated as the variation of the ambience charge distribution. Furthermore, the as constructed DNA sensors showed excellent sensitivity of detect limit at 0.07 fM with linear detect range from 0.1 fM to 0.1 pM. The results indicated that the HEMT functionalized with rGO paves a new avenue to design novel electronic devices for high sensitive and specific genetic material assays in biomedical applications.     

CMOS‐Compatible Silicon Nanowire Field‐Effect Transistors for Ultrasensitive and Label‐Free MicroRNAs Sensing

MicroRNAs (miRNAs) have been regarded as promising biomarkers for the diagnosis and prognosis of early‐stage cancer as their expression levels are associated with different types of human cancers. However, it is a challenge to produce low‐cost miRNA sensors, as well as retain a high sensitivity, both of which are essential factors that must be considered in fabricating nanoscale biosensors and in future biomedical applications. To address such challenges, we develop a complementary metal oxide semiconductor (CMOS)‐compatible SiNW‐FET biosensor fabricated by an anisotropic wet etching technology with self‐limitation which provides a much lower manufacturing cost and an ultrahigh sensitivity. This nanosensor shows a rapid (< 1 minute) detection of miR‐21 and miR‐205, with a low limit of detection (LOD) of 1 zeptomole (ca. 600 copies), as well as an excellent discrimination for single‐nucleotide mismatched sequences of tumor‐associated miRNAs. To investigate its applicability in real settings, we have detected miRNAs in total RNA extracted from lung cancer cells as well as human serum samples using the nanosensors, which demonstrates their potential use in identifying clinical samples for early diagnosis of cancer.     

Antibody‐Mimetic Peptoid Nanosheet for Label‐Free Serum‐Based Diagnosis of Alzheimer's Disease

Alzheimer's disease (AD) is the most common form of dementia characterized by progressive cognitive decline. Current diagnosis of AD is based on symptoms, neuropsychological tests, and neuroimaging, and is usually evident years after the pathological process. Early assessment at the preclinical or prodromal stage is in a great demand since treatment after the onset can hardly stop or reverse the disease progress. However, early diagnosis of AD is challenging due to the lack of reliable noninvasive approaches. Here, an antibody‐mimetic self‐assembling peptoid nanosheet containing surface‐exposed Aβ42‐recognizing loops is constructed, and a label‐free sensor for the detection of AD serum is developed. The loop‐displaying peptoid nanosheet is demonstrated to have high affinity to serum Aβ42, and to be able to identify AD sera with high sensitivity. The dense distribution of molecular recognition loops on the robust peptoid nanosheet scaffold not only mimics the architecture of antibodies, but also reduces the nonspecific binding in detecting multicomponent samples. This antibody‐mimetic 2D material holds great potential toward the blood‐based diagnosis of AD, and meanwhile provides novel insights into the antibody alternative engineering and the universal application in biological and chemical sensors.     

Plasmonic‐Nanopore Biosensors for Superior Single‐Molecule Detection

Plasmonic and nanopore sensors have separately received much attention for achieving single‐molecule precision. A plasmonic “hotspot” confines and enhances optical excitation at the nanometer length scale sufficient to optically detect surface–analyte interactions. A nanopore biosensor actively funnels and threads analytes through a molecular‐scale aperture, wherein they are interrogated by electrical or optical means. Recently, solid‐state plasmonic and nanopore structures have been integrated within monolithic devices that address fundamental challenges in each of the individual sensing methods and offer complimentary improvements in overall single‐molecule sensitivity, detection rates, dwell time and scalability. Here, the physical phenomena and sensing principles of plasmonic and nanopore sensing are summarized to highlight the novel complementarity in dovetailing these techniques for vastly improved single‐molecule sensing. A literature review of recent plasmonic nanopore devices is then presented to delineate methods for solid‐state fabrication of a range of hybrid device formats, evaluate the progress and challenges in the detection of unlabeled and labeled analyte, and assess the impact and utility of localized plasmonic heating. Finally, future directions and applications inspired by the present state of the art are discussed.     

Design of Hierarchical Beads for Efficient Label‐Free Cell Capture

Defined hierarchical materials promise cell analysis and call for application‐driven design in practical use. The further issue is to develop advanced materials and devices for efficient label‐free cell capture with minimum instrumentation. Herein, the design of hierarchical beads is reported for efficient label‐free cell capture. Silica nanoparticles (size of ≈15 nm) are coated onto silica spheres (size of ≈200 nm) to achieve nanoscale surface roughness, and then the rough silica spheres are combined with microbeads (≈150–1000 µm in diameter) to assemble hierarchical structures. These hierarchical beads are built via electrostatic interaction, covalent bonding, and nanoparticle adherence. Further, after functionalization by hyaluronic acid (HA), the hierarchical beads display desirable surface hydrophilicity, biocompatibility, and chemical/structural stability. Due to the controlled surface topology and chemistry, HA‐functionalized hierarchical beads afford high cell capture efficiency up to 98.7% in a facile label‐free manner. This work guides the development of label‐free cell capture techniques and contributes to the construction of smart interfaces in bio‐systems.     

Hyperboloid‐Drum Microdisk Laser Biosensors for Ultrasensitive Detection of Human IgG

Whispering gallery mode (WGM) microresonators have been used as optical sensors in fundamental research and practical applications. The majority of WGM sensors are passive resonators that require complex systems, thereby limiting their practicality. Active resonators enable the remote excitation and collection of WGM‐modulated fluorescence spectra, without requiring complex systems, and can be used as alternatives to passive microresonators. This paper demonstrates an active microresonator, which is a microdisk laser in a hyperboloid‐drum (HD) shape. The HD microdisk lasers are a combination of a rhodamine B‐doped photoresist and a silica microdisk. These HD microdisk lasers can be utilized for the detection of label‐free biomolecules. The biomolecule concentration can be as low as 1 ag mL^?1, whereas the theoretical detection limit of the biosensor for human IgG in phosphate buffer saline is 9 ag mL^?1 (0.06 a_M). Additionally, the biosensors are able to detect biomolecules in an artificial serum, with a theoretical detection limit of 9 ag mL^?1 (0.06 a_M). These results are approximately four orders of magnitude more sensitive than those for the typical active WGM biosensors. The proposed HD microdisk laser biosensors show enormous detection potential for biomarkers in protein secretions or body fluids.     

Nano Assessing Nano: Nanosensor‐Enabled Detection of Cell Phenotypic Changes Identifies Nanoparticle Toxicological Effects at Ultra‐Low Exposure Levels

Industrial use of nanomaterials is rapidly increasing, making the effects of these materials on the environment and human health of critical concern. Standard nanotoxicity evaluation methods rely on detecting cell death or major dysfunction and will miss early signs of toxicity. In this work, the use of rapid and sensitive nanosensors that can efficiently detect subtle phenotypic changes on the cell surface following nanomaterial exposure is reported. Importantly, the method reveals significant phenotypic changes at dosages where other conventional methods show normal cellular activity. This approach holds promise in toxicological and pharmacological evaluations to ensure safer and better use of nanomaterials.