Field Effect Transistor Nanosensor for Breast Cancer Diagnostics

Silicon nanochannel field effect transistor (FET) biosensors are one of the most promising technologies in the development of highly sensitive and label-free analyte detection for cancer diagnostics. With their exceptional electrical properties and small dimensions, silicon nanochannels are ideally suited for extraordinarily high sensitivity. In fact, the high surface-to-volume ratios of these systems make single molecule detection possible. Further, FET biosensors offer the benefits of high speed, low cost, and high yield manufacturing, without sacrificing the sensitivity typical for traditional optical methods in diagnostics. Top down manufacturing methods leverage advantages in Complementary Metal Oxide Semiconductor (CMOS) technologies, making richly multiplexed sensor arrays a reality. Here, we discuss the fabrication and use of silicon nanochannel FET devices as biosensors for breast cancer diagnosis and monitoring

Biosensors for Biomolecular Computing: a Review and Future Perspectives

Biomolecular computing is the field of engineering where computation, storage, communication, and coding are obtained by exploiting interactions between biomolecules, especially DNA, RNA, and enzymes. They are a promising solution in a long-term vision, bringing huge parallelism and negligible power consumption. Despite significant efforts in taking advantage of the massive computational power of biomolecules, many issues are still open along the way for considering biomolecular circuits as an alternative or a complement to competing with complementary metal–oxide–semiconductor (CMOS) architectures. According to the Von Neumann architecture, computing systems are composed of a central processing unit, a storage unit, and input and output (I/O). I/O operations are crucial to drive and read the computing core and to interface it to other devices. In emerging technologies, the complexity overhead and the bottleneck of I/O systems are usually limiting factors. While computing units and memories based on biomolecular systems have been successfully presented in literature, the published I/O operations are still based on laboratory equipment without a real development of integrated I/O. Biosensors are suitable devices for transducing biomolecular interactions by converting them into electrical signals. In this work, we explore the latest advancements in biomolecular computing, as well as in biosensors, with focus on technology suitable to provide the required and still missing I/O devices. Therefore, our goal is to picture out the present and future perspectives about DNA, RNA, and enzymatic-based computing according to the progression in its I/O technologies, and to understand how the field of biosensors contributes to the research beyond CMOS

Magnetoresistive biosensors with on-chip pulsed excitation and magnetic correlated double sampling.

Giant magnetoresistive (GMR) sensors have been shown to be among the most sensitive biosensors reported. While high-density and scalable sensor arrays are desirable for achieving multiplex detection, scalability remains challenging because of long data acquisition time using conventional readout methods. In this paper, we present a scalable magnetoresistive biosensor array with an on-chip magnetic field generator and a high-speed data acquisition method. The on-chip field generators enable magnetic correlated double sampling (MCDS) and global chopper stabilization to suppress 1/f noise and offset. A measurement with the proposed system takes only 20 ms, approximately 50× faster than conventional frequency domain analysis. A corresponding time domain temperature correction technique is also presented and shown to be able to remove temperature dependence from the measured signal without extra measurements or reference sensors. Measurements demonstrate detection of magnetic nanoparticles (MNPs) at a signal level as low as 6.92 ppm. The small form factor enables the proposed platform to be portable as well as having high sensitivity and rapid readout, desirable features for next generation diagnostic systems, especially in point-of-care (POC) settings

Lensfree optofluidic plasmonic sensor for real-time and label-free monitoring of molecular binding events over a wide field-of-view

We demonstrate a high-throughput biosensing device that utilizes microfluidics based plasmonic microarrays incorporated with dual-color on-chip imaging toward real-time and label-free monitoring of biomolecular interactions over a wide field-of-view of >20 mm^2. Weighing 40 grams with 8.8 cm in height, this biosensor utilizes an opto-electronic imager chip to record the diffraction patterns of plasmonic nanoapertures embedded within microfluidic channels, enabling real-time analyte exchange. This plasmonic chip is simultaneously illuminated by two different light-emitting-diodes that are spectrally located at the right and left sides of the plasmonic resonance mode, yielding two different diffraction patterns for each nanoaperture array. Refractive index changes of the medium surrounding the near-field of the nanostructures, e.g., due to molecular binding events, induce a frequency shift in the plasmonic modes of the nanoaperture array, causing a signal enhancement in one of the diffraction patterns while suppressing the other. Based on ratiometric analysis of these diffraction images acquired at the detector-array, we demonstrate the proof-of-concept of this biosensor by monitoring in real-time biomolecular interactions of protein A/G with immunoglobulin G (IgG) antibody. For high-throughput on-chip fabrication of these biosensors, we also introduce a deep ultra-violet lithography technique to simultaneously pattern thousands of plasmonic arrays in a cost-effective manner

Multimodal integrated sensor platform for rapid biomarker detection

Precision metabolomics and quantification for cost-effective, rapid diagnosis of disease are key goals in personalized medicine and point-of-care testing. Presently, patients are subjected to multiple test procedures requiring large laboratory equipment. Microelectronics has already made modern computing and communications possible by integration of complex functions within a single chip. As More than Moore technology increases in importance, integrated circuits for densely patterned sensor chips have grown in significance. Here, we present a versatile single CMOS chip forming a platform to address personalized needs through on-chip multimodal optical and electrochemical detection that will reduce the number of tests that patients must take. The chip integrates interleaved sensing subsystems for quadruple-mode colorimetric, chemiluminescent, surface plasmon resonance and hydrogen ion measurements. These subsystems include a photodiode array and a single photon avalanche diode array, with some elements functionalized to introduce a surface plasmon resonance mode. The chip also includes an array of ion sensitive field effect transistors. The sensor arrays are distributed uniformly over an active area on the chip surface in a scalable and modular design. Bio-functionalization of the physical sensors yields a highly selective simultaneous multiple-assay platform in a disposable format. We demonstrate its versatile capabilities through quantified bioassays performed on-chip for glucose, cholesterol, urea and urate, each within their naturally occurring physiological range

Highly sensitive and label-free digital detection of whole cell E. coli with interferometric reflectance imaging

Bacterial infectious diseases are a major threat to human health. Timely and sensitive pathogenic bacteria detection is crucial in identifying the bacterial contaminations and preventing the spread of infectious diseases. Due to limitations of conventional bacteria detection techniques there have been concerted research efforts towards development of new biosensors. Biosensors offering label free, whole bacteria detection are highly desirable over those relying on label based or pathogenic molecular components detection. The major advantage is eliminating the additional time and cost required for labeling or extracting the desired bacterial components. Here, we demonstrate rapid, sensitive and label free E. coli detection utilizing interferometric reflectance imaging enhancement allowing for visualizing individual pathogens captured on the surface. Enabled by our ability to count individual bacteria on a large sensor surface, we demonstrate a limit of detection of 2.2 CFU/ml from a buffer solution with no sample preparation. To the best of our knowledge, this high level of sensitivity for whole E. coli detection is unprecedented in label free biosensing. The specificity of our biosensor is validated by comparing the response to target bacteria E. coli and non target bacteria S. aureus, K. pneumonia and P. aeruginosa. The biosensor performance in tap water also proves that its detection capability is unaffected by the sample complexity. Furthermore, our sensor platform provides high optical magnification imaging and thus validation of recorded detection events as the target bacteria based on morphological characterization. Therefore, our sensitive and label free detection method offers new perspectives for direct bacterial detection in real matrices and clinical samples.First author draf

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

Digital detection of exosomes by interferometric imaging

Exosomes, which are membranous nanovesicles, are actively released by cells and have been attributed to roles in cell-cell communication, cancer metastasis, and early disease diagnostics. The small size (30–100 nm) along with low refractive index contrast of exosomes makes direct characterization and phenotypical classification very difficult. In this work we present a method based on Single Particle Interferometric Reflectance Imaging Sensor (SP-IRIS) that allows multiplexed phenotyping and digital counting of various populations of individual exosomes (>50 nm) captured on a microarray-based solid phase chip. We demonstrate these characterization concepts using purified exosomes from a HEK 293 cell culture. As a demonstration of clinical utility, we characterize exosomes directly from human cerebrospinal fluid (hCSF). Our interferometric imaging method could capture, from a very small hCSF volume (20 uL), nanoparticles that have a size compatible with exosomes, using antibodies directed against tetraspanins. With this unprecedented capability, we foresee revolutionary implications in the clinical field with improvements in diagnosis and stratification of patients affected by different disorders.This work was supported by Regione Lombardia and Fondazione Cariplo through POR-FESR, project MINER (ID 46875467); Italian Ministry of Health, Ricerca Corrente. This work was partially supported by The Scientific and Technological Research Council of Turkey (grant #113E643). (Regione Lombardia; 46875467 - Fondazione Cariplo through POR-FESR, project MINER; Italian Ministry of Health, Ricerca Corrente; 113E643 - Scientific and Technological Research Council of Turkey)Published versio