Real-time cancer detection with an integrated lensless fluorescence contact imager.

Microscopic tumor cell foci left in a patient after surgery significantly increase the chance of cancer recurrence. However, fluorescence microscopes used for intraoperative navigation lack the necessary sensitivity for imaging microscopic disease and are too bulky to maneuver within the resection cavity. We have developed a scalable chip-scale fluorescence contact imager for detecting microscopic cancer in vivo and in real-time. The imager has been characterized under simulated in vivo conditions using ex vivo samples, providing strong evidence that our device can be used in vivo. Angle-selective gratings enhance the resolution of the imager without impacting its physical size. We demonstrate detection of cancer cell clusters containing as few as 25 HCC1569 breast cancer cells and 400 LNCaP prostate cancer cells with integration times of only 50 ms and 70 ms, respectively. A cell cluster recognition algorithm is used to achieve both a sensitivity and specificity of 92 % for HCC1569 cell samples, indicating the reliability of the imager. The signal-to-noise ratio (SNR) degradation with increased separation is only 1.5 dB at 250 µm. Blood scattering and absorption reduce the SNR by less than 2 dB for typical concentrations. Moreover, HER2+ breast cancer tissue taken from a patient is distinguished from normal breast tissue with an integration time of only 75 ms.

Dielectric barrier discharge plasma treatment of modified SU-8 for biosensing applications.

In this work we demonstrate the use of a dielectric barrier discharge plasma for the treatment of SU-8. The resulting hydrophilic surface displays a 5° contact angle and (0.40 ± 0.012) nm roughness. Using this technique we also present a proof of concept of IgG and prostate specific antigen biodetection on a thin layer of SU-8 over gold via surface plasmon resonance detection.

Optical surface plasmon resonance sensor modified by mutant glucose/galactose-binding protein for affinity detection of glucose molecules.

Transdermal extraction of interstitial fluid (ISF) offers an attractive method for minimally invasive blood glucose monitoring. However, only a minute volume of ISF could be transdermally extracted, which is required to be diluted to form a manipulable volume of fluid for easy collection, transportation, and glucose detection. Therefore, a high-resolution glucose detection method is required for detecting glucose concentration in diluted ISF. In this paper, an optical surface plasmon resonance (SPR) sensor modified by the glucose/galactose-binding (GGB) protein which has good affinity to glucose molecules was presented for specific and sensitive glucose detection. The GGB protein was mutated at different sites for thiol coupling with the SPR surface and adjusting the affinity between glucose molecules and GGB protein. And the immobilization process of the GGB protein onto the surface of SPR sensor was optimized. Then, the stability of the SPR sensor modified with GGB protein was tested immediately and two weeks after immobilization. The coefficient of variation for glucose concentration measurement was less than 4.5%. By further mutation of the GGB protein at the A213S and L238S sites, the measurement range of the SPR sensor was adjusted to 0.1-100 mg/dL, which matches the glucose concentration range of 5-10 times diluted ISF (3-100 mg/dL). These results suggest that the SPR biosensor immobilized with GGB protein has the potential for continuous glucose monitoring by integrating into the microfluidic ISF extraction chip.

Detection of Echinococcus granulosus antigen by a quantum dot/porous silicon optical biosensor.

Highly sensitive labeled detection of Echinococcus granulosus using colloidal quantum dots (QDs) based on a porous silicon Bragg mirror sensor are demonstrated. Rabbit anti-p38 labeled CdSe/ZnS QDs was infiltrated in porous silicon pores immobilized Egp38 antigen. QD-antibodies are specifically bound to antigens linked covalently to the pore walls of PSi after the immune reaction. By the design of the transfer matrix method and the preparation of the electrochemical etching method, the fluorescence peak wavelength of the quantum dots is located in the forbidden band of the Bragg mirror. The fluorescence of QDs are enhanced by PSi Bragg mirror. Egp38 antigen detection limit of 300fg/mL is achievable. Our results exhibit that the biosensor combining PSi Bragg mirror and QDs can potentially be applied to the clinical detection of hydatid disease.

Asymmetric split H-shape nanoantennas for molecular sensing.

In this paper we report on a very sensitive biosensor based on gold asymmetric nanoantennas that are capable of enhancing the molecular resonances of C-H bonds. The nanoantennas are arranged as arrays of asymmetric-split H-shape (ASH) structures, tuned to produce plasmonic resonances with reflectance double peaks within the mid-infrared vibrational resonances of C-H bonds for the assay of deposited films of the molecule 17ß-estradiol (E2), used as an analyte. Measurements and numerical simulations of the reflectance spectra have enabled an estimated enhancement factor on the order of 105 to be obtained for a thin film of E2 on the ASH array. A high sensitivity value of 2335 nm/RIU was achieved, together with a figure of merit of approximately 8. Our experimental results were corroborated using numerical simulations for the C-H stretch vibrational resonances from the analyte, superimposed on the plasmonic resonances of the ASH nanoantennas.

Projection method for improving signal to noise ratio of localized surface plasmon resonance biosensors.

This paper presents a simple and accurate method (the projection method) to improve the signal to noise ratio of localized surface plasmon resonance (LSPR). The nanostructures presented in the paper can be readily fabricated by nanoimprint lithography. The finite difference time domain method is used to simulate the structures and generate a reference matrix for the method. The results are validated against experimental data and the proposed method is compared against several other recently published signal processing techniques. We also apply the projection method to biotin-streptavidin binding experimental data and determine the limit of detection (LoD). The method improves the signal to noise ratio (SNR) by one order of magnitude, and hence decreases the limit of detection when compared to the direct measurement of the transmission-dip. The projection method outperforms the established methods in terms of accuracy and achieves the best combination of signal to noise ratio and limit of detection.

Pulsed operation of a miniature scalar optically pumped magnetometer.

A scalar magnetic field sensor based on a millimeter-size 87Rb vapor cell is described. The magnetometer uses nearly copropagating pump and probe laser beams, amplitude modulation of the pump beam, and detection through monitoring the polarization rotation of the detuned probe beam. The circularly polarized pump laser resonantly drives a spin precession in the alkali atoms at the Larmor frequency. A modulation signal on the probe laser polarization is detected with a lock-in amplifier. Since the Larmor precession is driven all-optically, potential cross talk between sensors is minimized. And since the pump light is turned off during most of the precession cycle, large offsets of the resonance, typically present in a single-beam Bell-Bloom scheme, are avoided. At the same time, relatively high sensitivities can be reached even in millimeter-size vapor cells: The magnetometer achieves a sensitivity of 1 pT/Hz1/2 in a sensitive volume of 16 mm3, limited by environmental noise. When a gradiometer configuration is used to cancel the environmental noise, the magnetometer sensitivity reaches 300 fT/Hz1/2. We systematically study the dependence of the magnetometer performance on the optical duty cycles of the pump light and find that better performance is achieved with shorter duty cycles, with the highest values measured at 1.25% duty cycle.

Real-time, continuous, fluorescence sensing in a freely-moving subject with an implanted hybrid VCSEL/CMOS biosensor.

Performance improvements in instrumentation for optical imaging have contributed greatly to molecular imaging in living subjects. In order to advance molecular imaging in freely moving, untethered subjects, we designed a miniature vertical-cavity surface-emitting laser (VCSEL)-based biosensor measuring 1cm(3) and weighing 0.7g that accurately detects both fluorophore and tumor-targeted molecular probes in small animals. We integrated a critical enabling component, a complementary metal-oxide semiconductor (CMOS) read-out integrated circuit, which digitized the fluorescence signal to achieve autofluorescence-limited sensitivity. After surgical implantation of the lightweight sensor for two weeks, we obtained continuous and dynamic fluorophore measurements while the subject was un-anesthetized and mobile. The technology demonstrated here represents a critical step in the path toward untethered optical sensing using an integrated optoelectronic implant.

Biomolecule kinetics measurements in flow cell integrated porous silicon waveguides.

A grating-coupled porous silicon (PSi) waveguide with an integrated polydimethylsiloxane (PDMS) flow cell is demonstrated as a platform for near real-time detection of chemical and biological molecules. This sensor platform not only allows for quantification of molecular binding events, but also provides a means to improve understanding of diffusion and binding mechanisms in constricted nanoscale geometries. Molecular binding events in the waveguide are monitored by angle-resolved reflectance measurements. Diffusion coefficients and adsorption and desorption rate constants of different sized chemical linkers and nucleic acid molecules are determined based on the rate of change of the measured resonance angle. Experimental results show that the diffusion coefficient in PSi is smaller than that in free solutions, and the PSi morphology slows the molecular adsorption rate constant by a factor of 10(2)-10(4) compared to that of flat surface interactions. Calculations based on simplified mass balance equations and COMSOL simulations give good agreement with experimental data.

Hydrogenated amorphous silicon nitride photonic crystals for improved-performance surface electromagnetic wave biosensors.

We exploit the properties of surface electromagnetic waves propagating at the surface of finite one dimensional photonic crystals to improve the performance of optical biosensors with respect to the standard surface plasmon resonance approach. We demonstrate that the hydrogenated amorphous silicon nitride technology is a versatile platform for fabricating one dimensional photonic crystals with any desirable design and operating in a wide wavelength range, from the visible to the near infrared. We prepared sensors based on photonic crystals sustaining either guided modes or surface electromagnetic waves, also known as Bloch surface waves. We carried out for the first time a direct experimental comparison of their sensitivity and figure of merit with surface plasmon polaritons on metal layers, by making use of a commercial surface plasmon resonance instrument that was slightly adapted for the experiments. Our measurements demonstrate that the Bloch surface waves on silicon nitride photonic crystals outperform surface plasmon polaritons by a factor 1.3 in terms of figure of merit.

Optofluidic lab-on-a-chip for rapid algae population screening.

The rapid identification of algae species is not only of practical importance when monitoring unwanted adverse effects such as eutrophication, but also when assessing the water quality of watersheds. Here, we demonstrate a lab-on-a-chip that functions as a compact robust tool for the fast screening, real-time monitoring, and initial classification of algae. The water-algae sample, flowing in a microfluidic channel, is side-illuminated by an integrated subsurface waveguide. The waveguide is curved to improve the device sensitivity. The changes in the transmitted optical signal are monitored using a quadrant-cell photo-detector. The signal-wavelets from the different quadrants are used to qualitatively distinguish different families of algae. The channel and waveguide are fabricated out of a monolithic fused-silica substrate using a femtosecond laser-writing process combined with chemical etching. This proof-of-concept device paves the way for more elaborate femtosecond laser-based optofluidic micro-instruments incorporating waveguide networks designed for the real-time field analysis of cells and microorganisms.

On-chip spectrophotometry for bioanalysis using microring resonators.

We measure optical absorption in color-producing enzymatic reactions for biochemical analysis with a microscale optofluidic device. Cavity-enhanced laser spectrophotometry is performed on analytes within a microfluidic channel at visible wavelengths with silicon nitride microring resonators of 100 µm radius and quality factor of ~180,000. The resonator transmission spectrum is analyzed to determine optical absorption with a detection limit of 0.12 cm(-1). The device can be used to detect the activity of individual enzymes in a few minutes within a 100 fL sensing volume. The high sensitivity, small footprint, and low analyte consumption make absorption-based microring resonators attractive for lab-on-a-chip applications.