Time-of-flight resolved light field fluctuations reveal deep human tissue physiology.

Red blood cells (RBCs) transport oxygen to tissues and remove carbon dioxide. Diffuse optical flowmetry (DOF) assesses deep tissue RBC dynamics by measuring coherent fluctuations of multiply scattered near-infrared light intensity. While classical DOF measurements empirically correlate with blood flow, they remain far-removed from light scattering physics and difficult to interpret in layered media. To advance DOF measurements closer to the physics, here we introduce an interferometric technique, surmounting challenges of bulk motion to apply it in awake humans. We reveal two measurement dimensions: optical phase, and time-of-flight (TOF), the latter with 22 picosecond resolution. With this multidimensional data, we directly confirm the unordered, or Brownian, nature of optically probed RBC dynamics typically assumed in classical DOF. We illustrate how incorrect absorption assumptions, anisotropic RBC scattering, and layered tissues may confound classical DOF. By comparison, our direct method enables accurate and comprehensive assessment of blood flow dynamics in humans.

Environmental Copper Sensor Based on Polyethylenimine-Functionalized Nanoporous Anodic Alumina Interferometers.

Anthropogenic copper pollution of environmental waters from sources such as acid mine drainage, antifouling paints, and industrial waste discharge is a major threat to our environment and human health. This study presents an optical sensing system that combines self-assembled glutaraldehyde-cross-linked double-layered polyethylenimine (PEI-GA-PEI)-modified nanoporous anodic alumina (NAA) interferometers with reflectometric interference spectroscopy (RIfS) for label-free, selective monitoring of ionic copper in environmental waters. Calibration of the sensing system with analytical solutions of copper shows a linear working range between 1 and 100 mg L-1, and a low limit of detection of 0.007 ± 0.001 mg L-1 (i.e., ∼0.007 ppm). Changes in the effective optical thickness (ΔOTeff) of PEI-GA-PEI-functionalized NAA interferometers are monitored in real-time by RIfS, and correlated with the amount of ionic copper present in aqueous solutions. The system performance is validated through X-ray photoelectron spectroscopy (XPS) and the spatial distribution of copper within the nanoporous films is characterized by time-of-flight-secondary ion mass spectroscopy (TOF-SIMS). The specificity and chemical selectivity of the PEI-GA-PEI-NAA sensor to Cu2+ ions is verified by screening six different metal ion solutions containing potentially interfering ions such as Al3+, Cd2+, Fe3+, Pb2+, Ni2+, and Zn2+. Finally, the performance of the PEI-GA-PEI-NAA sensor for real-life applications is demonstrated using legacy acid mine drainage liquid and tap water for qualitative and quantitative detection of copper ions. This study provides new opportunities to develop portable, cost-competitive, and ultrasensitive sensing systems for real-life environmental applications.

Label-free real-time optical monitoring of DNA hybridization using SiN Mach-Zehnder interferometer-based integrated biosensing platform.

We report on the label-free real-time optical monitoring of DNA hybridization upon exposure to a flow of complementary DNA at different concentrations. The biosensor is composed of a silicon nitride integrated unbalanced Mach-Zehnder interferometer (MZI), with an integrated arrayed waveguide grating as a spectral filter. This MZI has been shown to have both sufficient multiplexing capability and limit of detection on the order of 10 - 6 RIU. Probe DNA, consisting of a 36-mer fragment is covalently immobilized on the silicon nitride integrated biosensor. The wavelength shift is monitored upon complementary DNA targets being flown over the sensor. Concentrations of 1 pM can be easily detected. Also, an alternative route to modify the sensor surface with carboxylic groups using the photochemical reaction of fatty acids is proposed and preliminary XPS results are presented. Moreover, preliminary results for DNA obtained from a rolling circle amplification (RCA-DNA) process and spiked in a realistic amplification buffer are presented.

Silicon Photonic Biosensors Using Label-Free Detection.

Thanks to advanced semiconductor microfabrication technology, chip-scale integration and miniaturization of lab-on-a-chip components, silicon-based optical biosensors have made significant progress for the purpose of point-of-care diagnosis. In this review, we provide an overview of the state-of-the-art in evanescent field biosensing technologies including interferometer, microcavity, photonic crystal, and Bragg grating waveguide-based sensors. Their sensing mechanisms and sensor performances, as well as real biomarkers for label-free detection, are exhibited and compared. We also review the development of chip-level integration for lab-on-a-chip photonic sensing platforms, which consist of the optical sensing device, flow delivery system, optical input and readout equipment. At last, some advanced system-level complementary metal-oxide semiconductor (CMOS) chip packaging examples are presented, indicating the commercialization potential for the low cost, high yield, portable biosensing platform leveraging CMOS processes.

Development of drug discovery screening system by molecular interaction kinetics-mass spectrometry.

RATIONALE: Drug discovery studies invariably require qualitative and quantitative analyses of target compounds at every stage of drug discovery. We have developed a system combining molecular interaction analysis and mass spectrometry (LC-MS) using the principle of nanopore optical interferometry (nPOI) called molecular interaction kinetics-mass spectrometry (MIK-MS). Since nPOI has high binding capacity, the bond-dissociated compound can be directly detected using LC-MS. In this study, we use carbonic anhydrase II (CAII) as a ligand and apply six small compounds as analytes and report the affinity analysis using MIK-MS. METHODS: CAII was immobilized onto a COOH sensor chip using standard amine coupling. A reference surface was prepared by activating and subsequently blocking the surface under identical conditions. An amount of 50 µL of mix solution was injected over the reference channel and sample channel for CAII immobilization. The solutions eluting from the sensor chip were collected from the waste-line of the SKi Pro system every 30 s. Reconstructed elution samples were then injected into the LC-MS/MS system. RESULTS: A mixture containing furosemide, acetazolamide, 4-sulfamoylbenzoic acid, 5-(dimethylamino)-1-naphthalene sulfonamide (DNSA), sulfanilamide and sulpiride (15 µM each) was injected into the CAII-immobilized sensor chip, and the fractions eluted from the SKi Pro system were collected and subjected to selected reaction monitoring LC-MS characterization. Specific results were obtained for acetazolamide, DNSA, furosemide and sulpiride. The results suggest that the association-dissociation curve of a mixed sample can be obtained by one-time MIK-MS analysis. CONCLUSIONS: Six small-molecule binders of CAII were analyzed quantitatively using nPOI and MIK-MS, and the results were compared to published surface plasmon resonance (SPR) results. The nPOI and SPR results show good agreement, confirming the reliability of the analysis. Time-dependent binding results may be obtained by our MS sensorgram approach. Drugs that meet medical needs in a short period are required; this nPOI-LC-MS system is considered an important tool for rapid drug discovery.

Determination of birefringence and slow axis distribution using an interferometric measurement system with liquid crystal phase shifter.

It is known that liquid crystal (LC) cells are useful as compact and easy-to-handle phase shifters that are readily coupled into the optics of standard microscope systems. Here, a uniformly aligned molecular LC phase shifter is introduced into a polarization microscope to attain a birefringence imaging system, using the phase-shift interferometric technique. Since the birefringence can be determined accurately only when the optical axis of the sample is parallel or perpendicular to the slow axis (variable axis) of the LC phase shifter, an improved data analysis method is proposed for determining the birefringence independently of the direction; a simple method of determining the slow axis distribution is also demonstrated. Measurements of the birefringence and slow axis distribution properties of a potato starch particle are demonstrated to confirm the novel determination method.

Nanoporous anodic alumina platforms: engineered surface chemistry and structure for optical sensing applications.

Electrochemical anodization of pure aluminum enables the growth of highly ordered nanoporous anodic alumina (NAA) structures. This has made NAA one of the most popular nanomaterials with applications including molecular separation, catalysis, photonics, optoelectronics, sensing, drug delivery, and template synthesis. Over the past decades, the ability to engineer the structure and surface chemistry of NAA and its optical properties has led to the establishment of distinctive photonic structures that can be explored for developing low-cost, portable, rapid-response and highly sensitive sensing devices in combination with surface plasmon resonance (SPR) and reflective interference spectroscopy (RIfS) techniques. This review article highlights the recent advances on fabrication, surface modification and structural engineering of NAA and its application and performance as a platform for SPR- and RIfS-based sensing and biosensing devices.

Fiber-optic combined FPI/FBG sensors for monitoring of radiofrequency thermal ablation of liver tumors: ex vivo experiments.

We present a biocompatible, all-glass, 0.2 mm diameter, fiber-optic probe that combines an extrinsic Fabry-Perot interferometry and a proximal fiber Bragg grating sensor; the probe enables dual pressure and temperature measurement on an active 4 mm length, with 40 Pa and 0.2°C nominal accuracy. The sensing system has been applied to monitor online the radiofrequency thermal ablation of tumors in liver tissue. Preliminary experiments have been performed in a reference chamber with uniform heating; further experiments have been carried out on ex vivo porcine liver, which allowed the measurement of a steep temperature gradient and monitoring of the local pressure increase during the ablation procedure.

High-sensitivity dynamical profilometry with a fiber-based composite interferometer.

We proposed and demonstrated a fiber-based composite interferometer, which can perform surface profile measurements with sensitivity at the nanometer scale. With the proposed phase-compensation mechanism, the phase deviation due to the instability of the optical delay component and environmental perturbations can be simultaneously compensated. The measurement sensitivity and imaging speed can be significantly improved such that the system can be used as a high-speed, high-resolution, and wide-field dynamical imaging system. The axial precision of the system was examined to be 0.82 nm. High-resolution time-lapsed dynamical imaging of onion cells during dehydration processes were performed with this system with one frame captured in 75 s.

Full-field optical coherence tomography using immersion Mirau interference microscope.

In this study, an immersion Mirau interference microscope was developed for full-field optical coherence tomography (FFOCT). Both the reference and measuring arms of the Mirau interferometer were filled with water to prevent the problems associated with imaging a sample in air with conventional FFOCT systems. The almost-common path interferometer makes the tomographic system less sensitive to environmental disturbances. En face OCT images at various depths were obtained with phase-shifting interferometry and Hariharan algorithm. This immersion interferometric method improves depth and quality in three-dimensional OCT imaging of scattering tissue.

Phase modulation in horizontal metal-insulator-silicon-insulator-metal plasmonic waveguides.

An extremely compact Si phase modulator is proposed and validated, which relies on effective modulation of the real part of modal index of horizontal metal-insulator-Si-insulator-metal plasmonic waveguides by a voltage applied between the metal cover and the Si core. Proof-of-concept devices are fabricated on silicon-on-insulator substrates using standard complementary metal-oxide-semiconductor technology using copper as the metal and thermal silicon dioxide as the insulator. A modulator with a 1-µm-long phase shifter inserted in an asymmetric Si Mach-Zehnder interferometer exhibits 9-dB extinction ratio under a 6-V/10-kHz voltage swing. Numerical simulations suggest that high speed and low driving voltage could be achieved by shortening the distance between the Si core and the n(+)-contact and by using a high-κ dielectric as the insulator, respectively.

Quantitative analysis of mechanically retentive ceramic bracket base surfaces with a three-dimensional imaging system.

OBJECTIVE: To investigate the three-dimensional structural features of three types of mechanically retentive ceramic bracket bases. MATERIALS AND METHODS: One type of stainless steel (MicroArch, Tomy, Tokyo, Japan) and three types of ceramic maxillary right central incisor brackets-Crystaline MB (Tomy), INVU (TP Orthodontics, La Porte, Ind), and Inspire Ice (Ormco, Glendora, Calif)-were tested to compare and quantitatively analyze differences in the surface features of each ceramic bracket base using scanning electron microscopy (SEM), a three-dimensional (3D) optical surface profiler, and microcomputed tomography (micro-CT). One-way analysis of variance was used to find differences in bracket base surface roughness values and surface areas between groups according to base designs. Tukey's honestly significant differences tests were used for post hoc comparisons. RESULTS: SEM revealed that each bracket exhibited a unique surface texture (MicroArch, double mesh; Crystaline MB, irregular; INVU, single mesh; Inspire Ice, bead ball). With a 3D optical surface profiler, the stainless steel bracket showed significantly higher surface roughness values. Crystaline MB had significantly higher surface roughness values than Inspire Ice. Micro-CT demonstrated that stainless steel brackets showed significantly higher whole and unit bracket base surface areas. Among ceramic brackets, INVU showed significantly higher whole bracket base surface area, and Crystaline MB showed a significantly higher unit bracket base surface area than Inspire Ice. CONCLUSION: Irregular bracket surface features showed the highest surface roughness values and unit bracket base surface area among ceramic brackets, which contributes to increased mechanically retentive bracket bonding strength.

Analysis of interferograms of multi-layered biological samples obtained from full field optical coherence tomography systems.

Several methods were developed in the past to analyze interferograms produced by optical coherence tomography, and successfully applied to simulated or animated samples. However, these techniques do not cope with noisy and distorted interferograms from biological tissues. In this paper, known techniques, including the fast Fourier transform and several variations of the continuous wavelet transform, were employed to analyze the interferogram data. However, to cope with the difficulties in biological data, pre- and post-processing procedures and adaptive thresholding were developed to provide stability and robustness. Additionally, three-dimensional structural models of the biological samples were constructed, and revealed information like the number and locations of interfaces, the layer thickness and pattern, and abnormalities.

Narrowband multispectral filter set for visible band.

We design, fabricate and characterise a narrowband Fabry-Pérot multispectral filter set for the visible range (400-750 nm) that is suitable for integration onto complementary-metal oxide-semiconductor image sensors. We reduce the fabrication steps by fixing the physical cavity length and altering the effective optical length instead. Using electron-beam lithography, a sub-wavelength hole array is patterned in a silicon nitride cavity layer, backfilled with poly(methyl methacrylate), and bounded by aluminium mirrors to create 23 filters with full-width half-maximums of 22-46 nm. Additionally, for colourmetric reproduction applications, using as few as 10 filters gives a colour difference (CIEDE2000) of 0.072, better than trichromatic filters.

Instrumentation for studies of cochlear mechanics: from von Békésy forward.

Georg von Békésy designed the instruments needed for his research. He also created physical models of the cochlea allowing him to manipulate the parameters (such as volume elasticity) that could be involved in controlling traveling waves. This review is about the specific devices that he used to study the motion of the basilar membrane thus allowing the analysis that lead to his Nobel Prize Award. The review moves forward in time mentioning the subsequent use of von Békésy's methods and later technologies important for motion studies of the organ of Corti. Some of the seminal findings and the controversies of cochlear mechanics are mentioned in relation to the technical developments.

3D displacement measurements of the tympanic membrane with digital holographic interferometry.

A digital holographic interferometry (DHI) system with three object-illumination beams is used for the first time to measure micro-deformations along the x, y and z axes (3D) on the tympanic membrane (TM) surface of a post-mortem cat. In order to completely and accurately measure the TM surface displacements its shape is required to map on it the x, y and z micro-deformations. The surface contour is obtained by applying small shifts to the object illumination source position. A cw laser in stroboscopic mode and a CCD camera were used and synchronized to the acoustic excitation wave that produces a resonant vibration mode on the tympanic membrane surface. This research work reports on the 3D full field of view response of the TM to sound pressure, and has as its main goal the presentation of DHI as an alternative technique to study the TM real displacement behavior when subjected to sound waves, so it can be used as a diagnostic tool to prevent and treat TM diseases.

High-resolution full-field optical coherence microscopy using a Mirau interferometer for the quantitative imaging of biological cells.

In this paper quantitative imaging of biological cells using high-resolution full-field optical coherence microscopy (FF-OCM) is reported. The FF-OCM was realized using a swept-source system, a Mirau interferometer, and a CCD camera (a two-dimensional detection unit). A Mirau-interferometric objective lens was used to generate the interferometric signal. The signal was analyzed by a Fourier analysis technique. Optically sectioned amplitude images and a quantitative phase map of biological cells such as onion skin and red blood cells (RBCs) are demonstrated. Further, the refractive index profile of the RBCs is also presented. For the 50× Mirau objective, the experimentally achieved axial and transverse resolution of the present system are 3.8 and 1.2 µm, respectively. The CCD provides parallel detection and measures enface images without X, Y, Z mechanical scanning.

Demonstration of a fast-reconfigurable silicon CMOS optical lattice filter.

We demonstrate a fully-reconfigurable fourth-order optical lattice filter built by cascading identical unit cells consisting of a Mach-Zehnder interferometer (MZI) and a ring resonator. The filter is fabricated using a commercial silicon complementary metal oxide semiconductor (CMOS) process and reconfigured by current injection into p-i-n diodes with a reconfiguration time of less than 10 ns. The experimental results show full control over the single unit cell pole and zero, switching the unit cell transfer function between a notch filter and a bandpass filter, narrowing the notch width down to 400 MHz, and tuning the center wavelength over the full free spectral range (FSR) of 10 GHz. Theoretical and experimental results show tuning dynamics and associated optical losses in the reconfigurable filters. The full-control of each of the four cascaded single unit cells resulted in demonstrations of a number of fourth-order transfer functions. The multimedia experimental data show live tuning and reconfiguration of optical lattice filters.

Nanoporous alumina-based interferometric transducers ennobled.

A high fidelity interferometric transducer is designed based on platinum-coated nanoporous alumina films. The ultrathin metal coating significantly improves fidelity of the interferometric fringe patterns in aqueous solution and increases the signal-to-noise ratio. The performance of this transducer is tested with respect to refractive index unit (RIU) sensitivity measured as a change in effective optical thickness (EOT) in response to a solvent change and compared to porous silicon based transducers. RIU sensitivity in the order of 55% is attainable for porous alumina providing excellent signal-to-noise ratio, which exceeds the sensitivity of current interferometric transducers. Finally, as a proof-of-principle, we demonstrate biosensing with two distinct immunoglobulin antibodies.

Motion of the surface of the human tympanic membrane measured with stroboscopic holography.

Sound-induced motion of the surface of the human tympanic membrane (TM) was studied by stroboscopic holographic interferometery, which measures the amplitude and phase of the displacement at each of about 40,000 points on the surface of the TM. Measurements were made with tonal stimuli of 0.5, 1, 4 and 8 kHz. The magnitude and phase of the sinusoidal displacement of the TM at each driven frequency were derived from the fundamental Fourier component of the raw displacement data computed from stroboscopic holograms of the TM recorded at eight stimulus phases. The correlation between the Fourier estimates and measured motion data was generally above 0.9 over the entire TM surface. We used three data presentations: (i) plots of the phasic displacements along a single chord across the surface of the TM, (ii) phasic surface maps of the displacement of the entire TM surface, and (iii) plots of the Fourier derived amplitude and phase-angle of the surface displacement along four diameter lines that define and bisect each of the four quadrants of the TM. These displays led to some common conclusions: at 0.5 and 1kHz, the entire TM moved roughly in-phase with some small phase delay apparent between local areas of maximal displacement in the posterior half of the TM. At 4 and 8 kHz, the motion of the TM became more complicated with multiple local displacement maxima arranged in rings around the manubrium. The displacements at most of these maxima were roughly in-phase, while some moved out-of-phase. Superposed on this in- and out-of-phase behavior were significant cyclic variations in-phase with location of less than 0.2 cycles or occasionally rapid half-cycle step-like changes in-phase. The high frequency displacement amplitude and phase maps discovered in this study can not be explained by any single wave motion, but are consistent with a combination of low and higher order modal motions plus some small traveling-wave-like components. The observations of the dynamics of TM surface motion from this study will help us better understand the sound-receiving function of the TM and how it couples sound to the ossicular chain and inner ear.