Two-site microendoscopic imaging probe for simultaneous three-dimensional imaging at two anatomic locations in tissues.

Systems that can image in three dimensions at cellular resolution and across different locations within an organism may enable insights into complex biological processes, such as immune responses, for which a single location measurement may be insufficient. In this Letter, we describe an in vivo two-site imaging probe (TIP) that can simultaneously image two anatomic sites with a maximum separation of a few centimeters. The TIP consists of two identical bendable graded index (GRIN) lenses and is demonstrated by a two-photon two-color fluorescence imaging system. Each GRIN lens has a field of view of 162 × 162 × 170 µm3, a nominal numerical aperture of 0.5, a magnification of 0.7, and working distances of 0.2 mm in air for both ends. A blind linear unmixing algorithm is applied to suppress bleedthrough between channels. We use this system to successfully demonstrate two-site two-photon two-color imaging of two biomedically relevant samples, i.e., (1) a mixture of two autofluorescent anti-cancer drugs and (2) a live hybrid tumor consisting of two spectrally distinct fluorescent cell lines.

Bendable long graded index lens microendoscopy.

Graded index (GRIN) lens endoscopy has broadly benefited biomedical microscopic imaging by enabling accessibility to sites not reachable by traditional benchtop microscopes. It is a long-held notion that GRIN lenses can only be used as rigid probes, which may limit their potential for certain applications. Here, we describe bendable and long-range GRIN microimaging probes for a variety of potential micro-endoscopic biomedical applications. Using a two-photon fluorescence imaging system, we have experimentally demonstrated the feasibility of three-dimensional imaging through a 500-µm-diameter and ∼11 cm long GRIN lens subject to a cantilever beam-like deflection with a minimum bend radius of ∼25 cm. Bend-induced perturbation to the field of view and resolution has also been investigated quantitatively. Our development alters the conventional notion of GRIN lenses and enables a range of innovative applications. For example, the demonstrated flexibility is highly desirable for implementation into current and emerging minimally invasive clinical procedures, including a pioneering microdevice for high-throughput cancer drug selection.

Analysis of single-mode fiber-optic extrinsic Fabry-Perot interferometric sensors with planar metal mirrors.

We theoretically study the spectral characteristics and noise performance of wavelength-interrogated fiber-optic sensors based on an extrinsic Fabry-Perot (FP) interferometer (EFPI) formed by thin metal mirrors. We develop a model and use it to analyze the effect of key sensor parameters on the visibility and spectral width of the sensors, including the beam width of the incident light, metal coating film thickness, FP cavity length, and wedge angle of the two mirrors. Through Monte Carlo simulations, we obtain an empirical equation that can be used to estimate the wavelength resolution from the visibility and spectral width, which can be used as a figure-of-merit that is inherent to the sensor and independent on the system noises. The work provides a useful tool for designing, constructing, and interrogating high-resolution fiber-optic EFPI sensors.

A Two-Photon Microimaging-Microdevice System for Four-Dimensional Imaging of Local Drug Delivery in Tissues.

Advances in the intratumor measurement of drug responses have included a pioneering biomedical microdevice for high throughput drug screening in vivo, which was further advanced by integrating a graded-index lens based two-dimensional fluorescence micro-endoscope to monitor tissue responses in situ across time. While the previous system provided a bulk measurement of both drug delivery and tissue response from a given region of the tumor, it was incapable of visualizing drug distribution and tissue responses in a three-dimensional (3D) way, thus missing the critical relationship between drug concentration and effect. Here we demonstrate a next-generation system that couples multiplexed intratumor drug release with continuous 3D spatial imaging of the tumor microenvironment via the integration of a miniaturized two-photon micro-endoscope. This enables optical sectioning within the live tissue microenvironment to effectively profile the entire tumor region adjacent to the microdevice across time. Using this novel microimaging-microdevice (MI-MD) system, we successfully demonstrated the four-dimensional imaging (3 spatial dimensions plus time) of local drug delivery in tissue phantom and tumors. Future studies include the use of the MI-MD system for monitoring of localized intra-tissue drug release and concurrent measurement of tissue responses in live organisms, with applications to study drug resistance due to nonuniform drug distribution in tumors, or immune cell responses to anti-cancer agents.

Polarization-insensitive, omnidirectional fiber-optic ultrasonic sensor with quadrature demodulation.

We report an ultrasonic sensor system based on a low-finesse Fabry-Perot interferometer (FPI) formed by two weak chirped fiber Bragg gratings (CFBGs) on a coiled single-mode fiber. The sensor system has several desirable features for practical applications in detecting ultrasound on a solid surface. By controlling the birefringence of the fiber coil during the sensor fabrication, the sensor is made insensitive to the polarization variations of the laser source. The circular symmetric structure of the fiber coil also renders the omnidirectional response of the sensor to ultrasound. While the fiber coil is bonded directly to the structure, the CFBGs are suspended from the structure and free from large background strains with little reduction to the sensitivity of the sensor. The low-finesse FPI features a sinusoidal reflection spectrum. Like the conventional phase-generated carried technique, a phase modulator is utilized to implement quadrature demodulation. Therefore, the sensing system is adaptive to large background perturbations experienced by the fiber coil.

Multiplexing fiber-optic ultrasound sensors using laser intensity modulation.

We propose and demonstrate the use of laser intensity modulation for the multiplexing and demultiplexing of fiber Bragg grating-based ultrasound sensors. The method utilizes an intensity modulator to modulate the output power of the laser with a frequency much higher than that of the ultrasounds. The high-frequency-modulated optical signal serves as a carrier signal. Ultrasonic signals impinged onto the sensor appear as the envelope of the carrier signal. In the frequency domain, the carrier signal and the sidebands encoded with the ultrasonic signal are separated from those of other channels and, thus, can be isolated using an electronic bandpass filter for crosstalk-free ultrasound detection. Each laser can be tuned to demodulate any sensor covered by the wavelength range of the laser, and a common photodetector is used for all channels. Both a theoretical analysis and experimental verification are provided to demonstrate the concept.

Constant temperature operation of fiber-optic hot-wire anemometers.

We demonstrate the constant temperature (CT) operation of a fiber-optic anemometer based on a laser-heated silicon Fabry-Perot interferometer (FPI), where the temperature of the FPI is kept constant by adjusting the heating laser power through a feedback control loop and the output signal is the heating laser power. We show that the CT operation can dramatically improve the frequency response over the commonly used constant power (CP) operation, where the laser heating power is kept constant and the output signal is the temperature of the FPI. For demonstration, we used a 100-µm-diameter, 200-µm-thick silicon FPI attached to the tip of a single-mode fiber as the anemometer. The FPI was heated by a 980-nm diode laser, and the temperature was measured using a 1550-nm diode laser. The effect of flow changes was simulated by exposing the silicon FPI to radiation from an external intensity-modulated laser beam. We show that the 10%-90% rise time of the step response in air was reduced from 625 ms for CP operation to 1.8 ms for CT operation, and the 3-dB bandwidth was increased from 0.5 Hz for CP operation to 2 kHz for CT operation. The response of the anemometer also shows good linearity to the radiation power.

Ultrasensitive measurement of gas refractive index using an optical nanofiber coupler.

We report an ultrasensitive gas refractive index (RI) sensor based on optical nanofiber couplers (ONCs). Theoretical analysis reveals that a dispersion turning point (DTP) exists when the diameter of the coupler is below 1000 nm. Leveraging this DTP, the gas RI sensitivity can be significantly improved to infinity. Then we experimentally demonstrate a DTP and achieve ultrahigh sensitivities of 46,470 nm/refractive index unit (RIU) and -45,550 nm/RIU around the DTP using an ONC with a diameter of 700 nm. More importantly, the unique twin dips/peaks interference characteristics around the DTP offers further enhancement on the sensitivity to 92,020 nm/RIU. The demonstrated sensor not only shows vast potential in ultrasensitive pressure sensing, acoustic sensing, gas sensing, and gas phase biomarker detection, but also provides a new tool for nonlinear optics, ultrafast optics, quantum optics, and ultracold atom optics.

Acoustic emission sensor system using a chirped fiber-Bragg-grating Fabry-Perot interferometer and smart feedback control.

We demonstrate a fiber-optic acoustic emission (AE) sensor system that is capable of performing AE detection, even when the sensor is experiencing large quasi-static strains. The sensor is a Fabry-Perot interferometer formed by cascaded chirped fiber-Bragg gratings (CFBGs). The reflection spectrum of the sensor features a number of narrow spectral notches equally spaced within the reflection bandwidth of the CFBG. A semiconductor laser whose wavelength can be fast tuned through current injection is used to lock the laser line to the center of a slope of a spectral notch. When the notch is knocked out of the tuning range of the laser, a neighboring notch moves into the range. Through a smart feedback control scheme, the laser is unlocked from the current spectral lock and relocked to the desired point of the new notch. The fast speed of the unlocking/relocking process (<1 ms) ensures that the AE signal is monitored without significant disruption.

Self-gauged fiber-optic micro-heater with an operation temperature above 1000°C.

We report a fiber-optic micro-heater based on a miniature crystalline silicon Fabry-Perot interferometer (FPI) fusion spliced to the endface of a single-mode fiber. The silicon FPI, having a diameter of 100 µm and a length of 10 or 200 µm, is heated by a 980 nm laser diode guided through the lead-in fiber, leading to a localized hot spot with a temperature that can be conveniently tuned from the ambient temperature to >1000°C in air. In the meantime, using a white light system operating in the 1550 nm wavelength window where the silicon is transparent, the silicon FPI itself also serves as a thermometer with high resolution and high speed for convenient monitoring and precise control of the heater temperature. Due to its small size, high temperature capability, and easy operation, the micro-heater is attractive for applications in a variety of fields, such as biology, microfluidics system, mechanical engineering, and high-temperature optical sensing. As an example, the application of this micro-heater as a micro-boiler and micro-bubble generator has been demonstrated.

Influence of fiber bending on wavelength demodulation of fiber-optic Fabry-Perot interferometric sensors.

In practical applications of fiber optic sensors based on Fabry-Perot interferometers (FPIs), the lead-in optical fiber often experiences dynamic or static bending due to environmental perturbations or limited installation space. Bending introduces wavelength-dependent losses to the sensors, which can cause erroneous readings for sensors based on wavelength demodulation interrogation. Here, we investigate the bending-induced wavelength shift (BIWS) to sensors based on FPIs. Partially explicit expressions of BIWSs for the reflection fringe peaks and valleys have been derived for sensors based on low-finesse FPI. The theoretical model predicts these findings: 1) provided that a fringe peak experiences the same modulation slope by bending losses with a fringe valley, BIWSs for the peak and valley have opposite signs and the BIWS for the valley has a smaller absolute value; 2) BIWS is a linear function of the length of the bending section; 3) a FPI with higher visibility and longer optical path length is more resistant to the influence of bending. Experiments have been carried out and the results agree well with the theoretical predictions.

Optical fiber vector flow sensor based on a silicon Fabry-Perot interferometer array.

We report a miniature fiber-optic water vector flow sensor based on an array of silicon Fabry-Perot interferometers (FPIs). The flow sensor is composed of four silicon FPIs, one in the center with the other three equally distributed around it. The center FPI is heated by a cw laser at 980 nm, which is guided through the lead-in single mode fiber. The temperature structure established within the sensor head due to laser heating is a function of the flow vector (speed and direction), which can be deduced from the wavelength shifts of the four FPIs. Theoretical analysis has been conducted to illustrate the operating principle and experimental demonstration has been provided.

High-resolution, large dynamic range fiber-optic thermometer with cascaded Fabry-Perot cavities.

The paradox between a large dynamic range and a high resolution commonly exists in nearly all kinds of sensors. Here, we propose a fiber-optic thermometer based on dual Fabry-Perot interferometers (FPIs) made from the same material (silicon), but with different cavity lengths, which enables unambiguous recognition of the dense fringes associated with the thick FPI over the free-spectral range determined by the thin FPI. Therefore, the sensor combines the large dynamic range of the thin FPI and the high resolution of the thick FPI. To verify this new concept, a sensor with one 200 µm thick silicon FPI cascaded by another 10 µm thick silicon FPI was fabricated. A temperature range of -50°C to 130°C and a resolution of 6.8×10-3°C were demonstrated using a simple average wavelength tracking demodulation. Compared to a sensor with only the thick silicon FPI, the dynamic range of the hybrid sensor was more than 10 times larger. Compared to a sensor with only the thin silicon FPI, the resolution of the hybrid sensor was more than 18 times higher.

High-resolution and fast-response fiber-optic temperature sensor using silicon Fabry-Pérot cavity.

We report a fiber-optic sensor based on a silicon Fabry-Pérot cavity, fabricated by attaching a silicon pillar on the tip of a single-mode fiber, for high-resolution and high-speed temperature measurement. The large thermo-optic coefficient and thermal expansion coefficient of the silicon material give rise to an experimental sensitivity of 84.6 pm/°C. The excellent transparency and large refractive index of silicon over the infrared wavelength range result in a visibility of 33 dB for the reflection spectrum. A novel average wavelength tracking method has been proposed and demonstrated for sensor demodulation with improved signal-to-noise ratio, which leads to a temperature resolution of 6 × 10⁻4 °C. Due to the high thermal diffusivity of silicon, a response time as short as 0.51 ms for a sensor with an 80-µm-diameter and 200-µm-long silicon pillar has been experimentally achieved, suggesting a maximum frequency of ~2 kHz can be reached, to address the needs for highly dynamic environmental variations such as those found in the ocean.

Fast-response fiber-optic anemometer with temperature self-compensation.

We report a novel fiber-optic anemometer with self-temperature compensation capability based on a Fabry-Pérot interferometer (FPI) formed by a thin silicon film attached to the end face of a single-mode fiber. Guided in the fiber are a visible laser beam from a 635 nm diode laser used to heat the FPI and a white-light in the infrared wavelength range as the signal light to interrogate the optical length of the FPI. Cooling effects on the heated sensor head by wind is converted to a wavelength blueshift of the reflection spectral fringes of the FPI. Self-temperature-compensated measurement of wind speed is achieved by recording the difference in fringe wavelengths when the heating laser is turned on and then off. Large thermal-optic coefficient and thermal expansion coefficient of silicon render a high sensitivity that can also be easily tuned by altering the heating laser power. Furthermore, the large thermal diffusivity and the small mass of the thin silicon film endow a fast sensor response.

Fiber-optic refractometer based on a phase-shifted fiber Bragg grating on a side-hole fiber.

A fiber-optic refractive index (RI) sensor based on a π-phase-shifted fiber-Bragg-grating (πFBG) inscribed on a side-hole fiber is presented. The reflection spectrum of the πFBG features two narrow notches associated with the two polarization modes and the spectral spacing of the notches is used for high-sensitivity RI sensing with little temperature cross-sensitivity. The side-hole fiber maintains its outer diameter and mechanical strength. The side-hole fiber is also naturally integrated into a microfluidic system for convenient sample delivery and reduced sample amount. A novel demodulation method based on laser frequency modulation to enhance the sensor dynamic range is proposed and demonstrated.

Fiber-optic gas pressure sensing with a laser-heated silicon-based Fabry-Perot interferometer.

We report a novel fiber-optic sensor for measurement of static gas pressure based on the natural convection of a heated silicon pillar attached to a fiber tip functioning as a Fabry-Perot interferometer (FPI). A visible laser beam is guided by the fiber to efficiently heat the silicon pillar, while an infrared whitelight source, also guided by the fiber, is used to measure the temperature of the FPI, which is influenced both by the laser power and the pressure through natural convection. We theoretically and experimentally show that, by monitoring the fringe shift caused by the laser heating, air pressure sensing with little temperature cross-sensitivity can be achieved. The pressure sensitivity can be easily tuned by adjusting the heating laser power. In our experiment, the sensor performance within the temperature range from 20°C to 50°C and the pressure range from 0 to 1400 psi has been characterized, showing an average sensitivity of -0.52 pm/psi. Compared to the passive version of the sensor, the pressure sensitivity was ∼15 times larger, and the temperature cross-sensitivity was ∼100 times smaller.

Tuning response range of a transmission-based fiber-optic refractometer through LP11 mode.

A kind of sensing scheme is theoretically proposed to efficiently tune the response range of a fiber-optic refractometer based on the adiabatic transmission of the higher-order LP11 mode. Near the cut-off condition, transmission of the LP11 mode is a strong function of the refractive index (RI) under detection; thus high sensitivity is achieved. The cut-off RI value is dependent on the waist diameter; therefore the response RI range with high sensitivity can be changed just by altering the waist diameter. Theoretical calculations reveal that the response range is effectively tuned from 1.43-1.438 to 1.35-1.365 when the waist diameter is reduced from 2.5 to 1 µm. The proposed fiber-optic sensor is also superior when used as an absorbing sensor since the higher-order mode LP11 has a much larger power fraction in the evanescent field compared with the fundamental mode LP01 of the same fiber.

Superparamagnetic iron oxide nanoparticle enhanced percutaneous microwave ablation: Ex-vivo characterization using magnetic resonance thermometry.

BACKGROUND: Percutaneous microwave ablation (pMWA) is a minimally invasive procedure that uses a microwave antenna placed at the tip of a needle to induce lethal tissue heating. It can treat cancer and other diseases with lower morbidity than conventional surgery, but one major limitation is the lack of control over the heating region around the ablation needle. Superparamagnetic iron oxide nanoparticles have the potential to enhance and control pMWA heating due to their ability to absorb microwave energy and their ease of local delivery. PURPOSE: The purpose of this study is to experimentally quantify the capabilities of FDA-approved superparamagnetic iron oxide Feraheme nanoparticles (FHNPs) to enhance and control pMWA heating. This study aims to determine the effectiveness of locally injected FHNPs in increasing the maximum temperature during pMWA and to investigate the ability of FHNPs to create a controlled ablation zone around the pMWA needle. METHODS: PMWA was performed using a clinical ablation system at 915 MHz in ex-vivo porcine liver tissues. Prior to ablation, 50 uL 5 mg/mL FHNP injections were made on one side of the pMWA needle via a 23-gauge needle. Local temperatures at the FHNP injection site were directly compared to equidistant control sites without FHNP. First, temperatures were compared using directly inserted thermocouples. Next, temperatures were measured non-invasively using magnetic resonance thermometry (MRT), which enabled comprehensive four-dimensional (volumetric and temporal) assessment of heating effects relative to nanoparticle distribution, which was quantified using dual-echo ultrashort echo time (UTE) subtraction MR imaging. Maximum heating within FHNP-exposed tissues versus control tissues were compared at multiple pMWA energy delivery settings. The ability to generate a controlled asymmetric ablation zone using multiple FHNP injections was also tested. Finally, intra-procedural MRT-derived heat maps were correlated with gold standard gross pathology using Dice similarity analysis. RESULTS: Maximum temperatures at the FHNP injection site were significantly higher than control (without FHNP) sites when measured using direct thermocouples (93.1 ± 6.0°C vs. 57.2 ± 8.1°C, p = 0.002) and using non-invasive MRT (115.6 ± 13.4°C vs. 49.0 ± 10.6°C, p = 0.02). Temperature difference between FHNP-exposed and control sites correlated with total energy deposition: 66.6 ± 17.6°C, 58.1 ± 8.5°C, and 20.8 ± 9.2°C at high (17.5 ± 2.2 kJ), medium (13.6 ± 1.8 kJ), and low (8.8 ± 1.1 kJ) energies, respectively (all pairwise p < 0.05). Each FHNP injection resulted in a nanoparticle distribution within 0.9 ± 0.2 cm radially of the injection site and a local lethal heating zone confined to within 1.1 ± 0.4 cm radially of the injection epicenter. Multiple injections enabled a controllable, asymmetric ablation zone to be generated around the ablation needle, with maximal ablation radius on the FHNP injection side of 1.6 ± 0.2 cm compared to 0.7 ± 0.2 cm on the non-FHNP side (p = 0.02). MRT intra-procedural predicted ablation zone correlated strongly with post procedure gold-standard gross pathology assessment (Dice similarity 0.9). CONCLUSIONS: Locally injected FHNPs significantly enhanced pMWA heating in liver tissues, and were able to control the ablation zone shape around a pMWA needle. MRI and MRT allowed volumetric real-time visualization of both FHNP distribution and FHNP-enhanced pMWA heating that was useful for intra-procedural monitoring. This work strongly supports further development of a FHNP-enhanced pMWA paradigm; as all individual components of this approach are approved for patient use, there is low barrier for clinical translation.

Extraordinary optical absorption based on guided-mode resonance.

We propose a novel structure that can achieve extraordinary optical absorption over the visible spectrum, based on the guided-mode resonance effect. An optical metal grating with moderate thickness and high filling factor can lead to coupling between the quasi-guided-mode and cavity mode. The resonant interaction between the two modes can influence the field distribution, such as the magnetic field near the grating, which results in extraordinary absorption. Absorption efficiency can be optimized up to 99.16%. We also show that the absorption peak can be readily tuned just by varying the subwavelength grating period.