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.

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.

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.

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.

Long-GRIN-Lens Microendoscopy Enabled by Wavefront Shaping for a Biomedical Microdevice: An Analytical Investigation.

We analytically investigate the feasibility of long graded-index (GRIN)-lens-based microendoscopes through wavefront shaping. Following the very well-defined ray trajectories in a GRIN lens, mode-dependent phase delay is first determined. Then, the phase compensation needed for obtaining diffraction limited resolution is derived. Finally, the diffraction pattern of the lens output is computed using the Rayleigh-Sommerfeld diffraction theory. We show that diffraction-limited resolution is obtained for a 0.5 mm diameter lens with a length over 1 m. It is also demonstrated that different imaging working distances (WDs) can be realized by modifying the phase compensation. When a short design WD is used, a large imaging numerical aperture (NA) higher than 0.4 is achievable even when a low NA lens (NA = 0.1) is used. The long- and thin-GRIN-lens-based microendoscope investigated here, which is attractive for biomedical applications, is being prioritized for use in a clinical stage microdevice that measures three-dimensional drug responses inside the body. The advance described in this work may enable superior imaging capabilities in clinical applications in which long and flexible imaging probes are favored.

A Miniaturized Platform for Multiplexed Drug Response Imaging in Live Tumors.

By observing the activity of anti-cancer agents directly in tumors, there is potential to greatly expand our understanding of drug response and develop more personalized cancer treatments. Implantable microdevices (IMD) have been recently developed to deliver microdoses of chemotherapeutic agents locally into confined regions of live tumors; the tissue can be subsequently removed and analyzed to evaluate drug response. This method has the potential to rapidly screen multiple drugs, but requires surgical tissue removal and only evaluates drug response at a single timepoint when the tissue is excised. Here, we describe a "lab-in-a-tumor" implantable microdevice (LIT-IMD) platform to image cell-death drug response within a live tumor, without requiring surgical resection or tissue processing. The LIT-IMD is inserted into a live tumor and delivers multiple drug microdoses into spatially discrete locations. In parallel, it locally delivers microdose levels of a fluorescent cell-death assay, which diffuses into drug-exposed tissues and accumulates at sites of cell death. An integrated miniaturized fluorescence imaging probe images each region to evaluate drug-induced cell death. We demonstrate ability to evaluate multi-drug response over 8 h using murine tumor models and show correlation with gold-standard conventional fluorescence microscopy and histopathology. This is the first demonstration of a fully integrated platform for evaluating multiple chemotherapy responses in situ. This approach could enable a more complete understanding of drug activity in live tumors, and could expand the utility of drug-response measurements to a wide range of settings where surgery is not feasible.

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.

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.

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.

A Silicon-tipped Fiber-optic Sensing Platform with High Resolution and Fast Response.

In this article, we introduce an innovative and practically promising fiber-optic sensing platform (FOSP) that we proposed and demonstrated recently. This FOSP relies on a silicon Fabry-Perot interferometer (FPI) attached to the fiber end, referred to as Si-FOSP in this work. The Si-FOSP generates an interferogram determined by the optical path length (OPL) of the silicon cavity. Measurand alters the OPL and thus shifts the interferogram. Due to the unique optical and thermal properties of the silicon material, this Si-FOSP exhibits an advantageous performance in terms of sensitivity and speed. Furthermore, the mature silicon fabrication industry endows the Si-FOSP with excellent reproducibility and low cost toward practical applications. Depending on the specific applications, either a low-finesse or high-finesse version will be utilized, and two different data demodulation methods will be adopted accordingly. Detailed protocols for fabricating both versions of the Si-FOSP will be provided. Three representative applications and their according results will be shown. The first one is a prototype underwater thermometer for profiling the ocean thermoclines, the second one is a flow meter to measure flow speed in the ocean, and the last one is a bolometer used for monitoring exhaust radiation from magnetically confined high-temperature plasma.

A fiber-optic bolometer based on a high-finesse silicon Fabry-Pérot interferometer.

We report a fiber-optic bolometer based on a high-finesse silicon Fabry-Perot interferometer (FPI). The silicon FPI absorbs and converts the incident radiation into temperature variations, which are interrogated by the shift of the reflection spectrum of the FPI. The FPI is a silicon pillar with one side coated with a high-reflectivity dielectric mirror and the other side coated with a gold mirror. A multimode fiber collimator is applied between the FPI and lead-in single-mode fiber to reduce the round-trip diffraction loss, giving rise to a high-finesse of 35 of the FPI. The sensor is demodulated using a low-cost distributed feedback diode laser. A dummy bolometer was used to effectively reduce the common noises from the laser wavelength drift and ambient temperature variations. Experimental results show that, compared with a previously reported fiber-optic bolometer, the one reported here has a 5-fold decrease in noise and a 7-fold increase in responsivity with a noise equivalent power density (NEPD) of 0.27 W/m2, which is comparable with the NEPDs of the state-of-the-art resistive bolometers.

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.

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.

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.

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.

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.

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.

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.

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 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.