MEMS-based two-photon microscopy with Lissajous scanning and image reconstruction under a feed-forward control strategy.

Two-photon microscopy (TPM) based on two-dimensional micro-electro-mechanical (MEMS) system mirrors shows promising applications in biomedicine and the life sciences. To improve the imaging quality and real-time performance of TPM, this paper proposes Lissajous scanning control and image reconstruction under a feed-forward control strategy, a dual-parameter alternating drive control algorithm and segmented phase synchronization mechanism, and pipe-lined fusion-mean filtering and median filtering to suppress image noise. A 10 fps frame rate (512 × 512 pixels), a 140 µm × 140 µm field of view, and a 0.62 µm lateral resolution were achieved. The imaging capability of MEMS-based Lissajous scanning TPM was verified by ex vivo and in vivo biological tissue imaging.

The development of cancers research based on mitochondrial heat shock protein 90.

Mitochondrial heat shock protein 90 (mtHsp90), including Tumor necrosis factor receptor-associated protein 1 (TRAP1) and Hsp90 translocated from cytoplasm, modulating cellular metabolism and signaling pathways by altering the conformation, activity, and stability of numerous client proteins, and is highly expressed in tumors. mtHsp90 inhibition results in the destabilization and eventual degradation of its client proteins, leading to interference with various tumor-related pathways and efficient control of cancer cell development. Among these compounds, gamitrinib, a specific mtHsp90 inhibitor, has demonstrated its safety and efficacy in several preclinical investigations and is currently undergoing evaluation in clinical trials. This review aims to provide a comprehensive overview of the present knowledge pertaining to mtHsp90, encompassing its structure and function. Moreover, our main emphasis is on the development of mtHsp90 inhibitors for various cancer therapies, to present a thorough overview of the recent pre-clinical and clinical advancements in this field.

The Development of Immunotherapy for the Treatment of Recurrent Glioblastoma.

Recurrent glioblastoma (rGBM) is a highly aggressive form of brain cancer that poses a significant challenge for treatment in neuro-oncology, and the survival status of patients after relapse usually means rapid deterioration, thus becoming the leading cause of death among patients. In recent years, immunotherapy has emerged as a promising strategy for the treatment of recurrent glioblastoma by stimulating the body's immune system to recognize and attack cancer cells, which could be used in combination with other treatments such as surgery, radiation, and chemotherapy to improve outcomes for patients with recurrent glioblastoma. This therapy combines several key methods such as the use of monoclonal antibodies, chimeric antigen receptor T cell (CAR-T) therapy, checkpoint inhibitors, oncolytic viral therapy cancer vaccines, and combination strategies. In this review, we mainly document the latest immunotherapies for the treatment of glioblastoma and especially focus on rGBM.

Miniature Two-Photon Microscopic Imaging Using Dielectric Metalens.

Miniature two-photon microscopy has emerged as a powerful technique for investigating brain activity in freely moving animals. Ongoing research objectives include reducing probe weight and minimizing animal behavior constraints caused by probe attachment. Employing dielectric metalenses, which enable the use of sizable optical components in flat device structures while maintaining imaging resolution, is a promising solution for addressing these challenges. In this study, we designed and fabricated a titanium dioxide metalens with a wavelength of 920 nm and a high aspect ratio. Furthermore, a meta-optic two-photon microscope weighing 1.36 g was developed. This meta-optic probe has a lateral resolution of 0.92 µm and an axial resolution of 18.08 µm. Experimentally, two-photon imaging of mouse brain structures in vivo was also demonstrated. The flat dielectric metalens technique holds promising opportunities for high-performance integrated miniature nonlinear microscopy and endomicroscopy platforms in the biomedical field.

High-power, sub-100-fs, 1600-1700-nm all-fiber laser for deep multiphoton microscopy.

The 1600-1700-nm ultrafast fiber lasers attract great interests in the deep multiphoton microscopy, due to the reduced levels of the tissue scattering and absorption. Here, we report on the 86.7-MHz, 717-mW, 91.2-fs, all-fiber laser located in the spectral range from 1600 nm to 1700nm. The soliton self-frequency shift (SSFS) was introduced into the Er:Yb co-doped fiber amplifier (EYDFA) to generate the high-power, 1600-1700-nm Raman soliton. Detailed investigations of the nonlinear fiber amplification process were implemented in optimizing the generated Raman soliton pulses. The miniature multiphoton microscopy was further realized with this home-built laser source. The clearly imaging results can be achieved by collecting the generated harmonic signals from the mouse tail skin tissue with a penetration depth of ∼500 µm. The experimental results indicate the great potential in utilizing this 1600-1700-nm fiber laser in the deep multiphoton microscopy.

Two-photon endomicroscopy with microsphere-spliced double-cladding antiresonant fiber for resolution enhancement.

We demonstrate a miniature fiber-optic two two-photon endomicroscopy with microsphere-spliced double-cladding antiresonant fiber for resolution enhancement. An easy-to-operate process for fixing microsphere permanently in an antiresonant fiber core, by arc discharge, is proposed. The flexible fiber-optic probe is integrated with a parameter of 5.8 mm × 49.1 mm (outer diameter × rigid length); the field of view is 210 µm, the resolution is 1.3 µm, and the frame rate is 0.7 fps. The imaging ability is verified using ex-vivo mouse kidney, heart, stomach, tail tendon, and in-vivo brain neural imaging.

Non-Invasive Skin Imaging Assessment of Human Stress During Head-Down Bed Rest Using a Portable Handheld Two-Photon Microscope.

Spaceflight presents a series of physiological and pathological challenges to astronauts resulting from ionizing radiation, microgravity, isolation, and other spaceflight hazards. These risks cause a series of aging-related diseases associated with increased oxidative stress and mitochondria dysfunction. The skin contains many autofluorescent substances, such as nicotinamide adenine dinucleotide phosphate (NAD(P)H), keratin, melanin, elastin, and collagen, which reflect physiological and pathological changes in vivo. In this study, we used a portable handheld two-photon microscope to conduct high-resolution in vivo skin imaging on volunteers during 15 days of head-down bed rest. The two-photon microscope, equipped with a flexible handheld scanning head, was used to measure two-photon excited fluorescence (TPEF) and second harmonic generation (SHG) images of the left forearm, left front chest, and forehead of volunteers. Changes in TPEF, SHG, and the extended SHG-to-AF(TPEF) aging index of the dermis (SAAID) were measured. It was found that TPEF intensity increased during bed rest and was restored to normal levels after recovery. Meanwhile, SHG increased slightly during bed rest, and the skin aging index increased. Moreover, we found the skin TPEF signals of the left forearm were significantly negatively associated with the oxidative stress marker malondialdehyde (MDA) and DNA damage marker 8-hydroxy-2'-desoxyguanosine (8-OHdG) values of subjects during head-down bed rest. Meanwhile, the SHG signals were also significantly negatively correlated with MDA and 8-OHDG. A significant negative correlation between the extended SAAID of the left chest and serum antioxidant superoxide dismutase (SOD) levels was also found. These results demonstrate that skin autofluorescence signals can reflect changes in human oxidant status. This study provides evidence for in-orbit monitoring of changes in human stress using a portable handheld two-photon microscope for skin imaging.

High-resolution micro-optical accelerometer with an electromagnetic driver: design and analysis.

Optical displacement detection is widely used in various micro-electro-mechanical system (MEMS) sensors because of its high sensitivity. The optical accelerometer has a high theoretical resolution. However, due to the small working range of optical detection, the open-loop measuring range of a high-resolution optical accelerometer is usually only tens to hundreds of milligrams. To increase the measurement range, we propose a high-resolution micro-optical accelerometer with electromagnetic force feedback. The optical principle, mechanical structure, and manufacturing process are analyzed. The accelerometer is predicted to work in the first modal with displacement sensitivity at 2.56 µm/g, corresponding to 0th diffraction beam optical sensitivity 1.93%/nm. The designed electromagnetic driver can increase the acceleration measurement range from 0.012 to ±20g. These results provide a theoretical basis for the design and fabrication of a high-resolution micro-optical accelerometer with an electromagnetic driver. The electromagnetic drive scheme introduced effectively improves the dynamic range of high-precision optical accelerometers and can be applied to other optical MEMS sensors.

Linewidth-related residual intensity modulation in lithium niobate phase modulators.

We present a modified model for residual intensity modulation (RIM) observed in lithium niobate phase modulators, which is suitable for both narrow linewidth and wide linewidth lasers. This model is based on two key points leading to RIM: one is the optical propagation loss, which is proportional to the applied voltage, and the other is the interference between an injected wave and its reflection from the lithium niobate substrate. In order to verify the model, the RIM is measured accurately with different linewidths of input lasers respectively. The experimental results are in good agreement with the theoretical model as the values of fitting determination coefficient R-square are all above 0.995. The results have revealed that the chief reasons causing RIM are different. When using a narrow linewidth laser, the interference is the dominant reason leading to RIM as the ratio of the reflection-related coefficient including linewidth effects to optical loss reaches 34.33. However, the optical loss is the dominant reason leading to RIM with the ratio mentioned above reaching 0.31 when using a wide linewidth laser.

Interferometric optical gyroscope based on an integrated silica waveguide coil with low loss.

An interferometric optical gyro (IOG) based on integrated devices are a promising alternative for miniaturized inertial sensors. However, improving their accuracy, which is determined by the sensing coil insertion loss, is crucial. In this work, an IOG is built using an integrated sensing coil produced from a 2.14-m-long SiO2 waveguide, the minimum bend radius and spacing of which are chosen to minimize the sensing coil insertion loss. The coil length is chosen by considering optimal detection limit constraints. Sinusoidal wave biasing modulation improves the system detection sensitivity. Finally, the IOG realizes the best yet reported bias drift of 7.32°/h.

Realization of Hollow-Core Photonic-Crystal Fiber Optic Gyro Based on Low-Noise Multi-Frequency Lasers with Intermediate-Frequency Difference.

Mainly focusing on the demand for a novel resonator optic gyro based on a hollow-core photonic-crystal fiber (HC-RFOG), we achieve a multi-frequency lasers generation with low relative phase noise via an acousto-optic modulation of light from a single laser diode. We design a homologous heterodyne digital optical phase-locked loop (HHD-OPLL), based on which we realize the low-noise multi-frequency lasers (LNMFLs) with an intermediate frequency difference. The noise between the lasers with a 20 MHz difference is 0.036 Hz, within the bandwidth of 10 Hz, in a tuning range of 120 kHz, approximately 40 dB lower than that produced without the HHD-OPLL. Finally, based on the LNMFLs, an HC-RFOG is realized and a bias stability of 5.8 °/h is successfully demonstrated.

Steady-state frequency-tracking distortion in the digital Pound-Drever-Hall technique.

We present here a general method for evaluating the steady-state frequency-tracking distortion in the digital Pound-Drever-Hall technique with modulation harmonic distortion. The theoretical tracking distortion model is established based on the multi-beam interference theory. The effects of the additional harmonic phase shift and the relative distortion ratio changes in the model are simulated by the Runge-Kutta method. Moreover, we demonstrate the steady-state frequency-tracking distortion caused by the modulation harmonic distortion in a resonant frequency tracking system with a 35 mm Si3N4 waveguide ring resonator. According to the measured and simulated results, we obtain the optimal modulation frequency and depth with minimal frequency-tracking distortion, which are 11.49 MHz and 3.96, respectively.

Resonant fiber optic gyroscope with three-frequency differential detection by sideband locking.

A new scheme of three-frequency differential detection with a sideband locking technique is firstly proposed to suppress backscattering noise for improving the accuracy of resonator fiber optic gyroscope (RFOG). In the system we proposed, one light path is divided into three paths and sinusoidal wave modulations of different frequencies are respectively applied to generate the sideband. The first-order sidebands of the three channels of light in the cavity are locked to the adjacent three resonance peaks by sideband locking technique. The carrier and the remaining sidebands of the three channels of light are moved to a position away from the resonance peak, thereby achieving the purpose of being suppressed by the cavity itself. As a result, the frequency difference between the CW light and the other two CCW lights reaches one free spectral range (FSR), eliminating the expected backscattering noise. The experimental results demonstrate that the RFOG has a bias stability 0.9°/h based on the Allan deviation, and the corresponding angular random walk (ARW) 0.016°/√h, which validate that our scheme can effectively suppress backscattering noise to promote performance of RFOG in practical applications.

High-resolution micro-grating accelerometer based on a gram-scale proof mass.

Micro-grating accelerometer detecting small displacement by an optical system can be widely applied in inertial navigation and seismic monitoring. We proposed a micro-grating accelerometer prototype with a proof mass of gram-scale to decrease the thermal mechanical noise, which is the fundamental limit of a high-resolution accelerometer. The theoretical model for the contrast ratio of a micro-grating accelerometer is established based on Gaussian beam theory, and the adjustment method based on a scanning slit beam profiler improves the contrast ratio of 0th order effectively. Compared to our former prototype, experiment results indicate the noise floor is decreased from 0.9 mg/√Hz to 137 ng/√Hz, and the bias stability is decreased from 0.35 mg to 3.1 µg.

Design of low-crosstalk polarizing resonator and homologous multi-frequency differential detection for hollow-core photonic-crystal fiber optic gyro.

In order to suppress the undesired polarization in the hollow-core photonic-crystal fiber (HCPCF) resonator and reduce the loss of the resonator, we realize a low-crosstalk polarizing resonator with the polarization-correlated phase modulation technique (PCPM). In addition, we put forward a homologous multi-frequency differential detection scheme, with which the backscattering noise and the backreflection noise of the gyro can be well suppressed. Finally, we realize a hollow-core photonic-crystal fiber optic gyro based on the low-crosstalk polarizing resonator and the homologous multi-frequency differential detection. With this novel gyro system, a bias stability of 1.23°/h is successfully demonstrated.

Free spectral range measurement using homologous heterodyne optical phase-locked loop based on acousto-optic modulation.

We demonstrate a homologous heterodyne optical phase-locked loop for free spectral range measurement of a fiber ring resonator. In this loop, the frequency noise within the 10 Hz bandwidth is reduced by more than 40 dB from 147.350 to 0.014 Hz, and the power spectral density of the frequency noise reaches 7.69×10-8 Hz2/Hz at 10 Hz. Finally, the relative measurement accuracy of 1.39×10-9 is achieved by this loop and the free spectral range coefficient of thermal expansion is measured as -174.1±0.2 Hz/°C with a cavity finesse of 26.65. This work provides a method to measure free spectral range by tracking the resonance modes of the resonator and reducing frequency noise, especially for two signals with frequency offset.

Optical sensitivity enhancement in grating based micromechanical accelerometer by reducing non-parallelism error.

We report on optical sensitivity enhancement in a grating-based micromechanical accelerometer, which was achieved by reducing the non-parallelism error between the grating and reflected mirror. Based on the multi-slit Fraunhofer diffraction theory, an equivalent optical model is proposed in order to discuss the non-parallelism induced error that is caused by the residual stress in material and fabrication. An integrated fabrication flow with optimized quartz based and silicon based procedure is then presented to improve the parallelism between the grating and mirror, and to realize a hermetic package using silicon islands for the electrical interconnection. We experimentally characterize accelerometers' behavior by an interferometric beam detecting setup, which reveals the acceleration measurement with a scale factor improvement, noise floor decrease, and thus a bias stability enhancement from 2 mg to 0.35 mg (20 seconds interval, 1 g = 9.8 m/s2).

Modulation index stabilization technique of integrated optic phase modulator used in resonant integrated optic gyro.

A novel modulation index stabilization technique for tracking the phase modulation index of integrated optic phase modulator (IOPM) is proposed to improve temperature performance of the resonant integrated optic gyro (RIOG). The influence mechanism of IOPM's modulation index fluctuation on the RIOG, especially the angular velocity tracking loop of RIOG, is investigated. A Mach-Zehnder Interferometer (MZI) is ingeniously added into the conventional RIOG structure for detecting the modulation index fluctuation. For synchronously demodulating the output of RIOG and the gain of IOPM in real time, a novel six-state wave modulation scheme is also proposed. Moreover, considering the disturbance and nonlinearity, the system model of IOPM's modulation index controller is established and designed to guarantee high speed and precision tracking. The experimental results demonstrate that the proposed modulation index stabilization technique can in real time demodulate and control the modulation index of IOPM. The gyro scale factor stability of RIOG resulting from the IOPM's modulation index fluctuation is decreased to 189.26 ppm within -40°C to +60°C, which, to the best of our knowledge, is the first time stabilizing the modulation index of IOPM in RIOG at full temperature.

Passive compensation of intensity and polarization-induced noise by a quadrature demodulation technique in a resonator optic gyroscope.

Polarization-induced noise is a dominant noise that seriously hinders the progress of resonator optic gyroscopes. Many countermeasures have been developed but showed insufficient performance. In this paper, we propose a quadrature demodulation technique (QDT) that adopts references of both sine and cosine to demodulate the signal. Theoretical analyses of the polarization effect and QDT are shown, and experimental results are listed and compared. Experimental results are consistent with theoretical analyses. QDT shows great performance in suppressing environment- and polarization-induced phase fluctuation of signal. We also demodulate the intensity-dependent coefficient of 2Ωt term, which is demonstrated effective for compensating polarization-induced intensity noise together with QDT. The scheme shows significant progress in improving long-term stability.

Imaging of guided waves using an all-fiber reflection-based NSOM with self-compensation of a phase drift.

A phase-resolved reflection-based near-field scanning optical microscopy (NSOM) technique with an original all-fiber configuration is presented. Our system consists of an intrinsically phase-stable common-path interferometer. The reflection from the waveguide input facet or from an integrated fiber Bragg grating is used as the reference beam. This arrangement effectively suppresses the phase drift caused by environmental fluctuations. By raster scanning a silicon atomic force microscope probe, we measure the complex near fields of the propagating and stationary waves in silicon nanowaveguides. Our robust, align-free, cost-effective, and shot-noise-limited near-field imaging technique paves the way for versatile optical characterizations of nanophotonic structures on a chip.