arXiv subjects

Ji-Xin Cheng

Publications and source records attributed to Ji-Xin Cheng.

At least 37 records · Page 2Linked to original sources

arXiv2023

Far-field Super-resolution Chemical Microscopy

Far-field chemical microscopy providing molecular electronic or vibrational fingerprint information opens a new window for the study of three-dimensional biological, material, and chemical systems. Chemical microscopy provides a nondestructive way of chemical identification without exterior labels. However, the diffraction limit of optics hindered it from discovering more details under the resolution limit. Recent development of super-resolution techniques gives enlightenment to open this door behind far-field chemical microscopy. Here, we review recent advances that have pushed the boundary of far-field chemical microscopy in terms of spatial resolution. We further highlight applications in biomedical research, material characterization, environmental study, cultural heritage conservation, and integrated chip inspection.

physics.optics↗

arXiv2023

Mid-infrared Chemical Imaging of Intracellular Tau Fibrils using Fluorescence-guided Computational Photothermal Microscopy

Amyloid proteins are associated with a broad spectrum of neurodegenerative diseases. However, it remains a grand challenge to extract molecular structure information from intracellular amyloid proteins in their native cellular environment. To address this challenge, we developed a computational chemical microscope integrating 3D mid-infrared photothermal imaging with fluorescence imaging, termed Fluorescence-guided Bond-Selective Intensity Diffraction Tomography (FBS-IDT). Based on a low-cost and simple optical design, FBS-IDT enables chemical-specific volumetric imaging and 3D site-specific mid-IR fingerprint spectroscopic analysis of tau fibrils, an important type of amyloid protein aggregates, in their intracellular environment. Label-free volumetric chemical imaging of human cells with/without seeded tau fibrils is demonstrated to show the potential correlation between lipid accumulation and tau aggregate formation. Depth-resolved mid-infrared fingerprint spectroscopy is performed to reveal the protein secondary structure of the intracellular tau fibrils. 3D visualization of the \b{eta}-sheet for tau fibril structure is achieved.

physics.optics↗

arXiv2023

Bond-Selective Full-Field Optical Coherence Tomography

Optical coherence tomography (OCT) is a label-free, non-invasive 3D imaging tool widely used in both biological research and clinical diagnosis. Current OCT modalities can only visualize specimen tomography without chemical information. Here, we report a bondselective full-field OCT (BS-FF-OCT), in which a pulsed mid-infrared laser is used to modulate the OCT signal through the photothermal effect, achieving label-free bond-selective 3D sectioned imaging of highly scattering samples. We first demonstrate BS-FF-OCT imaging of 1 μm PMMA beads embedded in agarose gel. Next, we then show 3D hyperspectral imaging of polypropylene fiber mattress from a standard surgical mask. We then demonstrate BS-FFOCT imaging on biological samples, including cancer cell spheroids and C. elegans. Using an alternative pulse timing configuration, we finally demonstrate the capability of BS-FF-OCT on a bulky and highly scattering 150 μm thick mouse brain slice.

physics.optics↗

arXiv2023

Multifunctional fiber-based optoacoustic emitter for non-genetic bidirectional neural communication

A bidirectional brain interface with both "write" and "read" functions can be an important tool for fundamental studies and potential clinical treatments for neurological diseases. Here we report a miniaturized multifunctional fiber based optoacoustic emitter (mFOE) that first integrates simultaneous non-genetic optoacoustic stimulation for "write" and electrophysiology recording of neural circuits for "read". The non-genetic feature addresses the challenges of the viral transfection required by optogenetics in primates and human. The orthogonality between optoacoustic waves and electrical field provides a solution to avoid the interference between electrical stimulation and recording. We first validated the non-genetic stimulation function of the mFOE in rat cultured neurons using calcium imaging. In vivo application of mFOE for successful simultaneous optoacoustic stimulation and electrical recording of brain activities was confirmed in mouse hippocampus in both acute and chronical applications up to 1 month. Minimal brain tissue damage has been confirmed after these applications. The capability of non-genetic neural stimulation and recording enabled by mFOE opens up new possibilities for the investigation of neural circuits and brings new insights into the study of ultrasound neurostimulation.

q-bio.NC↗

arXiv2022

Optically-generated focused ultrasound for noninvasive brain stimulation with ultrahigh precision

High precision neuromodulation is a powerful tool to decipher neurocircuits and treat neurological diseases. Current non-invasive neuromodulation methods offer limited precision at the millimeter level. Here, we report optically-generated focused ultrasound (OFUS) for non-invasive brain stimulation with ultrahigh precision. OFUS is generated by a soft optoacoustic pad (SOAP) fabricated through embedding candle soot nanoparticles in a curved polydimethylsiloxane film. SOAP generates a transcranial ultrasound focus at 15 MHz with an ultrahigh lateral resolution of 83 um, which is two orders of magnitude smaller than that of conventional transcranial-focused ultrasound (tFUS). Here, we show effective OFUS neurostimulation in vitro with a single ultrasound cycle. We demonstrate submillimeter transcranial stimulation of the mouse motor cortex in vivo. An acoustic energy of 0.6 mJ/cm^2, four orders of magnitude less than that of tFUS, is sufficient for successful OFUS neurostimulation. OFUS offers new capabilities for neuroscience studies and disease treatments by delivering a focus with ultrahigh precision non-invasively.

q-bio.NC↗

arXiv2022

Mid-Infrared Photothermal-Fluorescence in Situ Hybridization for Functional Analysis and Genetic Identification of Single Cells

Simultaneous identification and metabolic analysis of microbes with single-cell resolution and high throughput is necessary to answer the question of "who eats what, when, and where" in complex microbial communities. Here, we present a mid-infrared photothermal-fluorescence in situ hybridization (MIP-FISH) platform that enables direct bridging of genotype and phenotype. Through multiple improvements of MIP imaging, the sensitive detection of isotopically-labelled compounds incorporated into proteins of individual bacterial cells became possible, while simultaneous detection of FISH labelling with rRNA-targeted probes enabled the identification of the analyzed cells. In proof-of-concept experiments, we showed that the clear spectral red shift in the protein amide I region due to incorporation of $^{13}$C atoms originating from $^{13}$C-labelled-glucose can be exploited by MIP-FISH to discriminate and identify $^{13}$C-labelled bacterial cells within a complex human gut microbiome sample. The presented methods open new opportunities for single-cell structure-function analyses for microbiology.

physics.bio-ph↗

arXiv2022

Bond-Selective Intensity Diffraction Tomography

Recovering molecular information remains a grand challenge in the widely used holographic and computational imaging technologies. To address this challenge, we developed a computational mid-infrared photothermal microscope, termed Bond-selective Intensity Diffraction Tomography (BS-IDT). Based on a low-cost brightfield microscope with an add-on pulsed light source, BS-IDT recovers both infrared spectra and bond-selective 3D refractive index maps from intensity-only measurements. High-fidelity infrared fingerprint spectra extraction is validated. Volumetric chemical imaging of biological cells is demonstrated at a speed of ~20 seconds per volume, with a lateral and axial resolution of ~350 nm and ~1.1 micron, respectively. BS-IDT's application potential is investigated by chemically quantifying lipids stored in cancer cells and volumetric chemical imaging on Caenorhabditis elegans with a large field of view (~100 micron X 100 micron).

physics.optics↗

arXiv2021

Multi-window SRS imaging using a rapid widely tunable fiber laser

Spectroscopic stimulated Raman scattering (SRS) imaging has become a useful tool finding a broad range of applications. Yet, wider adoption is hindered by the bulky and environmentally-sensitive solid-state optical parametric oscillator (OPO) in current SRS microscope. Moreover, chemically-informative multi-window SRS imaging across C-H, C-D and fingerprint Raman regions is challenging due to the slow wavelength tuning speed of the solid-state OPO. In this work, we present a multi-window SRS imaging system based on a compact and robust fiber laser with rapid and widely tuning capability. To address the relative intensity noise intrinsic to fiber laser, we implemented auto-balanced detection which enhances the signal-to-noise ratio of stimulated Raman loss imaging by 23 times. We demonstrate high-quality SRS metabolic imaging of fungi, cancer cells, and Caenorhabditis elegans across the C-H, C-D and fingerprint Raman windows. Our re-sults showcase the potential of the compact multi-window SRS system for a broad range of applications.

physics.optics↗

arXiv2021

Bond-selective interferometric scattering microscopy

Interferometric scattering microscopy has been a very promising technology for highly sensitive label-free imaging of a broad spectrum of biological nanoparticles from proteins to viruses in a high-throughput manner. Although it can reveal the specimen's size and shape information, the chemical composition is inaccessible in interferometric measurements. Infrared spectroscopic imaging provides chemical specificity based on inherent chemical bond vibrations of specimens but lacks the ability to image and resolve individual nanoparticles due to long infrared wavelengths. Here, we describe a bond-selective interferometric scattering microscope where the mid-infrared induced photothermal signal is detected by a visible beam in a wide-field common-path interferometry configuration. A thin film layered substrate is utilized to reduce the reflected light and provide a reference field for the interferometric detection of the weakly scattered field. A pulsed mid-IR laser is employed to modulate the interferometric signal. Subsequent demodulation via a virtual lock-in camera offers simultaneous chemical information about tens of micro- or nano-particles. The chemical contrast arises from a minute change in the particle's scattered field in consequence of the vibrational absorption at the target molecule. We characterize the system with sub-wavelength polymer beads and highlight biological applications by chemically imaging several microorganisms including Staphylococcus aureus, Escherichia coli, and Candida albicans. A theoretical framework is established to extend bond-selective interferometric scattering microscopy to a broad range of biological micro- and nano-particles.

physics.optics↗

arXiv2021

Background-Suppressed High-Throughput Mid-Infrared Photothermal Microscopy via Pupil Engineering

Mid-infrared photothermal (MIP) microscopy has been a promising label-free chemical imaging technique for functional characterization of specimens owing to its enhanced spatial resolution and high specificity. Recently developed wide-field MIP imaging modalities have drastically improved speed and enabled high-throughput imaging of micron-scale subjects. However, the weakly scattered signal from sub-wavelength particles becomes indistinguishable from the shot-noise as a consequence of the strong background light, leading to limited sensitivity. Here, we demonstrate background-suppressed chemical fingerprinting at a single nanoparticle level by selectively attenuating the reflected light through pupil engineering in the collection path. Our technique provides over three orders of magnitude background suppression by quasi-darkfield illumination in epi-configuration without sacrificing lateral resolution. We demonstrate 6-fold signal-to-background noise ratio improvement, allowing for simultaneous detection and discrimination of hundreds of nanoparticles across a field of view of 70 um x 70 um. A comprehensive theoretical framework for photothermal image formation is provided and experimentally validated with 300 and 500~nm PMMA beads. The versatility and utility of our technique are demonstrated via hyperspectral dark-field MIP imaging of S. aureus and E. coli bacteria.

physics.optics↗

arXiv2021

Fluorescence-Enhanced Mid-Infrared Photothermal Microscopy

Mid-infrared photothermal microscopy is a new chemical imaging technology in which a visible beam senses the photothermal effect induced by a pulsed infrared laser. This technology provides infrared spectroscopic information at sub-micron spatial resolution and enables infrared spectroscopy and imaging of living cells and organisms. Yet, current mid-infrared photothermal imaging sensitivity suffers from a weak dependance of scattering on temperature and the image quality is vulnerable to the speckles caused by scattering. Here, we present a novel version of mid-infrared photothermal microscopy in which thermo-sensitive fluorescent probes are harnessed to sense the mid-infrared photothermal effect. The fluorescence intensity can be modulated at the level of 1% per Kelvin, which is 100 times larger than the modulation of scattering intensity. In addition, fluorescence emission is free of speckles, thus much improving the image quality. Moreover, fluorophores can target specific organelles or biomolecules, thus augmenting the specificity of photothermal imaging. Spectral fidelity is confirmed through fingerprinting a single bacterium. Finally, the photobleaching issue is successfully addressed through the development of a wide-field fluorescence-enhanced mid-infrared photothermal microscope which allows video rate bond-selective imaging of biological specimens.

physics.optics↗

arXiv2021

Vibrational Spectroscopic Detection of Single Virus by a Confocal Interferometric Mid-Infrared Photothermal Microscope

We report a confocal interferometric mid-infrared photothermal (MIP) microscope and its application to label-free detection of biological nanoparticles down to single virus level. We apply the interferometric scattering principle to detect the weak photothermal effect induced by infrared absorption in a viral particle. We validated this method with two kinds of viruses, namely the vesicular stomatitis virus (VSV) and poxvirus. The single virus spectra generated by MIP microscopy show high consistency in the same group, with dominant peaks contributed by the amide I and amide II vibrations. The ratio of these two peaks are significantly different between VSV and poxvirus, highlighting the potential of using MIP microscopy for label-free differentiation of viral particles. This all-optical chemical imaging method opens a new way for spectroscopic detection of biological nanoparticles in a label-free manner and may facilitate in predicting and controlling outbreaks of emerging virus strains.

physics.app-ph↗

arXiv2020

Non-genetic acoustic stimulation of single neurons by a tapered fiber optoacoustic emitter

As an emerging technology, transcranial focused ultrasound has been demonstrated to successfully evoke motor responses in mice, rabbits, and sensory/motor responses in humans. Yet, the spatial resolution of ultrasound does not allow for high-precision stimulation. Here, we developed a tapered fiber optoacoustic emitter (TFOE) for optoacoustic stimulation of neurons with an unprecedented spatial resolution of 20 microns, enabling selective activation of single neurons or subcellular structures, such as axons and dendrites. A single acoustic pulse of 1 microsecond converted by the TFOE from a single laser pulse of 3 nanoseconds is shown as the shortest acoustic stimuli so far for successful neuron activation. The highly localized ultrasound generated by the TFOE made it possible to integrate the optoacoustic stimulation and highly stable patch clamp recording on single neurons. Direct measurements of electrical response of single neurons to acoustic stimulation, which is difficult for conventional ultrasound stimulation, have been demonstrated for the first time. By coupling TFOE with ex vivo brain slice electrophysiology, we unveil cell-type-specific response of excitatory and inhibitory neurons to acoustic stimulation. These results demonstrate that TFOE is a non-genetic single-cell and sub-cellular modulation technology, which could shed new insights into the mechanism of neurostimulation.

q-bio.NC↗

arXiv2020

Rapid Determination of Antimicrobial Susceptibility by Stimulated Raman Scattering Imaging of D2O Metabolic Incorporation in a Single Bacterium

Rapid antimicrobial susceptibility testing (AST) is urgently needed for treating infections with correct antibiotics and slowing down the emergence of antibiotic-resistant bacteria. Here, we report a phenotypic platform that rapidly produces AST results by femtosecond stimulated Raman scattering imaging of deuterium oxide (D2O) metabolism. Metabolic incorporation of D2O into biomass in a single bacterium is probed in as short as 10 minutes after culture in 70% D2O medium, the fastest among current technologies. Single-cell metabolism inactivation concentration (SC-MIC) is obtained in less than 2.5 hours from colony to results. The SC-MIC results of 37 sets of samples, which include 8 major bacterial species and 14 different antibiotics often encountered in clinic, are validated by standard minimal inhibitory concentration blindly measured via broth microdilution. Towards clinical translation, SRS imaging of D2O metabolic incorporation and SC-MIC determination after 1-h antibiotics treatment and 30-minutes mixture of D2O and antibiotics incubation of bacteria in urine or whole blood is demonstrated.

physics.bio-ph↗

arXiv2020

Fingerprint Spectroscopic SRS Imaging of Single Living Cells and Whole Brain by Ultrafast Tuning and Spatial-Spectral Learning

Label-free vibrational imaging by stimulated Raman scattering (SRS) provides unprecedented insight into real-time chemical distributions in living systems. Specifically, SRS in the fingerprint region can resolve multiple chemicals in a complex bio-environment using specific and well-separated Raman signatures. Yet, fingerprint SRS imaging with microsecond spectral acquisition has not been achieved due to the small fingerprint Raman cross-sections and the lack of ultrafast acquisition scheme with high spectral resolution and high fidelity. Here, we report a fingerprint spectroscopic SRS platform that acquires a distortion-free SRS spectrum with 10 cm-1 spectral resolution in 20 microseconds using a lab-built ultrafast delay-line tuning system. Meanwhile, we significantly improve the signal-to-noise ratio by employing a spatial-spectral residual learning network, reaching comparable quality to images taken with two orders of magnitude longer pixel dwell times. Collectively, our system achieves reliable fingerprint spectroscopic SRS with microsecond spectral acquisition speed, enabling imaging and tracking of multiple biomolecules in samples ranging from a live single microbe to a tissue slice, which was not previously possible with SRS imaging in the highly congested carbon-hydrogen region. To show the broad utility of the approach, we have demonstrated high-speed compositional imaging of lipid metabolism in living pancreatic cancer Mia PaCa-2 cells. We then performed high-resolution mapping of cholesterol, fatty acid, and protein in the mouse whole brain. Finally, we mapped the production of two biofuels in microbial samples by harnessing the superior spectral and temporal resolutions of our system.

physics.med-ph↗

arXiv2019

Multiplex stimulated Raman scattering imaging cytometry reveals cancer metabolic signatures in a spatially, temporally, and spectrally resolved manner

In situ measurement of cellular metabolites is still a challenge in biology. Conventional methods, such as mass spectrometry or fluorescence microscopy, would either destruct the sample or introduce strong perturbations to the functions of target molecules. Here, we present multiplex stimulated Raman scattering (SRS) imaging cytometry as a label-free single-cell analysis platform with chemical specifity, and high-throughput capabilities. Cellular compartments such as lipid droplets, endoplasmic reticulum, and nuclei are seperated from the cytoplasm. Based on these chemical segmentations, 260 features from both morphology and molecular composition were generated and analyzed for each cell. Using SRS imaging cytometry, we studied the metabolic responses of human pancreatic cancer cells under stress by starvation and chemotherapy drug treatments. We unveiled lipid-facilitated protrusion as a metabolic marker for stress-resistant cancer cells through statistical analysis of thousands of cells. Our findings also demonstrate the potential of targeting lipid metabolism for selective treatment of starvation-resistant and chemotherapy-resistant cancers. These results highlight our SRS imaging cytometry as a powerful label-free tool for biological discoveries with a high-throughput, high-content capacity.

q-bio.QM↗

arXiv2019

Ultra-Efficient Conversion of Microwave into Ultrasound Wave through a Split Ring Resonator

Thermo-elastic conversion of electromagnetic wave into ultrasound wave has enabled diverse biomedical applications such as photoacoustic imaging. Microwave, which has ~10 cm long wavelength, can penetrate deeper into tissue than photons, heralding exciting applications such as deep tissue imaging via thermo-acoustic tomography. However, the thermo-acoustic conversion efficiency is very low even with an exogenous contrast agent such as carbon nanotube. Here, we break this low conversion limit through using a split ring resonator (SRR) to effectively collect and concentrate the microwave energy into a sub-millimeter hot spot and subsequently convert the energy into ultrasound wave. Our SRR achieves over three orders of magnitude higher thermo-acoustic conversion efficiency than commonly used thermo-acoustic contrast agents. We further harness the SRR as a wireless, battery-free ultrasound emitter placed under a breast phantom. These results promise exciting potential of SRR for precise thermo-acoustic localization and modulation of subjects in deep tissue.

physics.app-ph↗

arXiv2019

A Fiber Optoacoustic Emitter with Maximized Conversion Efficiency and Controlled Ultrasound Frequency for Biomedical Applications

Focused ultrasound has attracted great attention in minimally invasive therapy, gene delivery, brain stimulation, etc. Frequency below 1 MHz has been identified preferable for high-efficacy drug delivery, gene transfection and neurostimulation due to minimized tissue heating and cell fragmentation. However, the poor spatial resolution of several millimeters and the large device diameter of ~25 mm of current sub-MHz ultrasound technology severely hinders its further applications for effective, precise, safe and wearable biomedical studies and clinical use. To address this issue, we report the development of a novel fiber-based optoacoustic emitter (FOE). The FOE, a new miniaturized ultrasound source, is composed of an optical diffusion coating layer and an expansion coating layer at an optical fiber distal end with a diameter of approximately 500 microns. Taking advantage of the fiber size and diffusive nanoparticles introduced, the ultrasound generated by the FOEs showed a spatial confinement of sub-millimeter. The optoacoustic conversion efficiency was maximized through choosing absorbing nanomaterials and thermal expansion matrix. Controllable frequencies in the range of 0.083 MHz to 5.500 MHz were achieved through using the diffusion layer as a damping material or modifying the nano-composition in the expansion layer. This sub-MHz frequency controllability allows FOEs to be used as a localized ultrasound source for precise cell modulation. We demonstrated optoacoustic cell membrane sonoporation with a localization of sub-millimeter and negligible heat deposition, implicating its broad biomedical applications, including region-specific drug delivery, gene transfection as well as localized neuron stimulation.

physics.med-ph↗