Biomedical Imaging Applications Research Articles

Progress towards wafer-scale fabrication based on gel casting technique for 1–3 randomised piezocomposite μUS linear array

Microultrasound (μUS) linear arrays operating at frequencies over 25 MHz have applications in high resolution biomedical imaging. 1–3 connectively piezoceramic – polymer composite (“piezocomposite”) material is attractive for fabrication of these devices due to its high effective electromechanical coupling coefficient and low acoustic impedance for better acoustic matching between transducer and tissue. However, a major concern with this type of material comes from interference between the fundamental thickness-mode resonance and spurious modes, which is usually generated by wave propagation and reflection within the repetitive and symmetrical structure of classical piezocomposite. In general, a fine spatial scale is required of the material structure to suppress the spurious modes; however, the fabrication process is challenging using standard dice-and-fill methods at the fine scales required for high frequencies. A promising way to overcome this challenge is to manipulate the lateral geometry and spacing of the piezoceramic pillars with a random distribution. In this work, gel casting in association with a micromoulding technique has been developed for manufacturing 1–3 randomised piezocomposite active material for μUS linear arrays. 48 vol% solid loading of piezoceramic powder with 30 wt% Hydantoin resin content was employed to prepare a low viscosity aqueous suspension. Through varying powder size, it was found that the suspension with 1.22 µm powder had the highest viscosity, ~ 0.47 Pa.s, and a short gelation time, ~ 10 mins. However, all suspensions had viscosities less than 1 Pa.s at a shear rate of 100 s−1, indicating that they had good flowability. The green body samples showed mean flexural strength 49.7 ± 2.49 MPa. After piezocomposite fabrication with randomised pillars, surface planarisation was used to obtain reliable edge definition of photolithographically-defined electrodes. 20-element arrays with 50-μm element pitch were configured using a bilayer lift-off process. The 1–3 randomised piezocomposite demonstrated its capability to minimise the effects of spurious modes in the thickness mode frequency range, while the thickness resonances provided k33 = 0.67. Without a matching layer, the array produced a − 6 dB bandwidth of 38.4%- and − 20-dB pulse length of 0.26 μs. These results show that 1–3 randomised piezocomposite fabricated from gel-casting associated with a micromoulding technique is feasible for fabrication of μUS linear arrays and may offer a route to small wafer-scale production.

Acoustic, Phononic, Brillouin Light Scattering and Faraday Wave-Based Frequency Combs: Physical Foundations and Applications.

Frequency combs (FCs)—spectra containing equidistant coherent peaks—have enabled researchers and engineers to measure the frequencies of complex signals with high precision, thereby revolutionising the areas of sensing, metrology and communications and also benefiting the fundamental science. Although mostly optical FCs have found widespread applications thus far, in general FCs can be generated using waves other than light. Here, we review and summarise recent achievements in the emergent field of acoustic frequency combs (AFCs), including phononic FCs and relevant acousto-optical, Brillouin light scattering and Faraday wave-based techniques that have enabled the development of phonon lasers, quantum computers and advanced vibration sensors. In particular, our discussion is centred around potential applications of AFCs in precision measurements in various physical, chemical and biological systems in conditions where using light, and hence optical FCs, faces technical and fundamental limitations, which is, for example, the case in underwater distance measurements and biomedical imaging applications. This review article will also be of interest to readers seeking a discussion of specific theoretical aspects of different classes of AFCs. To that end, we support the mainstream discussion by the results of our original analysis and numerical simulations that can be used to design the spectra of AFCs generated using oscillations of gas bubbles in liquids, vibrations of liquid drops and plasmonic enhancement of Brillouin light scattering in metal nanostructures. We also discuss the application of non-toxic room-temperature liquid–metal alloys in the field of AFC generation.

Extrusion: A New Method for Rapid Formulation of High-Yield, Monodisperse Nanobubbles.

Shell-stabilized gas microbubbles (MB) and nanobubbles (NB) are frequently used for biomedical ultrasound imaging and therapeutic applications. While it is widely recognized that monodisperse bubbles can be more effective in these applications, the efficient formulation of uniform bubbles at high concentrations is difficult to achieve. Here, it is demonstrated that a standard mini-extruder setup, commonly used to make vesicles or liposomes, can be used to quickly and efficiently generate monodisperse NBs with high yield. In this highly reproducible technique, the NBs obtained have an average diameter of 0.16± 0.05µm and concentration of 6.2± 1.8 × 1010 NBs mL-1 compared to 0.32± 0.1µm and 3.2± 0.7 × 1011 mL-1 for NBs made using mechanical agitation. Parameters affecting the extrusion and NB generation process including the temperature, concentration of the lipid solution, and the number of passages through the extruder are also examined. Moreover, it is demonstrated that extruded NBs show a strong acoustic response in vitro and a strong and persistent US signal enhancement under nonlinear contrast enhanced ultrasound imaging in mice. The extrusion process is a new, efficient, and scalable technique that can be used to easily produce high yield smaller monodispersed nanobubbles.

Detecting the orbital angular momentum from speckle via convolutional neural network

The inhomogeneity of turbid medium disrupts the coherent vortex structure of the vortex beam and causes the formation of a speckle pattern. Here, we propose a new, flexible approach to measure the orbital angular momentum (OAM) of vortex beams through a turbid medium by a convolutional neural network. The proposed technique directly recognizes the speckle image and obtains the corresponding OAM mode information. The accuracies exceed 99% and 97% in simulations and experiments respectively. In addition, the relationship between the recognition accuracy and environmental noise level, is present. The results show great potential in fiber communication, biomedical imaging and astronomical application, etc.

Fast and Inexpensive Separation of Bright Phosphor Particles from Commercial Sources by Gravitational and Centrifugal Sedimentation for Deep Tissue X-ray Luminescence Imaging

X-ray luminescence tomography (XLT) detects X-ray scintillators contrast agents using a focused or collimated X-ray beam to provide high spatial resolution excitation through thick tissue. The approach requires bright nanophosphors that are either synthesized or purchased. However, currently available commercial nanophosphors are mostly composed of a polydisperse mixture of several micro- to nano-sized particles that are unsuitable for biomedical imaging applications because of their size and aggregated form. Here, we demonstrate a fast and robust method to obtain uniform nano to submicron phosphor particles from a commercial source of polydisperse Eu- and Tb-doped Gd2O2S particles by separating the smaller particles present using gravitational and centrifugal sedimentation. In contrast to ball milling for 15–60 min, which drastically degraded the particles’ brightness while reducing their size, our sedimentation method enabled the extraction of comparatively bright nanophosphors (≈100–300 nm in size) with a luminescence intensity of ≈10–20% of the several micron particles in the sample. Moreover, if scale up for higher yielding is required, the sedimentation process can be accelerated using fixed-angle and/or swinging bucket rotating centrifugation. Finally, after separation and characterization, nano and submicron phosphors were suspended and imaged through 5 mm thick porcine tissue using our in-house-built scanning X-ray induced luminescence chemical imaging (XELCI) system.

Quinolinium-based viscosity probes for lysosome imaging and tracing lysosomal viscosity changes in living cells

Lysosomal viscosity fluctuation is related to various diseases such as diabetes, neurodegenerative diseases, and cancer. We designed and synthesized four novel pH-insensitive fluorescent viscosity probes (Lyso-QAP1–4) using a quinolinium as the fluorophore and acceptor group while an internal amino benzene ring was incorporated as a donor group and a targeting group for monitoring the viscosity change of lysosomes. Lyso-QAP1–4 possessed a highly sensitive response toward viscosity change with red emission at around 625–640 nm (excited around 570–580 nm), excellent water solubility, good photostability, favorable membrane permeabilization, and moderate cytotoxicity. Colocalization study proved that Lyso-QAP1–4 probes exhibited fast lysosomal detection (within 15 min) without influencing effect from other microenvironments like pH, polarity, and interferent species but Lyso-QAP4 (without a phenyl ring on C2 of quinolinium) also localized in nucleus. Importantly, we demonstrated that a phenyl ring on C2 of quinolinium and an internal amino benzene played an important role in the lysosome specificity. Lyso-QAP1–4 probes can be applied for intracellular viscosity detection. Moreover, Lyso-QAP3 was successfully applied to living cell imaging for cellular and lysosomal viscosity changes. These results suggest that Lyso-QAP3 would provide new opportunities for biomedical diagnosis and imaging applications.

Recent Progress of Squaraine-Based Fluorescent Materials and Their Biomedical Applications

Squaraines (SQs) are unusual cyanine dyes with a unique resonance-stabilized zwitterionic structure. These dyes have attracted significant attention in the fields of organic electronics and organic photonics, due to their facile synthesis, intense and narrow visible and near-infrared absorption/emission, high photostability, low biotoxicity, etc. In this review, we summarize the recent progress of SQ-based fluorescent materials and their biomedical applications. After a brief introduction to SQs, general synthetic routes and design principles of SQ-based fluorescent materials, as well as their aggregation-induced luminescence behaviors, are discussed. Subsequently, their biomedical applications for cell imaging and as fluorescent sensors and therapeutic agents are introduced. Finally, a summary and perspective are given for promoting the development of SQs-based fluorescent materials.

Upconversion of NaYF4: Yb, Er Nanoparticles Co-doped with Zr 4+ for Magnetic Phase Transition and Biomedical Imaging Applications

Upconversion of NaYF4: Yb, Er Nanoparticles Co-doped with Zr 4+ for Magnetic Phase Transition and Biomedical Imaging Applications

FPI Based Hyperspectral Imager for the Complex Surfaces-Calibration, Illumination and Applications.

Hyperspectral imaging (HSI) applications for biomedical imaging and dermatological applications have been recently under research interest. Medical HSI applications are non-invasive methods with high spatial and spectral resolution. HS imaging can be used to delineate malignant tumours, detect invasions, and classify lesion types. Typical challenges of these applications relate to complex skin surfaces, leaving some skin areas unreachable. In this study, we introduce a novel spectral imaging concept and conduct a clinical pre-test, the findings of which can be used to develop the concept towards a clinical application. The SICSURFIS spectral imager concept combines a piezo-actuated Fabry–Pérot interferometer (FPI) based hyperspectral imager, a specially designed LED module and several sizes of stray light protection cones for reaching and adapting to the complex skin surfaces. The imager is designed for the needs of photometric stereo imaging for providing the skin surface models (3D) for each captured wavelength. The captured HS images contained 33 selected wavelengths (ranging from 477 nm to 891 nm), which were captured simultaneously with accordingly selected LEDs and three specific angles of light. The pre-test results show that the data collected with the new SICSURFIS imager enable the use of the spectral and spatial domains with surface model information. The imager can reach complex skin surfaces. Healthy skin, basal cell carcinomas and intradermal nevi lesions were classified and delineated pixel-wise with promising results, but further studies are needed. The results were obtained with a convolutional neural network.

Bioconvective electromagnetohydrodynamic hybrid nanoliquid flow over a stretching sheet with stratification effects: a four-factor response surface optimized model

The current work presents a theoretical investigation on the bioconvective electromagnetohydrodynamic (EMHD) hybrid nanofluid flow over a stretching surface considering viscous dissipation, chemical reaction, and stratification effects. The highly nonlinear system of partial differential equations (PDEs) is reduced to a system of ordinary differential equations (ODEs) with the aid of effectual similarity transformations. The transmuted ODEs are then treated numerically using bvp4c (a finite difference-based built-in numerical procedure) in MATLAB. It is observed that an increase in the electric field parameter augments the velocity profile. It is also noted that the Nusselt number is a decreasing function of the thermal stratification parameter. Further, the influence of nanoparticle volume fraction of carbon nanotubes , the nanoparticle volume fraction of magnetite nanoparticles , Hartmann number , and electric field parameter on the drag coefficient has been statistically scrutinized utilizing the four-factor response surface methodology. The highest drag coefficient is experienced for smaller values of Hartmann number and larger values of electric field parameter. The current work finds application in cancer therapy, bio-microsystems, biomedical imaging, and therapeutic drug delivery.

High-speed super-resolution imaging with compressive imaging-based structured illumination microscopy.

Structured illumination microscopy (SIM) has been widely applied to investigating fine structures of biological samples by breaking the optical diffraction limitation. So far, video-rate imaging has been obtained in SIM, but the imaging speed was still limited due to the reconstruction of a super-solution image through multi-sampling, which hindered the applications in high-speed biomedical imaging. To overcome this limitation, here we develop compressive imaging-based structured illumination microscopy (CISIM) by synergizing SIM and compressive sensing (CS). Compared with conventional SIM, CISIM can greatly improve the super-resolution imaging speed by extracting multiple super-resolution images from one compressed image. Based on CISIM, we successfully reconstruct the super-resolution images in biological dynamics, and analyze the effect factors of image reconstruction quality, which verify the feasibility of CISIM. CISIM paves a way for high-speed super-resolution imaging, which may bring technological breakthroughs and significant applications in biomedical imaging.

Simultaneous visualization of multiple radionuclides in vivo.

The insufficient energy and spatial resolutions of radionuclide imaging with conventional scintillation detectors restrict the visualization of multiple radionuclides and of microstructures in tissue. Here we report the development and performance of an imaging system equipped with a cadmium telluride diode detector that achieves an energy resolution of 1.7% at 140 keV and a spatial resolution of 250 μm. The combination of high-resolution spectra fitted to an X-ray analysis model of the emission lines of the radionuclides in a chosen energy band allowed us to accurately determine individual radiation activities from three radionuclides to simultaneously visualize thyroid tissue (via intravenously administered iodine-125), mandibular lymph nodes (via the intramuscular injection of indium-111) and parotid lymph nodes (via a subcutaneous injection of technetium-99m) in mice. Multi-radionuclide imaging may find advantageous applications in biomedical imaging.

Gadolinium doped red-emissive carbon dots as targeted theranostic agents for fluorescence and MR imaging guided cancer phototherapy

As a new type of fluorescent agents, carbon dots (CDs) have revealed great potential in biomedical imaging applications attributed to their unique optical properties and good biocompatibility. However, engineering a versatile CDs nanoplatform integrating multifunctional imaging and therapeutic functionalities has always been an intractable challenge in targeted cancer treatment based on carbon nanomaterials. Herein, a gadolinium-doped CD conjugated with AS1411 aptamers (AS1411-Gd-CD) was prepared via facile solvothermal approach for targeted fluorescence (FL)/MR imaging guided photothermal therapy (PTT). The synthesized AS1411-Gd-CDs exhibited uniform nanostructure, good biocompatibility, strong red-fluorescence emission, significant MR contrast and efficient photothermal conversion. Benefiting from these outstanding properties, the AS1411-Gd-CDs were successfully employed in tumor-specific FL/MR dual-modal imaging in vitro and in vivo. Furthermore, under the guidance of FL/MR imaging, the AS1411-Gd-CDs demonstrated significant tumor inhibition effect owing to the outstanding photothermal effect. Thus, this study provided a versatile CDs nanoplatform as a multifunctional theranostic agent for synergistic FL/MR imaging and PTT in cancer treatment.

Fluorescence conjugated nanostructured cobalt-doped hydroxyapatite platform for imaging-guided drug delivery application

Multifunctional nanomaterials developed from hydroxyapatite (HAp) with enhanced biological characteristics have recently attracted attention in the biomedical field. The goal of this study is to investigate the potential applications of cobalt-doped HAp (Co-HAp) in the biomedical imaging and therapeutic applications. The co-precipitation approach was used to substitute different molar concentrations of Ca2+ ions with cobalt (Co2+) in HAp structure. The synthesized Co-HAp nanoparticles were studied using various sophisticated techniques to verify the success rate of the doping method. The specific crystal structure, functional groups, size, morphology, photoluminescence property, and thermal stability of the Co-HAp nanoparticles were analyzed based on the characterization results. The computational modelling of doped and undoped HAp reveals the difference in crystal structure parameters. The cytotoxicity study (MTT assay and AO/PI/Hoechst fluorescence staining) reveals the non-toxic characteristics of Co-HAp nanoparticles on MDA-MB-231 breast cancer cell lines. The DOX was loaded onto Co-HAp, showing the maximum drug loading capacity for 2.0 mol% Co-HAp. Drug release was estimated in five different pH environments with various time intervals over 72 h. Furthermore, 2.0 mol% Co-HAp shows excellent fluorescence sensitivity with FITC-conjugated MDA-MB-231 cell lines. These results suggest that cobalt improved the fluorescence intensity of FITC-labeled HAp nanoparticles. This work highlights the promising application of Co-HAp nanoparticles with significant enhanced fluorescence activity for imaging-guided drug delivery system.

Hybrid Dirac semimetal-based photodetector with efficient low-energy photon harvesting

Despite the considerable effort, fast and highly sensitive photodetection is not widely available at the low-photon-energy range (~meV) of the electromagnetic spectrum, owing to the challenging light funneling into small active areas with efficient conversion into an electrical signal. Here, we provide an alternative strategy by efficiently integrating and manipulating at the nanoscale the optoelectronic properties of topological Dirac semimetal PtSe2 and its van der Waals heterostructures. Explicitly, we realize strong plasmonic antenna coupling to semimetal states near the skin-depth regime (λ/104), featuring colossal photoresponse by in-plane symmetry breaking. The observed spontaneous and polarization-sensitive photocurrent are correlated to strong coupling with the nonequilibrium states in PtSe2 Dirac semimetal, yielding efficient light absorption in the photon range below 1.24 meV with responsivity exceeding ∼0.2 A/W and noise-equivalent power (NEP) less than ~38 pW/Hz0.5, as well as superb ambient stability. Present results pave the way to efficient engineering of a topological semimetal for high-speed and low-energy photon harvesting in areas such as biomedical imaging, remote sensing or security applications.

Chemical Design of Activatable Photoacoustic Probes for Precise Biomedical Applications.

Photoacoustic (PA) imaging technology, a three-dimensional hybrid imaging modality that integrates the advantage of optical and acoustic imaging, has great application prospects in molecular imaging due to its high imaging depth and resolution. To endow PA imaging with the ability for real-time molecular visualization and precise biomedical diagnosis, numerous activatable molecular PA probes which can specifically alter their PA intensities upon reacting with the targets or biological events of interest have been developed. This review highlights the recent developments of activatable PA probes for precise biomedical applications including molecular detection of the biotargets and imaging of the biological events. First, the generation mechanism of PA signals will be given, followed by a brief introduction to contrast agents used for PA probe design. Then we will particularly summarize the general design principles for the alteration of PA signals and activatable strategies for developing precise PA probes. Furthermore, we will give a detailed discussion of activatable PA probes in molecular detection and biomedical imaging applications in living systems. At last, the current challenges and outlooks of future PA probes will be discussed. We hope that this review will stimulate new ideas to explore the potentials of activatable PA probes for precise biomedical applications in the future.

Extreme material parameters accessible by active acoustic metamaterials with Willis coupling.

Active acoustic metamaterials incorporate electric circuit elements that input energy into an otherwise passive medium to aptly modulate the effective material properties. Here, we propose an active acoustic metamaterial with Willis coupling to drastically extend the tunability of the effective density and bulk modulus with the accessible parameter range enlarged by at least two orders of magnitude compared to that of a non-Willis metamaterial. Traditional active metamaterial designs are based on local resonances without considering the Willis coupling that limit their accessible effective material parameter range. Our design adopts a unit cell structure with two sensor-transducer pairs coupling the acoustic response on both sides of the metamaterial by detecting incident waves and driving active signals asymmetrically superimposed onto the passive response of the material. The Willis coupling results from feedback control circuits with unequal gains. These asymmetric feedback control circuits use Willis coupling to expand the accessible range of the effective density and bulk modulus of the metamaterial. The extreme effective material parameters realizable by the metamaterials will remarkably broaden their applications in biomedical imaging, noise control, and transformation acoustics-based cloaking.

Generation of broadband parabolic pulses based on a pre-chirper free, core-pumped nonlinear fiber amplifier for coherent anti-Stokes Raman imaging

We report the generation of parabolic pulses with broadband spectrum from a core-pumped Yb-doped fiber amplifier seeded by a dispersion managed fiber oscillator. The net cavity dispersion of Yb-doped oscillator was continuously changed from 0.074 to -0.170ps2, which enabled us to achieve dissipative soliton, stretched pulse and soliton mode-locking operations. Spectral evolution processes in the core-pumped nonlinear fiber amplifier seeded by various input solitons were investigated experimentally and theoretically. Our finding indicates that cavity dispersion of oscillator can be used to engineer the input pulse parameter for amplifier, thus forming a pre-chirper free fiber amplification structure. In the experiment, we obtained 410-mW parabolic pulses with spectral bandwidth up to 56 nm. In combination with a passively synchronized frequency-doubled Er-doped fiber laser, we have demonstrated coherent anti-Stokes Raman imaging. The compact dual-color fiber laser source may facilitate practical applications of nonlinear biomedical imaging beyond the laboratory environment.

Effect of Thermal History and Hydrocarbon Core Size on Perfluorocarbon Endoskeletal Droplet Vaporization.

Vaporizable hydrocarbon-in-fluorocarbon endoskeletal droplets are a unique category of phase-change emulsions with interesting physical and thermodynamic features. Here, we show microfluidic fabrication of various morphologies, such as solid-in-liquid, liquid-in-solid, and Janus-type, of complex solid n-C20H42 or n-C21H44 and liquid n-C5F12 droplets. Furthermore, we investigated the vaporization behavior of these endoskeletal droplets, focusing on the effects of heat treatment and core size. Comparison of vaporization and differential scanning calorimetry results indicated that vaporization occurs prior to melting of the bulk hydrocarbon phase for C20H42/C5F10 droplets and near the rotator phase for C21H44/C5F10 droplets. We found that heat treatment of the droplets increased the fraction of droplets that vaporized and also increased the vaporization temperature of the droplets, although the effect was temporary. Furthermore, we found that changing the relative size of the solid hydrocarbon core compared to the surrounding liquid shell increased the vaporization temperature and the vaporizing fraction. Taken together, these data support the hypothesis that surface melting behavior exhibited by the linear alkane may trigger the fluorocarbon vaporization event. These results may aid in the understanding of the interfacial thermodynamics and transport and the engineering of novel vaporizable endoskeletal droplets for biomedical imaging and other applications.

A low-profile flexible planar monopole antenna for biomedical applications

This article proposes a low profile planar monopole antenna on flexible substrate. The antenna is designed with an elliptical slot inserted in a rectangular patch by utilizing the coplanar waveguide (CPW) feeding technique on a polyimide substrate. The proposed antenna operates within 7–14 GHz (S11 < − 10 dB) with a minimum return loss is observed as low as – 58 dB by simulation, whereas the entire X-band is covered by the – 20 dB bandwidth while maintaining an excellent VSWR of almost 1. Also, the antenna exhibits an average gain of 4 dBi while the average radiation efficiency is 92%. The maximum SAR of the proposed antenna for 1 g mass is below 1.0 W/Kg throughout the entire bandwidth. To observe flexibility, four different bending conditions of the antenna have been analyzed. For experimentation, the antenna has been realized as a prototype by using a low-cost fabrication process. The measurement reveals that the prototype has a −10 dB bandwidth of 5.4 GHz. During In-Vivo test, over the variation of 0 ∼ 3 mm distance between the antenna-prototype and the human chest/chicken breast tissue, the best performance is obtained at 3 mm in terms of the return loss. One of the significant features of the proposed design is its measured average and peak gain of 4.4 dBi and of 6.33 dBi respectively with a measured average efficiency of 65%. The proposed antenna has a compact size of 13 × 13 mm2 (0.35λg×0.35λg), and its performance remains nominally constant even under different bending conditions which makes the antenna suitable for biomedical imaging applications. A new figure-of-merit has been introduced to evaluate the overall performance based on different antenna key parameters. The fabricated antenna would contribute to the future biomedical research by utilizing X-band frequencies.