Numerical Investigation of Layered Homogeneous Skull Model for Simulations of Transcranial Focused Ultrasound.

BACKGROUND AND OBJECTIVES: The influence of the intracranial pressure field must be discussed with the development of a single-element transducer for low-intensity transcranial focused ultrasound because the skull plays a significant role in blocking and dispersing ultrasound wave propagation. Ultrasound propagation is mainly affected by the structure and acoustic properties of the skull; thus, we aimed to investigate the impact of simplifying the acoustic properties of the skull on the simulation of the transcranial pressure field to present guidance for efficient skull modeling in full-wave simulations. MATERIALS AND METHODS: We constructed a three-dimensional computational model for ultrasound transmission with the same structure but varying acoustic properties of the skull. The structural information and heterogeneous acoustic properties of the skull were acquired from computed tomography images, and we segmented the skull into three layers (3 L), including spongy and compact bones. We then assigned homogeneous acoustic properties to a single layer (1 L) or 3 L of the skull. In addition, we investigated the influence of different types of transducers and different ultrasound frequencies (1.1 MHz, 0.5 MHz, and 0.25 MHz) on the intracranial pressure field to provide a comparison of the heterogenous and homogeneous models. RESULTS: We indicated the importance of numerical simulations in estimating the intracranial pressure field of the skull owing to beam distortions. When we simplified the skull model, both the 1 L and 3 L models showed contours of the acoustic focus comparable to those of the heterogeneous model. When we evaluated the peak pressure and volume of the acoustic focus, the 1 L model produced a better estimation of peak pressure with a difference <10%, and the 3 L model is suitable to obtain smaller errors in the volume of the acoustic focus. CONCLUSIONS: In conclusion, we examined the possibility of simplification of skull models using 1 L and 3 L homogeneous properties in the numerical simulation for focused ultrasound. The results show that the layered homogeneous model can provide characteristics comparable to those of the acoustic focus in heterogeneous models.

Resolution-enhanced optical inspection system to examine metallic nanostructures using structured illumination.

We developed a structured illumination-based optical inspection system to inspect metallic nanostructures in real time. To address this, we used post-image-processing techniques to enhance the image resolution. To examine the fabricated metallic nanostructures in real time, a compact and highly resolved optical inspection system was designed for practical industrial use. Structured illumination microscopy yields multiple images with various linear illumination patterns, which can be used to reconstruct resolution-enhanced images. Images of nanosized posts and complex structures reflected in the structured illumination were reconstructed into images with improved resolution. A comparison with wide-field images demonstrates that the optical inspection system exhibits high performance and is available as a real-time nanostructure inspection platform. Because it does not require special environmental conditions and enables multiple systems to be covered in arrays, the developed system is expected to provide real-time and noninvasive inspections during the production of large-area nanostructured components.

Fiber-Optic Localized Surface Plasmon Resonance Sensors Based on Nanomaterials.

Applying fiber-optics on surface plasmon resonance (SPR) sensors is aimed at practical usability over conventional SPR sensors. Recently, field localization techniques using nanostructures or nanoparticles have been investigated on optical fibers for further sensitivity enhancement and significant target selectivity. In this review article, we explored varied recent research approaches of fiber-optics based localized surface plasmon resonance (LSPR) sensors. The article contains interesting experimental results using fiber-optic LSPR sensors for three different application categories: (1) chemical reactions measurements, (2) physical properties measurements, and (3) biological events monitoring. In addition, novel techniques which can create synergy combined with fiber-optic LSPR sensors were introduced. The review article suggests fiber-optic LSPR sensors have lots of potential for measurements of varied targets with high sensitivity. Moreover, the previous results show that the sensitivity enhancements which can be applied with creative varied plasmonic nanomaterials make it possible to detect minute changes including quick chemical reactions and tiny molecular activities.

A Localized Surface Plasmon Resonance Sensor Using Double-Metal-Complex Nanostructures and a Review of Recent Approaches.

From active developments and applications of various devices to acquire outside and inside information and to operate based on feedback from that information, the sensor market is growing rapidly. In accordance to this trend, the surface plasmon resonance (SPR) sensor, an optical sensor, has been actively developed for high-sensitivity real-time detection. In this study, the fundamentals of SPR sensors and recent approaches for enhancing sensing performance are reported. In the section on the fundamentals of SPR sensors, a brief description of surface plasmon phenomena, SPR, SPR-based sensing applications, and several configuration types of SPR sensors are introduced. In addition, advanced nanotechnology- and nanofabrication-based techniques for improving the sensing performance of SPR sensors are proposed: (1) localized SPR (LSPR) using nanostructures or nanoparticles; (2) long-range SPR (LRSPR); and (3) double-metal-layer SPR sensors for additional performance improvements. Consequently, a high-sensitivity, high-biocompatibility SPR sensor method is suggested. Moreover, we briefly describe issues (miniaturization and communication technology integration) for future SPR sensors.

Surface plasmon-enhanced nanoscopy of intracellular cytoskeletal actin filaments using random nanodot arrays.

The feasibility of super-resolution microscopy has been investigated based on random localization of surface plasmon using blocked random nanodot arrays. The resolution is mainly determined by the size of localized fields in the range of 100-150 nm. The concept was validated by imaging FITC-conjugated phalloidin that binds to cellular actin filaments. The experimental results confirm improved resolution in reconstructed images. Effect of far-field registration on image reconstruction was also analyzed. Correlation between reconstructed images was maintained to be above 81% after registration. Nanodot arrays are synthesized by temperature-annealing without sophisticated lithography and thus can be mass-produced in an extremely large substrate. The results suggest a super-resolution imaging technique that can be accessible and available in large amounts.

Plasmonic Nanopillars-A Brief Investigation of Fabrication Techniques and Biological Applications.

Nanopillars (NPs) are submicron-sized pillars composed of dielectrics, semiconductors, or metals. They have been employed to develop advanced optical components such as solar cells, light-emitting diodes, and biophotonic devices. To integrate localized surface plasmon resonance (LSPR) with NPs, plasmonic NPs consisting of dielectric nanoscale pillars with metal capping have been developed and used for plasmonic optical sensing and imaging applications. In this study, we studied plasmonic NPs in terms of their fabrication techniques and applications in biophotonics. We briefly described three methods for fabricating NPs, namely etching, nanoimprinting, and growing NPs on a substrate. Furthermore, we explored the role of metal capping in plasmonic enhancement. Then, we presented the biophotonic applications of high-sensitivity LSPR sensors, enhanced Raman spectroscopy, and high-resolution plasmonic optical imaging. After exploring plasmonic NPs, we determined that they had sufficient potential for advanced biophotonic instruments and biomedical applications.

Enhanced image reconstruction of three-dimensional fluorescent assays by subtractive structured-light illumination microscopy.

We investigate improved image reconstruction of structured light illumination for high-resolution imaging of three-dimensional (3D) cell-based assays. For proof of concept, an in situ fluorescence optical detection system was built with a digital micromirror device as a spatial light modulator, for which phase and tilting angle in a grid pattern were varied to implement specific image reconstruction schemes. Subtractive reconstruction algorithms based on structured light illumination were used to acquire images of fluorescent microbeads deposited as a two-dimensional monolayer or in 3D alginate matrix. We have confirmed that an optical subtraction algorithm improves axial and lateral resolution by effectively removing out-of-focus fluorescence. The results suggest that subtractive image reconstruction can be useful for structured illumination microscopy of broad types of cell-based assays with high image resolution.

Plasmonic sensing, imaging, and stimulation techniques for neuron studies.

Studies to understand the structure, functions, and electrophysiological properties of neurons have been conducted at the frontmost end of neuroscience. Such studies have led to the active development of high-performance research tools for exploring the neurobiology at the cellular and molecular level. Following this trend, research and application of plasmonics, which is a technology employed in high-sensitivity optical biosensors and high-resolution imaging, is essential for studying neurons, as plasmonic nanoprobes can be used to stimulate specific areas of cells. In this study, three plasmonic modalities were explored as tools to study neurons and their responses: (1) plasmonic sensing of neuronal activities and neuron-related chemicals; (2) performance-improved optical imaging of neurons using plasmonic enhancements; and (3) plasmonic neuromodulations. Through a detailed investigation of these plasmonic modalities and research subjects that can be combined with them, it was confirmed that plasmonic sensing, imaging, and stimulation techniques have the potential to be effectively employed for the study of neurons and understanding their specific molecular activities.

Development of a photochemical thrombosis investigation system to obtain a rabbit ischemic stroke model.

Photochemical thrombosis is a method for the induction of ischemic stroke in the cerebral cortex. It can generate localized ischemic infarcts in the desired region; therefore, it has been actively employed in establishing an ischemic stroke animal model and in vivo assays of diagnostic and therapeutic techniques for stroke. To establish a rabbit ischemic stroke model and overcome the shortcoming of previous studies that were difficult to build a standardized photothrombotic rabbit model, we developed a photochemical thrombosis induction system that can produce consistent brain damage on a specific area. To verify the generation of photothrombotic brain damage using the system, longitudinal magnetic resonance imaging, 2,3,5-triphenyltetrazolium chloride staining, and histological staining were applied. These analytical methods have a high correlation for ischemic infarction and are appropriate for analyzing photothrombotic brain damage in the rabbit brain. The results indicated that the photothrombosis induction system has a main advantage of being accurately controlled a targeted region of photothrombosis and can produce cerebral hemisphere lesions on the target region of the rabbit brain. In conjugation with brain atlas, it can induce photochemical ischemic stroke locally in the part of the brain that is responsible for a particular brain function and the system can be used to develop animal models with degraded specific functions. Also, the photochemical thrombosis induction system and a standardized rabbit ischemic stroke model that uses this system have the potential to be used for verifications of biomedical techniques for ischemic stroke at a preclinical stage in parallel with further performance improvements.

A Review of Advanced Impedance Biosensors with Microfluidic Chips for Single-Cell Analysis.

Electrical impedance biosensors combined with microfluidic devices can be used to analyze fundamental biological processes for high-throughput analysis at the single-cell scale. These specialized analytical tools can determine the effectiveness and toxicity of drugs with high sensitivity and demonstrate biological functions on a single-cell scale. Because the various parameters of the cells can be measured depending on methods of single-cell trapping, technological development ultimately determine the efficiency and performance of the sensors. Identifying the latest trends in single-cell trapping technologies afford opportunities such as new structural design and combination with other technologies. This will lead to more advanced applications towards improving measurement sensitivity to the desired target. In this review, we examined the basic principles of impedance sensors and their applications in various biological fields. In the next step, we introduced the latest trend of microfluidic chip technology for trapping single cells and summarized the important findings on the characteristics of single cells in impedance biosensor systems that successfully trapped single cells. This is expected to be used as a leading technology in cell biology, pathology, and pharmacological fields, promoting the further understanding of complex functions and mechanisms within individual cells with numerous data sampling and accurate analysis capabilities.

Investigation of portable in situ fluorescence optical detection for microfluidic 3D cell culture assays.

A portable fluorescence optical detection system was developed to demonstrate real-time in situ analysis of cells that are three-dimensionally cultured in an extracellular matrix under microfluidic environment. The system was designed to provide a large field of view in the lateral plane to average out cellular processes in an axial layer and simultaneously diffraction-limited axial resolution. In this proof-of-concept study, the detection system was applied to quantitative analyses of short-term measurements of cell staining and cell cytotoxicity and long-term monitoring of a cell-invasion assay. For assays, colon cancer cells were cultured in a Matrigel or alginate matrix. The measured data were largely consistent with predicted results and revealed quantitatively cell dynamics specific to 3D cell cultures. The detection system has a potential as a single package to investigate 3D cultures in a microfluidic system.

Machine learning-based design of meta-plasmonic biosensors with negative index metamaterials.

In this work, we explore the performance of plasmonic biosensor designs that integrate metamaterials based on machine learning algorithms. The meta-plasmonic biosensors were designed for optimized detection of DNA with a layer of double negative metamaterial modeled by an effective medium. An iterative transfer matrix approach was employed to generate training and test sets of resonance characteristics in the parameter space for machine learning. As a machine learning-based prediction of optical characteristics of a meta-plasmonic biosensor, multilayer perceptron and autoencoder (AE) were used as an algorithm, while the clustering algorithm was constructed by dimensional reduction based on AE and t-Stochastic Neighbor Embedding (t-SNE) as well as k-means clustering. Use of meta-plasmonic structure with analysis based on machine learning has found that enhancement of detection sensitivity by more than 13 times over conventional detection should be achievable with excellent reflectance curves. Further enhancement may be attained by expanding the parameter space.

Fluorescence optical detection in situ for real-time monitoring of cytochrome P450 enzymatic activity of liver cells in multiple microfluidic devices.

We describe an in situ fluorescence optical detection system to demonstrate real-time and non-invasive detection of reaction products in a microfluidic device while under perfusion within a standard incubator. The detection system is designed to be compact and robust for operation inside a mammalian cell culture incubator for quantitative detection of fluorescent signal from microfluidic devices. When compared to a standard plate reader, both systems showed similar biphasic response curves with two linear regions. Such a detection system allows real-time measurements in microfluidic devices with cells without perturbing the culture environment. In a proof-of-concept experiment, the cytochrome P450 1A1/1A2 activity of a hepatoma cell line (HepG2/C3A) was monitored by measuring the enzymatic conversion of ethoxyresorufin to resorufin. The hepatoma cell line was embedded in Matrigel(TM) construct and cultured in a microfluidic device with medium perfusion. The response of the cells, in terms of P450 1A1/1A2 activity, was significantly different in a plate well system and the microfluidic device. Uninduced cells showed almost no activity in the plate assay, while uninduced cells in Matrigel(TM) with perfusion in a microfluidic device showed high activity. Cells in the plate assay showed a significant response to induction with 3-Methylcholanthrene while cells in the microfluidic device did not respond to the inducer. These results demonstrate that the system is a potentially useful method to measure cell response in a microfluidic system.

EEG Beta Oscillations in the Temporoparietal Area Related to the Accuracy in Estimating Others' Preference.

Humans often attempt to predict what others prefer based on a narrow slice of experience, called thin-slicing. According to the theoretical bases for how humans can predict the preference of others, one tends to estimate the other's preference using a perceived difference between the other and self. Previous neuroimaging studies have revealed that the network of dorsal medial prefrontal cortex (dmPFC) and right temporoparietal junction (rTPJ) is related to the ability of predicting others' preference. However, it still remains unknown about the temporal patterns of neural activities for others' preference prediction through thin-slicing. To investigate such temporal aspects of neural activities, we investigated human electroencephalography (EEG) recorded during the task of predicting the preference of others while only a facial picture of others was provided. Twenty participants (all female, average age: 21.86) participated in the study. In each trial of the task, participants were shown a picture of either a target person or self for 3 s, followed by the presentation of a movie poster over which participants predicted the target person's preference as liking or disliking. The time-frequency EEG analysis was employed to analyze temporal changes in the amplitudes of brain oscillations. Participants could predict others' preference for movies with accuracy of 56.89 ± 3.16% and 10 out of 20 participants exhibited prediction accuracy higher than a chance level (95% interval). There was a significant difference in the power of the parietal alpha (10~13 Hz) oscillation 0.6~0.8 s after the onset of poster presentation between the cases when participants predicted others' preference and when they reported self-preference (p < 0.05). The power of brain oscillations at any frequency band and time period during the trial did not show a significant correlation with individual prediction accuracy. However, when we measured differences of the power between the trials of predicting other's preference and reporting self-preference, the right temporal beta oscillations 1.6~1.8 s after the onset of facial picture presentation exhibited a significant correlation with individual accuracy. Our results suggest that right temporoparietal beta oscillations may be correlated with one's ability to predict what others prefer with minimal information.

Implantable Neural Probes for Brain-Machine Interfaces - Current Developments and Future Prospects.

A Brain-Machine interface (BMI) allows for direct communication between the brain and machines. Neural probes for recording neural signals are among the essential components of a BMI system. In this report, we review research regarding implantable neural probes and their applications to BMIs. We first discuss conventional neural probes such as the tetrode, Utah array, Michigan probe, and electroencephalography (ECoG), following which we cover advancements in next-generation neural probes. These next-generation probes are associated with improvements in electrical properties, mechanical durability, biocompatibility, and offer a high degree of freedom in practical settings. Specifically, we focus on three key topics: (1) novel implantable neural probes that decrease the level of invasiveness without sacrificing performance, (2) multi-modal neural probes that measure both electrical and optical signals, (3) and neural probes developed using advanced materials. Because safety and precision are critical for practical applications of BMI systems, future studies should aim to enhance these properties when developing next-generation neural probes.

Microfluidic assay-based optical measurement techniques for cell analysis: A review of recent progress.

Since the early 2000s, microfluidic cell culture systems have attracted significant attention as a promising alternative to conventional cell culture methods and the importance of designing an efficient detection system to analyze cell behavior on a chip in real time is raised. For this reason, various measurement techniques for microfluidic devices have been developed with the development of microfluidic assays for high-throughput screening and mimicking of in vivo conditions. In this review, we discuss optical measurement techniques for microfluidic assays. First of all, the recent development of fluorescence- and absorbance-based optical measurement systems is described. Next, advanced optical detection systems are introduced with respect to three emphases: 1) optimization for long-term, real-time, and in situ measurements; 2) performance improvements; and 3) multimodal analysis conjugations. Moreover, we explore presents future prospects for the establishment of optical detection systems following the development of complex, multi-dimensional microfluidic cell culture assays to mimic in vivo tissue, organ, and human systems.

Current achievements of nanoparticle applications in developing optical sensing and imaging techniques.

Metallic nanostructures have recently been demonstrated to improve the performance of optical sensing and imaging techniques due to their remarkable localization capability of electromagnetic fields. Particularly, the zero-dimensional nanostructure, commonly called a nanoparticle, is a promising component for optical measurement systems due to its attractive features, e.g., ease of fabrication, capability of surface modification and relatively high biocompatibility. This review summarizes the work to date on metallic nanoparticles for optical sensing and imaging applications, starting with the theoretical backgrounds of plasmonic effects in nanoparticles and moving through the applications in Raman spectroscopy and fluorescence biosensors. Various efforts for enhancing the sensitivity, selectivity and biocompatibility are summarized, and the future outlooks for this field are discussed. Convergent studies in optical sensing and imaging have been emerging field for the development of medical applications, including clinical diagnosis and therapeutic applications.

Localized Down-regulation of P-glycoprotein by Focused Ultrasound and Microbubbles induced Blood-Brain Barrier Disruption in Rat Brain.

Multi-drug resistant efflux transporters found in Blood-Brain Barrier (BBB) acts as a functional barrier, by pumping out most of the drugs into the blood. Previous studies showed focused ultrasound (FUS) induced microbubble oscillation can disrupt the BBB by loosening the tight junctions in the brain endothelial cells; however, no study was performed to investigate its impact on the functional barrier of the BBB. In this study, the BBB in rat brains were disrupted using the MRI guided FUS and microbubbles. The immunofluorescence study evaluated the expression of the P-glycoprotein (P-gp), the most dominant multi-drug resistant protein found in the BBB. Intensity of the P-gp expression at the BBB disruption (BBBD) regions was significantly reduced (63.2 ± 18.4%) compared to the control area. The magnitude of the BBBD and the level of the P-gp down-regulation were significantly correlated. Both the immunofluorescence and histologic analysis at the BBBD regions revealed no apparent damage in the brain endothelial cells. The results demonstrate that the FUS and microbubbles can induce a localized down-regulation of P-gp expression in rat brain. The study suggests a clinically translation of this method to treat neural diseases through targeted delivery of the wide ranges of brain disorder related drugs.

A microfluidic device for evaluating the dynamics of the metabolism-dependent antioxidant activity of nutrients.

Various food components are known for their health-promoting effects. However, their biochemical effects are generally evaluated in vitro, and their actual in vivo effect can vary significantly, depending on their metabolic profiles. To evaluate the effect of the liver metabolism on the antioxidant activity, we have developed a two-compartment microfluidic system that integrates the dynamics of liver metabolism and the subsequent antioxidant activity of food components. In the first compartment of the device, human liver enzyme fractions were immobilized inside a poly(ethylene glycol) diacrylate (PEGDA) hydrogel to mimic the liver metabolism. The radical scavenging activity was evaluated by the change of the 2,2-diphenyl-1-picrylhydrazyl (DPPH) absorbance in the second compartment. Reaction engineering and fluid mechanics principles were used to develop a simplified analytical model and a more complex finite element model, which were used to design the chip and determine the optimal flow conditions. For real-time measurements of the reaction on a chip, we developed a custom-made photospectrometer system with an LED light source. The developed microfluidic system showed a linear and dose-dependent antioxidant activity in response to increasing concentration of flavonoid. We also compared the antioxidant activity of flavonoid after various liver metabolic reactions. This microfluidic system can serve as a novel in vitro platform for predicting the antioxidant activity of various food components in a more physiologically realistic manner, as well as for studying the mechanism of action of such food components.

Metabolic activities of ginseng and its constituents, ginsenoside rb1 and rg1, by human intestinal microflora.

To evaluate the difference in expressing pharmacological effects of ginseng by intestinal microflora between Koreans, metabolic activities of ginseng, ginsenoside Rb1 and Rg1 by 100 fecal specimens were measured. The ß-glucosidase activity for p-nitrophenyl- ß-D-glucopyranoside was 0 to 0.42 µmol/min/mg and its average activity (mean±SD) was 0.10±0.07 µmol/min/mg. The metabolic activities of ginsenosides Rb1 and Rg1 were 0.01 to 0.42 and 0.01 to 0.38 pmol/min/mg, respectively. Their average activities were 0.25±0.08 and 0.15±0.09 pmol/min/mg, respectively. The compound K-forming activities from ginsenoside Rb1 and ginseng extract were 0 to 0.11 and 0 to 0.02 pmol/min/mg, respectively. Their average compound K-forming activities were 0.24±0.09 pmol/min/ mg and 2.14±3.66 fmol/min/mg, respectively. These activities all were not different between males and females, or between ages. Although compound K-forming activity from the aqueous extract of ginseng was low compared to that from ginenoside Rb1, their profiles were similar to those of isolated compounds. Based on these findings, we believe that the intestinal bacterial metabolic activities of ginseng components are variable in individuals and may be used as selection markers for responders to ginseng.