Efficacy of wearable vibration dressings on full-thickness wound healing in a hyperglycemic rat model.

Local low-frequency vibration promotes blood flow and wound healing in hard-to-heal diabetic foot ulcers (DFUs). However, vibration treatment is challenging in patients with DFUs due to wound management difficulties and low adherence. Consequently, developing wearable self-care devices becomes imperative for effective wound healing. This study introduces a wearable vibration dressing and assesses its impact on wound healing in hyperglycemic rats. Low-frequency vibration at 52 Hz was applied to the wound for 40 min/day in awake rats. Relative wound areas on post-wounding days (PWDs) 4-7 were significantly smaller and the wound closure rate was significantly higher in the vibration group than in the control group (p < 0.05, respectively). The total haemoglobin at baseline and after vibration on post-wounding day 7 was significantly larger in the vibration group than in the control group (p < 0.05). On PWD 7, the thickness of the granulation tissue was significantly higher in the vibration group than in the control group (p < 0.05). Moreover, the number of blood vessels at the wound site and vascular endothelial growth factor A protein expression were significantly higher in the vibration group than in the control group (p < 0.05, respectively). The ratio of (CD68+ /iNOS+ )/(CD163+ ) macrophages in the vibration group was significantly lower than that in the control group (p < 0.05). These results indicate the potential of wearable vibration dressings as new self-care devices that can promote angiogenesis and blood flow, improve inflammation, and enhance wound healing in DFUs.

Brain Response to Interferential Current Compared with Alternating Current Stimulation.

Temporal interference (TI) stimulation, which utilizes multiple external electric fields with amplitude modulation for neural modulation, has emerged as a potential noninvasive brain stimulation methodology. However, the clinical application of TI stimulation is inhibited by its uncertain fundamental mechanisms, and research has previously been restricted to numerical simulations and immunohistology without considering the acute in vivo response of the neural circuit. To address the characterization and understanding of the mechanisms underlying the approach, we investigated instantaneous brainwide activation patterns in response to invasive interferential current (IFC) stimulation compared with low-frequency alternative current stimulation (ACS). Results demonstrated that IFC stimulation is capable of inducing regional neural responses and modulating brain networks; however, the activation threshold for significantly recruiting a neural response using IFC was higher (at least twofold) than stimulation via alternating current, and the spatial distribution of the activation signal was restricted. A distinct blood oxygenation level-dependent (BOLD) response pattern was observed, which could be accounted for by the activation of distinct types of cells, such as inhibitory cells, by IFC. These results suggest that IFC stimulation might not be as efficient as conventional brain modulation methods, especially when considering TI stimulation as a potential alternative for stimulating subcortical brain areas. Therefore, we argue that a future transcranial application of TI on human subjects should take these implications into account and consider other stimulation effects using this technique.

Investigating the technical feasibility of magnetoencephalography during transcranial direct current stimulation.

Introduction: Magnetoencephalography (MEG) can measure weak magnetic fields produced by electrical brain activity. Transcranial direct current stimulation (tDCS) can affect such brain activities. The concurrent application of both, however, is challenging because tDCS presents artifacts on the MEG signal. If brain activity during tDCS can be elucidated by MEG, mechanisms of plasticity-inducing and other effects of tDCS would be more comprehensively understood. We tested the technical feasibility of MEG during tDCS using a phantom that produces an artificial current dipole simulating focal brain activity. An earlier study investigated estimation of a single oscillating phantom dipole during tDCS, and we systematically tested multiple dipole locations with a different MEG device. Methods: A phantom provided by the manufacturer was used to produce current dipoles from 32 locations. For the 32 dipoles, MEG was recorded with and without tDCS. Temporally extended signal space separation (tSSS) was applied for artifact rejection. Current dipole sources were estimated as equivalent current dipoles (ECDs). The ECD modeling quality was assessed using localization error, amplitude error, and goodness of fit (GOF). The ECD modeling performance with and without tDCS, and with and without tSSS was assessed. Results: Mean localization errors of the 32 dipoles were 1.70 ± 0.72 mm (tDCS off, tSSS off, mean ± standard deviation), 6.13 ± 3.32 mm (tDCS on, tSSS off), 1.78 ± 0.83 mm (tDCS off, tSSS on), and 5.73 ± 1.60 mm (tDCS on, tSSS on). Mean GOF findings were, respectively, 92.3, 87.4, 97.5, and 96.7%. Modeling was affected by tDCS and restored by tSSS, but improvement of the localization error was marginal, even with tSSS. Also, the quality was dependent on the dipole location. Discussion: Concurrent tDCS-MEG recording is feasible, especially when tSSS is applied for artifact rejection and when the assumed location of the source of activity is favorable for modeling. More technical studies must be conducted to confirm its feasibility with different source modeling methods and stimulation protocols. Recovery of single-trial activity under tDCS warrants further research.

Wearable, wireless, multi-sensor device for monitoring tissue circulation after free-tissue transplantation: a multicentre clinical trial.

Wearable sensors have seen remarkable recent technological developments, and their role in healthcare is expected to expand. Specifically, monitoring tissue circulation in patients who have undergone reconstructive surgery is critical because blood flow deficiencies must be rescued within hours or the transplant will fail due to thrombosis/haematoma within the artery or vein. We design a wearable, wireless, continuous, multipoint sensor to monitor tissue circulation. The system measures pulse waves, skin colour, and tissue temperature to reproduce physician assessment. Data are analysed in real time for patient risk using an algorithm. This multicentre clinical trial involved 73 patients who underwent transplant surgery and had their tissue circulation monitored until postoperative day 7. Herein, we show that the overall agreement rate between physician and sensor findings is 99.2%. In addition, the patient questionnaire results indicate that the device is easy to wear. The sensor demonstrates non-invasive, real-time, continuous, multi-point, wireless, and reliable monitoring for postoperative care. This wearable system can improve the success rate of reconstructive surgeries.

Depression induced by low-frequency repetitive transcranial magnetic stimulation to ventral medial frontal cortex in monkeys.

The medial frontal cortex (MFC), especially its ventral part, has long been of great interest with respect to the pathology of mood disorders. A number of human brain imaging studies have demonstrated the abnormalities of this brain region in patients with mood disorders, however, whether it is critically and causally involved in the pathogenesis of such disorders remains to be fully elucidated. In this study, we examined how the suppression of neural activity in the ventral region of the MFC (vMFC) affects the behavioral and physiological states of monkeys by using repetitive transcranial magnetic stimulation (rTMS). By using low-frequency rTMS (LF-rTMS) as an inhibitory intervention, we found that LF-rTMS targeting the vMFC temporarily induced a depression-like state in monkeys, which was characterized by a reduced movement activity level, impaired sociability, and decreased motivation level, as well as increased plasma cortisol level. On the other hand, no such significant changes in behavioral and physiological states were observed when targeting the other MFC regions, dorsal or posterior. We further found that the administration of an antidepressant agent, ketamine, ameliorated the abnormal behavioral and physiological states induced by the LF-rTMS intervention. These findings causally indicate the involvement of the vMFC in the regulation of mood and the validity of the LF-rTMS-induced dysfunction of the vMFC as a nonhuman primate model of depression.

Exploratory Study of Superparamagnetic Iron Oxide Dose Optimization in Breast Cancer Sentinel Lymph Node Identification Using a Handheld Magnetic Probe and Iron Quantitation.

This exploratory study compared doses of ferucarbotran, a superparamagnetic iron oxide nanoparticle, in sentinel lymph nodes (SLNs) and quantified the SLN iron load by dose and localization. Eighteen females aged ≥20 years scheduled for an SLN biopsy with node-negative breast cancer were divided into two equal groups and administered either 1 mL or 0.5 mL ferucarbotran. Iron content was evaluated with a handheld magnetometer and quantification device. The average iron content was 42.8 µg (range, 1.3-95.0; 0.15% of the injected dose) and 21.9 µg (1.1-71.0; 0.16%) in the 1-mL and 0.5-mL groups, respectively (p = 0.131). The iron content of the closest SLN compared to the second SLN was 53.0 vs. 10.0 µg (19% of the injected dose) and 34.8 vs. 4.1 µg (11.1%) for the 1-mL and 0.5-mL groups, respectively (p = 0.001 for both). The magnetic field was high in both groups (average 7.30 µT and 6.00 µT in the 1-mL and 0.5-mL groups, respectively) but was not statistically significant (p = 0.918). The magnetic field and iron content were correlated (overall SLNs, p = 0.02; 1-mL, p = 0.014; 0.5-mL, p = 0.010). A 0.5-mL dose was sufficient for SLN identification. Primary and secondary SLNs could be differentiated based on iron content. Handheld magnetometers could be used to assess the SLN iron content.

Application of Magnetic Nanoparticles for Rapid Detection and In Situ Diagnosis in Clinical Oncology.

Screening, monitoring, and diagnosis are critical in oncology treatment. However, there are limitations with the current clinical methods, notably the time, cost, and special facilities required for radioisotope-based methods. An alternative approach, which uses magnetic beads, offers faster analyses with safer materials over a wide range of oncological applications. Magnetic beads have been used to detect extracellular vesicles (EVs) in the serum of pancreatic cancer patients with statistically different EV levels in preoperative, postoperative, and negative control samples. By incorporating fluorescence, magnetic beads have been used to quantitatively measure prostate-specific antigen (PSA), a prostate cancer biomarker, which is sensitive enough even at levels found in healthy patients. Immunostaining has also been incorporated with magnetic beads and compared with conventional immunohistochemical methods to detect lesions; the results suggest that immunostained magnetic beads could be used for pathological diagnosis during surgery. Furthermore, magnetic nanoparticles, such as superparamagnetic iron oxide nanoparticles (SPIONs), can detect sentinel lymph nodes in breast cancer in a clinical setting, as well as those in gallbladder cancer in animal models, in a surgery-applicable timeframe. Ultimately, recent research into the applications of magnetic beads in oncology suggests that the screening, monitoring, and diagnosis of cancers could be improved and made more accessible through the adoption of this technology.

Sentinel lymph node biopsy with a handheld cordless magnetic probe following preoperative MR lymphography using superparamagnetic iron oxide for clinically N0 early oral cancer: A feasibility study.

PURPOSE: Radioisotope (RI) tracers are generally used for preoperative mapping of sentinel lymph node (SLN) and intraoperative detection with a portable γ probe. However, the use of RI has several limitations. Therefore, a method without RI is required for the widespread application of SLN biopsy. The purpose of this study was to evaluate the feasibility of SLN biopsy with a handheld cordless magnetic probe following magnetic resonance lymphography (MRL) using superparamagnetic iron oxide (SPIO) and for clinically N0 early oral cancer. MATERIALS AND METHODS: MRL using SPIO and SLNB with the handheld cordless magnetic probe were performed for 27 patients with clinically N0 early oral cancer. RESULTS: In all 27 patients (100%), SLNs were detected by MRL, and the total and mean number of SLNs were 73 and 2.7, respectively. All SLNs identified by MRL were detectable using the magnetic probe in all patients. CONCLUSIONS: SLNB with handheld cordless magnetic probe following preoperative SLN mapping by MRL using SPIO is feasible, without RI use, for neck management in cases of clinically N0 early oral cancer.

DeepSPIO: Super Paramagnetic Iron Oxide Particle Quantification Using Deep Learning in Magnetic Resonance Imaging.

The susceptibility of super paramagnetic iron oxide (SPIO) particles makes them a useful contrast agent for different purposes in MRI. These particles are typically quantified with relaxometry or by measuring the inhomogeneities they produced. These methods rely on the phase, which is unreliable for high concentrations. We present in this study a novel Deep Learning method to quantify the SPIO concentration distribution. We acquired the data with a new sequence called View Line in which the field map information is encoded in the geometry of the image. The novelty of our network is that it uses residual blocks as the bottleneck and multiple decoders to improve the gradient flow in the network. Each decoder predicts a different part of the wavelet decomposition of the concentration map. This decomposition improves the estimation of the concentration, and also it accelerates the convergence of the model. We tested our SPIO concentration reconstruction technique with simulated images and data from actual scans from phantoms. The simulations were done using images from the IXI dataset, and the phantoms consisted of plastic cylinders containing agar with SPIO particles at different concentrations. In both experiments, the model was able to quantify the distribution accurately.

Optimization of SPIO Injection for Sentinel Lymph Node Dissection in a Rat Model.

The magnetic technique, consisting of a magnetic tracer and a handheld magnetometer, is a promising alternative technique for sentinel lymph node dissection (SLND) and was shown to be non-inferior to the standard technique in terms of identification rates. In this study, injection characteristics (iron dose, dilution, time course and massaging) were evaluated to optimize magnetic tracer uptake in the sentinel lymph nodes (SLN) in a rat hindleg model. 202 successful SLNDs were performed. Iron uptake in the SLN is proportional (10% utilization rate) to the injection dose between 20 and 200 µg, showing a plateau uptake of 80 µg in the SLN around 1000 µg injection. Linear regression showed that time had a higher impact than dilution, on the SLN iron uptake. Massaging showed no significant change in iron uptake. The amount of residual iron at the injection site was also proportional to the injection dose without any plateau. Time was a significant factor for wash-out of residual iron. From these results, preoperative injection may be advantageous for SLN detection as well as reduction in residual iron at the injection site by potential decrease in required injection dose.

Magnetically Induced Temporal Interference for Focal and Deep-Brain Stimulation.

Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation technique that has been clinically applied for neural modulation. Conventional TMS systems are restricted by the trade-off between depth penetration and the focality of the induced electric field. In this study, we integrated the concept of temporal interference (TI) stimulation, which has been demonstrated as a non-invasive deep-brain stimulation method, with magnetic stimulation in a four-coil configuration. The attenuation depth and spread of the electric field were obtained by performing numerical simulation. Consequently, the proposed temporally interfered magnetic stimulation scheme was demonstrated to be capable of stimulating deeper regions of the brain model while maintaining a relatively narrow spread of the electric field, in comparison to conventional TMS systems. These results demonstrate that TI magnetic stimulation could be a potential candidate to recruit brain regions underneath the cortex. Additionally, by controlling the geometry of the coil array, an analogous relationship between the field depth and focality was observed, in the case of the newly proposed method. The major limitations of the methods, however, would be the considerable intensity and frequency of the input current, followed by the frustration in the thermal management of the hardware.

All-Optical Wide-Field Selective Imaging of Fluorescent Nanodiamonds in Cells, In Vivo and Ex Vivo.

Fluorescence imaging is a critical tool to understand the spatial distribution of biomacromolecules in cells and in vivo, providing information on molecular dynamics and interactions. Numerous valuable insights into biological systems have been provided by the specific detection of various molecular species. However, molecule-selective detection is often hampered by background fluorescence, such as cell autofluorescence and fluorescence leakage from molecules stained by other dyes. Here we describe a method for all-optical selective imaging of fluorescent nanodiamonds containing nitrogen-vacancy centers (NVCs) for wide-field fluorescence bioimaging. The method is based on the fact that the fluorescence intensity of NVCs strictly depends on the configuration of ground-state electron spins, which can be controlled by changing the pulse recurrence intervals of microsecond excitation laser pulses. Therefore, by using regulated laser pulses, we can oscillate the fluorescence from NVCs in a nanodiamond, while oscillating other optical signals in the opposite phase to NVCs. As a result, we can reconstruct a selective image of a nanodiamond by using a series of oscillated fluorescence images. We demonstrate application of the method to the selective imaging of nanodiamonds in live cells, in microanimals, and on a hippocampal slice culture obtained from a rat. Our approach potentially enables us to achieve high-contrast images of nanodiamond-labeled biomolecules with a signal-to-background ratio improved by up to 100-fold over the standard fluorescence image, thereby providing a more powerful tool for the investigation of molecular dynamics in cells and in vivo.

Magnetically Guided Localization Using a Guiding-Marker System® and a Handheld Magnetic Probe for Nonpalpable Breast Lesions: A Multicenter Feasibility Study in Japan.

Accurate pre-operative localization of nonpalpable lesions plays a pivotal role in guiding breast-conserving surgery (BCS). In this multicenter feasibility study, nonpalpable breast lesions were localized using a handheld magnetic probe (TAKUMI) and a magnetic marker (Guiding-Marker System®). The magnetic marker was preoperatively placed within the target lesion under ultrasound or stereo-guidance. Additionally, a dye was injected subcutaneously to indicate the extent of the tumor excision. Surgeons checked for the marker within the lesion using a magnetic probe. The magnetic probe could detect the guiding marker and accurately localize the target lesion intraoperatively. All patients with breast cancer underwent wide excision with a safety margin of ≥5 mm. The presence of the guiding-marker within the resected specimen was the primary outcome and the pathological margin status and re-excision rate were the secondary outcomes. Eighty-seven patients with nonpalpable lesions who underwent BCS, from January to March of 2019 and from January to July of 2020, were recruited. The magnetic marker was detected in all resected specimens. The surgical margin was positive only in 5/82 (6.1%) patients; these patients underwent re-excision. This feasibility study demonstrated that the magnetic guiding localization system is useful for the detection and excision of nonpalpable breast lesions.

Intraoperative laparoscopic detection of sentinel lymph nodes with indocyanine green and superparamagnetic iron oxide in a swine gallbladder cancer model.

Mapping of sentinel lymph nodes (SLNs) can enable less invasive surgery. However, mapping is challenging for cancers of difficult-to-access visceral organs, such as the gallbladder, because the standard method using radioisotopes (RIs) requires preoperative tracer injection. Indocyanine green (ICG) and superparamagnetic iron oxide (SPIO) have also been used as alternative tracers. In this study, we modified a previously reported magnetic probe for laparoscopic use and evaluated the feasibility of detecting SLNs of the gallbladder using a laparoscopic dual tracer method by injecting ICG and SPIO into five swine and one cancer-bearing swine. The laparoscopic probe identified SPIO nanoparticles in the nodes of 4/5 swine in situ, the magnetic field counts were 2.5-15.9 µT, and fluorescence was detected in SLNs in all five swine. ICG showed a visual lymph flow map, and SPIO more accurately identified each SLN with a measurable magnetic field quite similar to the RI. We then developed an advanced gallbladder cancer model with lymph node metastasis using recombination activating gene 2-knockout swine. We identified an SLN in the laparoscopic investigation, and the magnetic field count was 3.5 µT. The SLN was histologically determined to be one of the two metastatic lymph nodes. In conclusion, detecting the SLNs of gallbladder cancer in situ using a dual tracer laparoscopic technique with ICG and SPIO was feasible in a swine model.

Flexible Light Sources.

Various light sources have been developed for the application of optical stimulation in the optogenetics field. Light transmission inside living tissue is limited to a distance of a few millimeters; hence, it is necessary to insert the light source near the nerve tissue to be stimulated. If a device is rigid, it causes mechanical stimulation to act on the nerve tissue. The application of mechanical stimulation may induce inflammation, obstructing neural activity. Fabricating such a device out of a soft material can prevent mechanical stimulation of cells and mitigate biological reactions such as inflammation or encapsulation. Minimizing the sizes of LED and other light sources as much as possible and mounting them on a flexible substrate can provide the entire device with flexibility. Micro-LEDs can be reduced to a size almost comparable to that of a cell and it has even been reported that some have been mounted on the tip of needle-shaped devices inserted into living tissue. A device using organic semiconductors is sufficiently soft to be bent, which is a characteristic not observed in inorganic semiconductors. Using organic LEDs can realize wide-area flexible light-emitting surfaces and they are widely anticipated to be the next generation of light sources. This chapter introduces technologies used to manufacture these soft light sources and examples of optical stimulation devices that incorporate them.

Figure-Eight Coils for Magnetic Stimulation: From Focal Stimulation to Deep Stimulation.

This article reviews the evolution and recent developments of transcranial magnetic brain stimulation using figure-eight coils to stimulate localized areas in the human brain. Geometric variations of figure-eight coils and their characteristics are reviewed and discussed for applications in neuroscience and medicine. Recent topics of figure-eight coils, such as focality of figure-eight coils, tradeoff between depth and focality, and approaches for extending depth, are discussed.

Direct Impact of Motor Cortical Stimulation on the Blood Oxygen-level Dependent Response in Rats.

PURPOSE: Neuropathic pain is a complex and distressing chronic illness in modern medicine. Since 1990s, motor cortex stimulation (MCS) has emerged as a potential treatment for chronic neuropathic pain; however, the precise mechanisms underlying analgesia induced by MCS are not completely understood. The purpose of the present study was to investigate the blood oxygen-level dependent (BOLD) response in the brain during MCS. METHODS: We inserted a bipolar tungsten electrode into the primary motor cortex (M1) of adult male Wistar rats. Functional magnetic resonance imaging (fMRI) scans were implemented simultaneously with the electrical stimulation of M1 and the BOLD signals taken from the fMRI were used as an index to reflect the response against MCS. RESULTS: Our results demonstrated that the bilateral M1, ipsilateral caudate-putamen, and ipsilateral primary somatosensory cortex to the stimulation spot were activated after the onset of MCS. The BOLD signal time courses were analysed in these regions and similar temporal characteristics were found. CONCLUSION: By conducting direct cortical stimulation of the rodent brain to investigate its instant effect using fMRI, we identified encephalic regions directly involved in the instant motor cortical stimulation effects in healthy rat models. This result may be essential in establishing a foundation for further research on the underlying neuropathways associated with the MCS effects.

MR lymphography with superparamagnetic iron oxide for sentinel lymph node mapping of N0 early oral cancer: A pilot study.

OBJECTIVES: The purpose of this pilot study was to evaluate the usefulness of magnetic resonance lymphography (MRL) with superparamagnetic iron oxide (SPIO) in sentinel lymph node (SLN) mapping of clinically N0 early oral cancer, and to conduct a comparative study of this MRL with CT lymphography (CTL). METHODS: CTL and MRL were performed for SLN mapping before surgery for 20 patients with clinically N0 early oral cancer. The detection rate, number, and location of SLNs in CTL and MRL were evaluated. Furthermore, optimal scanning/imaging timing in MRL was examined. RESULTS: SLNs were detected by CTL in 18 (90%) patients, and the total and mean number of SLN were 35 and 1.8, respectively. All SLNs could be detected 2 min and 3.5-5 min after contrast medium injection. In all patients, SLNs were detected by MRL at 10 min after SPIO injection, and the total and mean number of SLN was 53 and 2.7, respectively. MRL at 30 min after the injection showed additional 18 secondary lymph nodes. CONCLUSION: MRL with SPIO is safe and useful imaging for the detection of SLNs in clinically N0 early oral cancer, and the optimal imaging timing is 10 min after SPIO injection.

Ultraflexible organic light-emitting diodes for optogenetic nerve stimulation.

Organic electronic devices implemented on flexible thin films are attracting increased attention for biomedical applications because they possess extraordinary conformity to curved surfaces. A neuronal device equipped with an organic light-emitting diode (OLED), used in combination with animals that are genetically engineered to include a light-gated ion channel, would enable cell type-specific stimulation to neurons as well as conformal contact to brain tissue and peripheral soft tissue. This potential application of the OLEDs requires strong luminescence, well over the neuronal excitation threshold in addition to flexibility. Compatibility with neuroimaging techniques such as MRI provides a method to investigate the evoked activities in the whole brain. Here, we developed an ultrathin, flexible, MRI-compatible OLED device and demonstrated the activation of channelrhodopsin-2-expressing neurons in animals. Optical stimulation from the OLED attached to nerve fibers induced contractions in the innervated muscles. Mechanical damage to the tissues was significantly reduced because of the flexibility. Owing to the MRI compatibility, neuronal activities induced by direct optical stimulation of the brain were visualized using MRI. The OLED provides an optical interface for modulating the activity of soft neuronal tissues.