Non-invasively enhanced intracranial transplantation of mesenchymal stem cells using focused ultrasound mediated by overexpression of cell-adhesion molecules

Although there have been reports of promising results regarding the transplantation of mesenchymal stem cells (MSCs) for neurodegenerative diseases through the use of neuronal differentiation or control of the microenvironment, traditional surgical transplantation methods like parenchymal or intravenous injection have limitations such as secondary injuries in the brain, infection, and low survival rate of stem cells in the target site. Focused ultrasound (FUS) treatment is an emerging modality for the treatment of brain diseases, including neurodegenerative disorders. The various biological effects of FUS treatment have been investigated; therefore, the goal is now to improve the delivery efficiency and function of MSCs by capitalizing on the advantages of FUS. In this study, we demonstrated that FUS increases MSC transplantation into brain tissue by >2-fold, and that this finding might be related to the activation of intercellular adhesion molecule-1 in endothelial and subendothelial cells and vascular adhesion molecule-1 in endothelial cells.ope

A Study on the Development and Effectiveness of ISO13485: 2016 Education Programs for Domestic Medical Device Manufacturers

Purpose As ISO 13485 was revised in 2016, the domestic GMP (Good Manufacturing Practice) system was also revised and implemented in 2019. However, there are many problems in the domestic medical device industry because most of the small and medium-sized enterprises lack human and material resources. Accordingly, this study was conducted to provide education programs for domestic medical device companies to induce information provision and improve the company’s quality management ability. Methods First, analyze existing education. Second, based on the revised GMP system, a survey paper was produced to investigate difficulties and problems experienced by companies. Third, a two-week survey was conducted on domestic medical device manufacturers, and a total of 77 companies responded to this survey. Fourth, educational program development was conducted based on the results of the survey. Results and Conclusion The developed education program consists of a total of five sessions. In this study, the educational program developed by grasping the needs of the company through a survey consists of a total of five sessions. The first session consisted of theoretical education and the second to fifth sessions of practical education. Through the education program developed in this study, it is expected to contribute to the overall development of medical device quality by establishing a domestic medical device manufacturing environment that secures the safety and performance of domestic medical device companies.ope

The Potential Usefulness of Magnetic Resonance Guided Focused Ultrasound for Obsessive Compulsive Disorders

Obsessive compulsive disorder is a debilitating condition characterized by recurrent obsessive thoughts and compulsive reactions. A great portion of the obsessive compulsive disorder (OCD) patients are managed successfully with psychiatric treatment such as selective serotonin-reuptake inhibitor and cognitive behavioral psychotherapy, but more than 10% of patients are remained as nonresponder who needs neurosurgical treatments. These patients are potential candidates for the neurosurgical management. There had been various kind of operation, lesioning such as leucotomy or cingulotomy or capsulotomy or limbic leucotomy, and with advent of stereotaxic approach and technical advances, deep brain stimulation was more chosen by neurosurgeon due to its characteristic of reversibility and adjustability. Gamma knife radiosurgery are also applied to make lesion targeting based on magnetic resonance (MR) imaging, but the complication of adverse radiation effect is not predictable. In the neurosurgical field, MR guided focused ultrasound has advantage of less invasiveness, real-time monitored procedure which is now growing to attempt to apply for various brain disorder. In this review, the neurosurgical treatment modalities for the treatment of OCD will be briefly reviewed and the current state of MR guided focused ultrasound for OCD will be suggested.ope

Ex Vivo Raman Spectroscopy Measurement of a Mouse Model of Alzheimer's Disease

Raman spectroscopy is an optical technique that can identify molecules in a label-free manner, and is therefore heavily investigated in various areas ranging from biomedical engineering to materials science. Probe-based Raman spectroscopy can perform minimally invasive chemical analysis, and thus has potential as a real-time diagnostic tool during surgery. In this study, Raman experimentation was calibrated by examining the Raman shifts with respect to the concentrations of chemical substances. Raman signal characteristics, targeted for normal mice and cerebral tissues of the 5xFAD dementia mutant model with accumulated amyloid beta plaques, were measured and analyzed to explore the possibility of diagnosis of Alzheimer's disease. The application to the diagnosis of dementia was cross-validated by measuring Raman signals of amyloid beta. The results suggest the potential of Raman spectroscopy as a diagnostic tool that may be useful in various areas of application.ope

Regional Connectivity Changes According to Seizure Outcome of Temporal Epilepsy Surgery- A Magnetoencephalography Study

Objective: Temporal lobectomy is often successful in treatment of patients with medically intractable temporal lobe epilepsy (TLE), but prediction of its long-term outcome is of great interest. Here, we investigated usefulness of comparison analysis of pre- and post-surgical magnetoencephalopgrahy data in predicting prognosis of temporal lobectomy. Methods: The authors retrospectively analyzed pre-and post-operative MEG and presence of any seizures after temporal lobectomy in 8 patients with TLE. Spectral powers averaged from spike-free epochs in each condition (pre- and post-operation) were compared between 4 patients free from seizures and the other 4 with recurrent seizures. We also performed connectivity analysis based on phase locking values (PLVs) around resection margins of possible epileptogenic focus as regions of interest. Results: Spectral analysis on peri-lesional areas demonstrated relative increase of delta power in the patients without seizure freedom. On connectivity analysis, decrease of PLVs between other areas and temporal lobe focus after surgery were noted in patients with good surgical outcome while persistence or increase were found in patients with recurred seizures. Conclusion: This pilot study on comparison of power spectrum and connectivity metrics between pre- and post-op MEG exhibits a potential for predicting seizure outcome after TLE surgery.ope

A Study on the Improvement of Domestic Medical Device Product Classification through Analysis of Medical Device Classification System in the U.S. and Europe

The purpose of this study is to derive medical devices with different management systems through com- parison of domestic and overseas medical device product classification systems and to propose management con- version measures for the products. The definitions of medical devices were compared and the scope of medical devices defined by each country was confirmed through surveys of the Medical Device Act, Federal Food, Drug & Cosmetics Act (FD&C) in the U.S., and Medical Device Regulations (MDR) in Europe. Using the Ministry of Food and Drug Safety’s regulations on medical device products and grades, 21 CFR part 860-892 and product code clas- sification files in U.S., and EMDN in Europe as basic data to compare medical device products and derive medical devices with different management systems. As a result of comparing the definition and product classification sys- tems of medical devices in Korea, the U.S. and Europe, medical device accessories, prosthetic limbs and aids among assistive devices for persons with disabilities, drugs, quasi-drugs and industrial products that are not managed by medical devices in Korea are managed as medical devices in the U.S. and Europe. This study aims to improve public health by securing systematic product safety management and essential performance under med- ical device regulations. Management within a single medical device system will increase the efficiency of licensing work of domestic medical device manufacturers and related organizations. It is also expected to help advance the system according to the international harmony of the item classification system and enhance smooth import and export competitiveness.ope

Focused ultrasound-induced blood-brain barrier opening improves adult hippocampal neurogenesis and cognitive function in a cholinergic degeneration dementia rat model

BACKGROUND: The persistence of adult hippocampal neurogenesis (AHN) is sharply decreased in Alzheimer's disease (AD). The neuropathologies of AD include the presence of amyloid-β deposition in plaques, tau hyperphosphorylation in neurofibrillary tangles, and cholinergic system degeneration. The focused ultrasound (FUS)-mediated blood-brain barrier opening modulates tau hyperphosphorylation, the accumulation of amyloid-β proteins, and increases in AHN. However, it remains unclear whether FUS can modulate AHN in cholinergic-deficient conditions. In this study, we investigated the effect of FUS on AHN in a cholinergic degeneration rat model of dementia. METHODS: Adult male Sprague-Dawley rats (n = 48; 200-250 g) were divided into control (phosphate-buffered saline injection), 192 IgG-saporin (SAP), and SAP+FUS groups; in the two latter groups, SAP was injected bilaterally into the lateral ventricle. We applied FUS to the bilateral hippocampus with microbubbles. Immunohistochemistry, enzyme-linked immunosorbent assay, immunoblotting, 5-bromo-2'-deoxyuridine labeling, an acetylcholinesterase assay, and the Morris water maze test were performed to assess choline acetyltransferase, acetylcholinesterase activity, brain-derived neurotrophic factor expression, neural proliferation, and spatial memory, respectively. Statistical significance of differences in between groups was calculated using one-way and two-way analyses of variance followed by Tukey's multiple comparison test to determine the individual and interactive effects of FUS on immunochemistry and behavioral analysis. P < 0.05 was considered significant. RESULTS: Cholinergic degeneration in rats significantly decreased the number of choline acetyltransferase neurons (P < 0.05) in the basal forebrain, as well as AHN and spatial memory function. Rats that underwent FUS-mediated brain-blood barrier opening exhibited significant increases in brain-derived neurotrophic factor (BDNF; P < 0.05), early growth response protein 1 (EGR1) (P < 0.01), AHN (P < 0.01), and acetylcholinesterase activity in the frontal cortex (P < 0.05) and hippocampus (P < 0.01) and crossing over (P < 0.01) the platform in the Morris water maze relative to the SAP group after sonication. CONCLUSIONS: FUS treatment increased AHN and improved spatial memory. This improvement was mediated by increased hippocampal BDNF and EGR1. FUS treatment may also restore AHN and protect against neurodegeneration, providing a potentially powerful therapeutic strategy for AD.ope

Design and Implementation of a New Wireless Carotid Neckband Doppler System with Wearable Ultrasound Sensors: Preliminary Results

Noninvasive monitoring of blood flow in the carotid artery is important for evaluating not only cerebrovascular but also cardiovascular diseases. In this paper, a wireless neckband ultrasound Doppler system, in which two 2.5-MHz ultrasonic sensors are utilized for acquiring Doppler signals from both carotid arteries, is presented for continuously evaluating blood flow dynamics. In the developed wireless neckband Doppler system, the acquired Doppler signals are quantized by 14-bit analog-to-digital-converters running at 40 MHz, and pre-processing operations (i.e., demodulation and clutter filtering) are performed in an embedded field programmable gate array chip. Then, these data are transferred to an external smartphone (i.e., Galaxy S7, Samsung Electronics Co., Suwon, Korea) via Bluetooth 2.0. Post-processing (i.e., Fourier transform and image processing) is performed using an embedded application processor in the smartphone. The developed carotid neckband Doppler system was evaluated with phantom and in vivo studies. In a phantom study, the neckband Doppler system showed comparable results with a commercial ultrasound machine in terms of peak systolicvelocityandresistiveindex,i.e.,131.49±3.97and0.75±0.02vs. 131.89±2.06and0.74±0.02, respectively. Inaddition,inthein vivostudy,theneckbandDopplersystemsuccessfullydemonstrated its capability to continuously evaluate hemodynamics in both common carotid arteries. These results indicatethatthedevelopedwirelessneckbandDopplersystemcanbeusedforcontinuousmonitoring of blood flow dynamics in the common carotid arteries in point-of-care settings.ope

Safety and Efficacy of Magnetic Resonance-Guided Focused Ultrasound Surgery With Autofocusing Echo Imaging

Objective: Magnetic resonance-guided focused ultrasound surgery (MRgFUS) lesioning is a new treatment for brain disorders. However, the skull is a major barrier of ultrasound sonication in MRgFUS because it has an irregular surface and varies its size and shape among individuals. We recently developed the concept of skull density ratio (SDR) to select candidates for MRgFUS from among patients with essential tremor (ET). However, SDR is not the only factor contributing to successful MRgFUS lesioning treatment-refining the target through exact measurement of the ultrasonic echo in the transducer also improves treatment efficacy. In the present study, we carried out MRgFUS lesioning using an autofocusing echo imaging technique. We aimed to evaluate the safety and efficacy of this new approach, especially in patients with low SDR in whom previous focusing methods have failed. Methods: From December 2019 to March 2020, we recruited 10 patients with ET or Parkinson's disease (PD) who had a low SDR. Two patients dropped out of the trial due to the screening failure of other medical diseases. In total, eight patients were included: six with ET who underwent MRgFUS thalamotomy and two with PD who underwent MRgFUS pallidotomy. The autofocusing echo imaging technique was used in all cases. Results: The mean SDR of the patients with ET was 0.34 (range: 0.29-0.39), while that of the patients with PD was 0.41 (range: 0.38-0.44). The mean skull volume of patients with ET was 280.57 cm3 (range: 227-319 cm3), while that of the patients with PD was 287.13 cm3 (range: 271-303 cm3). During MRgFUS, a mean of 15 sonications were performed, among which a mean of 5.63 used the autofocusing technique. The mean maximal temperature (Tmax) achieved was 55.88°C (range: 52-59°C), while the mean energy delivered was 34.75 kJ (range: 20-42 kJ) among all patients. No serious adverse events occurred during or after treatment. Tmax or sonication factors (skull volume, SDR, sonication number, autofocusing score, similarity score, energy range, and power) were not correlated with autofocusing technique (p > 0.05, autofocusing score showed a p-value of 0.071). Conclusion: Using autofocusing echo imaging lesioning, a safe and efficient MRgFUS treatment, is available even for patients with a low SDR. Therefore, the indications for MRgFUS lesioning could be expanded to include patients with ET who have an SDR < 0.4 and those with PD who have an SDR < 0.45. Clinical trial registration: clinicaltrials.gov, identifier: NCT03935581.ope

(-)-Gallocatechin gallate from green tea rescues cognitive impairment through restoring hippocampal silent synapses in post-menopausal depression

Post-menopausal depression (PMD) is a common psychological disorder accompanied by a cognitive deficit, which is caused by a series of uncontrolled emotional disruptions by strong environmental stressors during menopause. To overcome PMD-induced cognitive deficit, Green tea has been suggested as a dietary supplement because of its ameliorating effect on cognitive dysfunction induced by normal aging or neurodegenerative syndromes; however, its clinical use to improve PMD-accompanied cognitive deficit is still limited due to the controversy for the active ingredients and ambiguous mechanism of its action. Here, we developed modified high-temperature-processed green tea extract (HTP-GTE), which showed lower neuronal toxicity than the conventional green tea extract (GTE). We also demonstrated that HTP-GTE administration prevented the development of learned helplessness (LH) in a rat post-menopausal model. Additionally, HTP-GTE improved LH-induced cognitive impairments simultaneously with rescued the long-term synaptic plasticity. This occurred via the restoration of silent synapse formation by increasing the hippocampal BDNF-tyrosine receptor kinase B pathway in the helpless ovariectomized (OVX) rats. Likewise, we also identified that (-)-gallocatechin gallate was the main contributor of the HTP-GTE effect. Our findings suggested that HTP-GTE has a potential as a preventive nutritional supplement to ameliorate cognitive dysfunctions associated with PMD.ope