Electrical Stimulation System Research Articles

The Biomimetic Electrical Stimulation System Inducing Osteogenic Differentiations of BMSCs.

Electrical stimulation has been used clinically as an adjunct therapy to accelerate the healing of bone defects, and its mechanism requires further investigations. The complexity of the physiological microenvironment makes it challenging to study the effect of electrical signal on cells alone. Therefore, an artificial system mimicking cell microenvironment in vitro was developed to address this issue. In this work, a novel electrical stimulation system was constructed based on polypyrrole nanowires (ppyNWs) with a high aspect ratio. Synthesized ppyNWs formed a conductive network in the composited hydrogel which contained modified gelatin with methacrylate, providing a conductive cell culture matrix for bone marrow mesenchymal stem cells. The dual-network conductive hydrogel had improved mechanical, electrical, and hydrophilic properties. It was able to imitate the three-dimensional structure of the cell microenvironment and allowed adjustable electrical stimulations in the following system. This hydrogel was integrated with cell culture plates, platinum electrodes, copper wires, and external power sources to construct the artificial electrical stimulation system. The optimum voltage of the electrical stimulation system was determined to be 2 V, which exhibited remarkable biocompatibility. Moreover, this system had significant promotion in cell spreading, osteogenic makers, and bone-related gene expression of stem cells. RNA-seq analysis revealed that osteogenesis was correlated to Notch, BMP/Smad, and calcium signal pathways. It was proven that this biomimetic system could regulate the osteogenesis procedure, and it provided further information about how the electrical signal regulates osteogenic differentiations.

We Will, We Will Shock You: Adaptive Versus Conventional Functional Electrical Stimulation in Individuals Post-Stroke.

Functional electrical stimulation (FES) is often used in poststroke gait rehabilitation to address decreased walking speed, foot drop, and decreased forward propulsion. However, not all individuals experience clinically meaningful improvements in gait function with stimulation. Previous research has developed adaptive functional electrical stimulation (AFES) systems that adjust stimulation timing and amplitude at every stride to deliver optimal stimulation. The purpose of this work was to determine the effects of a novel AFES system on functional gait outcomes and compare them to the effects of the existing FES system. Twenty-four individuals with chronic poststroke hemiparesis completed 64-min walking trials on an adaptive and fixed-speed treadmill with no stimulation, stimulation from the existing FES system, and stimulation from the AFES system. There was no significant effect of stimulation condition on walking speed, peak dorsiflexion angle, or peak propulsive force. Walking speed was significantly faster and peak propulsive force was significantly larger on the adaptive treadmill (ATM) than the fixed-speed treadmill (both p < 0.0001). Dorsiflexor stimulation timing was similar between stimulation conditions, but plantarflexor stimulation timing was significantly improved with the AFES system compared to the FES system (p = 0.0059). Variability between and within subjects was substantial, and some subjects experienced clinically meaningful improvements in walking speed, peak dorsiflexion angle, and peak propulsive force. However, not all subjects experienced benefits, suggesting that further research to characterize which subjects exhibit the best instantaneous response to FES is needed to optimize poststroke gait rehabilitation using FES.

234. EFFECTS OF TRANSCUTANEOUS ELECTRICAL STIMULATION SYSTEM ON HEARTBURN, REGURGITATION AND ESOPHAGEAL ACID EXPOSURE IN GERD PATIENTS

Abstract Background Chronic PPI treatment in GERD is associated with high failure rate and concerns regarding PPI's side effects. In a previously published proof of concept study, a non-pharmacological, non-invasive transcutaneous, electrical stimulation system, reduced esophageal acid exposure in GERD patients unresponsive to standard dose PPI. However, in that study, a symptomatic response to electrical stimulation was not assessed. Aim To determine the effect of a transcutaneous electrical stimulation system (TESS) on symptoms (heartburn and regurgitation) and the percentage of esophageal acid exposure time in GERD patients. Methods Patients suffering from heartburn and regurgitation were recruited into this multicenter study. The first phase of this study was a one week, run-in period, off-PPI's, during which, patients completed symptoms diaries and demographic questionnaires. Thereafter, all patients underwent upper endoscopy with subsequently wireless esophageal pH capsule placement (off PPI). Based on pH analysis in the first 24-hours, (day 0) only those with increased acid exposure time (percent total time pH &amp;lt;4 above 6%) continued to the next phase. During phase two of the study, patients were treated for two weeks with TESS and documented their symptoms. Primary end points included the reduction of baseline (pretreatment) number of heartburn and regurgitation episodes as well as 24-hour percent total time pH &amp;lt;4 and/or DeMeester score by at least 50%. Results 26 GERD patients (16 male, aged 47±15 years, mean BMI 25±3 kg/m2) completed the study. At baseline, mean number of daily heartburn and regurgitation events was 2.41±0.36 and 1.38±0.35, respectively. Following TESS, mean number of daily heartburn and regurgitation events dropped to 0.69±0.16 and 0.31±0.19, respectively (p=0.01). At baseline, mean percent total time pH &amp;lt; 4 was 11.8±0.9. Following TESS, mean percent total time pH &amp;lt; 4 dropped to 7.3±0.8, 7.8±1.0, 6.7±1.1 and 5.0±0.7 for day 1, 2, 3 and 4, respectively (p=0.01). At baseline, mean DeMeester score was 31.4±2.1. Following TESS, mean DeMeester score dropped to 20.1±2.0, 20.4±2.5, 17.3±2.6 and 14.3±2.0 for day 1, 2, 3 and 4, respectively (p=0.01). Conclusions TESS is effective in reducing both symptoms (heartburn and regurgitation) and esophageal acid exposure time in GERD patients.

Effects of electrical stimulation with alternating fields on the osseointegration of titanium implants in the rabbit tibia - a pilot study.

Introduction: Electrical stimulation has been used as a promising approach in bone repair for several decades. However, the therapeutic use is hampered by inconsistent results due to a lack of standardized application protocols. Recently, electrical stimulation has been considered for the improvement of the osseointegration of dental and endoprosthetic implants. Methods: In a pilot study, the suitability of a specifically developed device for electrical stimulation in situ was assessed. Here, the impact of alternating electric fields on implant osseointegration was tested in a gap model using New Zealand White Rabbits. Stimulation parameters were transmitted to the device via a radio transceiver, thus allowing for real-time monitoring and, if required, variations of stimulation parameters. The effect of electrical stimulation on implant osseointegration was quantified by the bone-implant contact (BIC) assessed by histomorphometric (2D) and µCT (3D) analysis. Results: Direct stimulation with an alternating electric potential of 150mV and 20Hz for three times a day (45min per unit) resulted in improved osseointegration of the triangular titanium implants in the tibiae of the rabbits. The ratio of bone area in histomorphometry (2D analysis) and bone volume (3D analysis) around the implant were significantly increased after stimulation compared to the untreated controls at sacrifice 84days after implantation. Conclusion: The developed experimental design of an electrical stimulation system, which was directly located in the defect zone of rabbit tibiae, provided feedback regarding the integrity of the stimulation device throughout an experiment and would allow variations in the stimulation parameters in future studies. Within this study, electrical stimulation resulted in enhanced implant osseointegration. However, direct electrical stimulation of bone tissue requires the definition of dose-response curves and optimal duration of treatment, which should be the subject of subsequent studies.

A single-center, assessor-blinded, randomized controlled clinical trial to test the safety and efficacy of a novel brain-computer interface controlled functional electrical stimulation (BCI-FES) intervention for gait rehabilitation in the chronic stroke population

BackgroundIn the United States, there are over seven million stroke survivors, with many facing gait impairments due to foot drop. This restricts their community ambulation and hinders functional independence, leading to several long-term health complications. Despite the best available physical therapy, gait function is incompletely recovered, and this occurs mainly during the acute phase post-stroke. Therapeutic options are limited currently. Novel therapies based on neurobiological principles have the potential to lead to long-term functional improvements. The Brain-Computer Interface (BCI) controlled Functional Electrical Stimulation (FES) system is one such strategy. It is based on Hebbian principles and has shown promise in early feasibility studies. The current study describes the BCI-FES clinical trial, which examines the safety and efficacy of this system, compared to conventional physical therapy (PT), to improve gait velocity for those with chronic gait impairment post-stroke. The trial also aims to find other secondary factors that may impact or accompany these improvements and establish the potential of Hebbian-based rehabilitation therapies.MethodsThis Phase II clinical trial is a two-arm, randomized, controlled, longitudinal study with 66 stroke participants in the chronic (> 6 months) stage of gait impairment. The participants undergo either BCI-FES paired with PT or dose-matched PT sessions (three times weekly for four weeks). The primary outcome is gait velocity (10-meter walk test), and secondary outcomes include gait endurance, range of motion, strength, sensation, quality of life, and neurophysiological biomarkers. These measures are acquired longitudinally.DiscussionBCI-FES holds promise for gait velocity improvements in stroke patients. This clinical trial will evaluate the safety and efficacy of BCI-FES therapy when compared to dose-matched conventional therapy. The success of this trial will inform the potential utility of a Phase III efficacy trial.Trial registrationThe trial was registered as ”BCI-FES Therapy for Stroke Rehabilitation” on February 19, 2020, at clinicaltrials.gov with the identifier NCT04279067.

Effect of different electrical stimulation systems on beef quality and palatability: Constant current compared to constant voltage

This study examined the effects of constant current electrical stimulation (CCES) compared to constant voltage electrical stimulation (CVES), when applied within the same beef carcass (n = 79), on longissimus thoracis et lumborum (LTL) quality and palatability. There was a stimulation method × time interaction for pH, with CCES reducing the 3 h post-mortem pH, but increasing the 72 h post-mortem pH compared to CVES (P < 0.001). The CCES decreased the meat subjective Japanese Meat Grading Agency (JMGA) colour scores (P < 0.05) and increased the objective L⁎ (P < 0.01), a⁎ (P < 0.05) and b⁎ (P < 0.05) colour values at 3 d post-mortem and L⁎ and b⁎ values (P < 0.05) during retail display compared to CVES, although the objective values from both stimulation methods were above established consumer acceptability thresholds. Additionally, CCES reduced the purge (P < 0.05) and drip (P < 0.01) losses, and tended to reduce shear force values (P = 0.089) compared to CVES, although these did not translate into differences in juiciness or tenderness evaluated by trained panelists (P > 0.1). Regarding flavour, the CCES meat had greater bloody/serumy flavour (P < 0.05) and corn aroma (P < 0.05), less unidentified aroma (P < 0.05), and tended to have greater corn flavour (P = 0.077) and less barnyard aroma (P = 0.079) than CVES meat. There were also increased concentrations of flavour-related volatile compounds including 2-methyl-butanal, 3-methyl-butanal and 2–5-dimethyl pyrazine levels (P < 0.05) with CCES. Overall, the CCES system slightly improved meat quality and flavour compared to CVES when applied to the same beef carcasses. Further consumer studies would be warranted to determine whether these differences translate into more acceptable meat.

Maturation of Human iPSC-Derived Cardiac Microfiber with Electrical Stimulation Device.

Here an electrical stimulation system is described for maturing microfiber-shaped cardiac tissue (cardiac microfibers, CMFs). The system enables stable culturing of CMFs with electrical stimulation by placing the tissue between electrodes. The electrical stimulation device provides an electric field covering whole CMFs within the stimulation area and can control the beating of the cardiac microfibers. In addition, CMFs under electrical stimulation with different frequencies are examined to evaluate the maturation levels by their sarcomere lengths, electrophysiological characteristics, and gene expression. Sarcomere elongation (14% increase compared to control) is observed at day 10, and a significant upregulation of electrodynamic properties such as gap junction protein alpha 1 (GJA1) and potassium inwardly rectifying channel subfamily J member 2 (KCNJ2) (maximum fourfold increase compared to control) is observed at day 30. These results suggest that electrically stimulated cultures can accelerate the maturation of microfiber-shaped cardiac tissues compared to those without electrical stimulation. This model will contribute to the pathological research of unexplained cardiac diseases and pharmacologic testing by stably constructing matured CMFs.

New tools for treating chronic wounds

Advances in electrical stimulation, cell and drug delivery systems, and 3D printing hold potential for chronic wound treatment.

Functional Gastrointestinal Disorders (FGID): Information Technology Adoption Based on Power Transmission

One of the most investigated topics in information systems (IS) has been the adoption of new technologies. While several models have been developed in the past ten years to address the acceptance or rejection of information systems, there is still a dearth of studies that provide a thorough analysis and classification of the literature in this field. Many functional gastrointestinal illnesses have been linked to potential treatments with electrical stimulation (FGID). An implanted electrical stimulation system with a transcutaneous power supply is presented in this research. The issue of providing an implanted electrical stimulator with prolonged power is resolved by this technology. Following implantation, the external controller can reprogram the stimulation parameters, which are subsequently communicated to the implanted stimulator. This would make it possible to do parametric research to find out how well different stimulation parameters work to encourage gastric contractions. Feedback on changes in the gastrointestinal tract can be received in real time via an internal stimulator pressure detector. The investigation provides academics and practitioners with insights and future directions on technology adoption by looking into related research works to gather data on IT adoption patterns. This paper outlines potential future research directions for scholars interested in pursuing studies on technology adoption. It also provides a summary of the major discoveries from earlier investigations, including statistical conclusions about variables that were added in IT adoption research.

Integrated Electrostimulation Cell Culture Systems Driven by Chemically Modified Twistron Mechanical Energy Harvesting Electrodes

AbstractDeveloping mechanical energy harvesters for electrical stimulation (ES) needed to augment cell behavior is a burgeoning area of interest. Mechanical energy harvesters that can generate electrical energy in electrolyte‐containing aqueous environments offer a unique solution for delivering ES to cells. In this work, a fully integrated ES assembly (FESA) is introduced that comprises coiled polydopamine (PDA) containing carbon nanotube yarn (CNT) harvesters, serving as ES generators, and poly(3,4‐ethylenedioxythiophene) coated carbon nanotube (PEDOT/CNT) sheets employed as a conductive scaffold. The PDA containing CNT (PDA/CNT) yarn, a novel twistron electrode, achieves an enhanced electrical power at a lower matching impedance than coiled CNT yarn to efficiently transfer ES to the conductive scaffold. The PEDOT used for the scaffold provides a suitable surface for cell adhesion and low resistance for effective ES transmission. In addition, the upscaled array of coiled PDA/CNT yarns provides an ES current density range up to 75.4 µA cm−2, which is much higher than for ES systems using different mechanical energy harvesters. This FESA is designed to provide an optimal level of ES for the proliferation and differentiation of chondrocytes. The findings illuminate the potential of chemically modified twistron energy harvesters as an innovative and effective strategy to promote biological response.

The effect of using the electrical muscle stimulation system ((EMS) that accompanies special exercises in developing some physical abilities by fencing on chairs)

&#x0D; The problem under study tackles the weakness of the physical and technical level of the wheelchair fencers in particular. This is mainly reflected in the poor performance of the required movements due to the weakness of the back and upper limb muscles caused by their limited movement as a handicap and the inability to perform physical exercises completely. The study aims at showing the effect of the EMS on the development of the muscles and the level of performance. As far as the theoretical studies are concerned, the researcher has introduced several topics on electrical stimulation, types of muscles, special exercises, and the physical and technical abilities embraced in the study variables. Previous and similar studies have been discussed also, The experimental method of two groups design (control and experimental) has been used with pretest and posttest style to suit the nature of the problem. The community of the study has been intentionally identified to consist of 10 wheelchair fencers training with the juniors of the Iraqi Federation for Wheelchair Fencing at the Ministry of Youth and Sports in the Paralympic court. Having the experimental method applied by using the electrical stimulation with special exercises, and conducting the scientific foundations, the results were statistically processed by the statistical bag.&#x0D; &#x0D;

Closed-Loop Wearable Device Network of Intrinsically-Controlled, Bilateral Coordinated Functional Electrical Stimulation for Stroke.

Innovative functional electrical stimulation has demonstrated effectiveness in enhancing daily walking and rehabilitating stroke patients with foot drop. However, its lack of precision in stimulating timing, individual adaptivity, and bilateral symmetry, resulted in diminished clinical efficacy. Therefore, a closed-loop wearable device network of intrinsically controlled functional electrical stimulation (CI-FES) system is proposed, which utilizes the personal surface myoelectricity, derived from the intrinsic neuro signal, as the switch to activate/deactivate the stimulation on the affected side. Simultaneously, it decodes the myoelectricity signal of the patient's healthy side to adjust the stimulation intensity, forming an intrinsically controlled loop with the inertial measurement units. With CI-FES assistance, patients' walking ability significantly improved, evidenced by the shift in ankle joint angle mean and variance from 105.53° and 28.84 to 102.81° and 17.71, and the oxyhemoglobin concentration tested by the functional near-infrared spectroscopy. In long-term CI-FES-assisted clinical testing, the discriminability in machine learning classification between patients and healthy individuals gradually decreased from 100% to 92.5%, suggesting a remarkable recovery tendency, further substantiated by performance on the functional movement scales. The developed CI-FES system is crucial for contralateral-hemiplegic stroke recovery, paving the way for future closed-loop stimulation systems in stroke rehabilitation is anticipated.

Impact of electrical muscle stimulation on serum myostatin level and maintenance of skeletal muscle mass in patients undergoing living-donor liver transplantation: Single-center controlled trial.

Sarcopenia is reportedly associated with a poor prognosis in patients who undergo living-donor liver transplantation (LDLT), most of whom are not able to tolerate muscle strengthening exercise training. Myostatin is one of the myokines and a negative regulator of skeletal muscle growth. The clinical feasibility of an electrical muscle stimulation (EMS) system, which exercises muscle automatically by direct electrical stimulation, has been reported. In this study, we aimed to determine the effect of perioperative application of SIXPAD, which is a type of EMS system, with reference to the serum myostatin and sarcopenia in LDLT patients. Thirty patients scheduled for LDLT were divided into a SIXPAD group (n=16) and a control group (n=14). In the SIXPAD group, EMS was applied to the thighs twice daily. The serum myostatin was measured in samples obtained before use of SIXPAD and immediately before LDLT. The psoas muscle index (PMI) at the level of the third lumbar vertebra and the quadriceps muscle area were compared on computed tomography images before use of SIXPAD and 1month after LDLT. The preoperative serum myostatin was found to be higher in LDLT patients than in healthy volunteers and EMS significantly reduced the serum myostatin. Electrical muscle stimulation prevented a postoperative reduction not only in the area of the quadriceps muscles but also in the PMI despite direct stimulation of the thigh muscles. Stimulation of muscles by EMS decreases the serum myostatin and helps to maintain skeletal muscle in patients who have undergone LDLT.

Abstract 30: Pharyngeal Electric Stimulation: The Initial U.S. Experience With a Novel Device for Treatment of Severe Dysphagia After Stroke

Background: Based on over 20 years of international research, FDA recently granted De Novo classification to the Phagenyx® Neurostimulation System for pharyngeal electrical stimulation (PES) for patients with severe dysphagia post stroke. Subjects &amp; Methods: We report on the design and outcomes of the first U.S. post market multi-center experience with the Phagenyx® Neurostimulation System (Phagenesis Limited, Manchester, UK). Eligible patients were determined to have severe dysphagia post-stroke (ischemic or hemorrhagic) by the treating stroke neurologists (MD) and standard assessments by Speech-Language Pathologists (SLPs). Treatment was implemented in addition to standard of care during hospitalization with institutional informed consents obtained prior to treatment. PES stimulation levels were optimized for each patient and each treatment through sensory threshold and tolerance testing by the SLPs. This was followed by a fixed 10 minute treatment session. The treatment regimen was: 1 treatment per day, 10 min/day x 3 days with interim speech therapy reassessment. Treatment could be extended up to 3 additional treatments for a total of 6 treatments if deemed necessary by medical team. SLPs monitored for adverse events during the optimization and treatment. Results: PES was administered to a minimum of 5 patients at each participating institution during the initial implementation. An instrumental assessment was completed at the conclusion of the treatment period as indicated, showing outcomes that ranged from improved secretion management and diet advancement, to swallow restoration. Patient experiences and suggestions were captured and will be presented. Conclusions: A novel FDA-approved PES device for treatment of severe dysphagia shows a potential to be safely tolerated with the magnitude of swallowing improvement and restoration similar to the pivotal trials conducted overseas. Final results of the multi-center study will be presented at the meeting.

A Performance Evaluation of Repetitive and Iterative Learning Algorithms for Periodic Tracking Control of Functional Electrical Stimulation System

Functional electrical stimulation (FES) is a medical device that delivers electrical pulses to the muscle, allowing patients with spinal cord injuries to perform activities such as walking, cycling, and grasping. It is critical for the FES to generate stimuli with the appropriate controller so that the desired movements can be precisely tracked. By considering the repetitive nature of the movements, the learning-based control algorithms are utilized for regulating the FES. Iterative learning control (ILC) and repetitive control (RC) are two learning algorithms that can be used to accomplish accurate repetitive motions. This study investigates a variety of ILC and RC designs with distinct learning functions; this constitutes our contribution to the field. The FES model of ankle angle, which is in a class of discrete-time linear systems is considered in this study. Two learning functions, i.e., proportional, and zero-phase learning functions, are simulated for the second-order FES model running at a sampling time of 0.1 s. The results indicate the superior performance of the ILC and RC in terms of convergence rate using the zero-phase learning function. ILC and RC with a zero-phase learning function can reach a zero root-mean-square error in two iterations if the model of the plant is correct. This is faster than proportional-based ILC and RC, which takes about 40 iterations. This indicates that the zero-phase learning function requires two iterations to ensure that the patient's ankle angle precisely tracks the intended trajectory. However, the tracking performance is degraded for both control methods, especially when the model is subject to uncertainties. This specific problem can lead to future research directions.

Dual electrical stimulation at spinal-muscular interface reconstructs spinal sensorimotor circuits after spinal cord injury

The neural signals produced by varying electrical stimulation parameters lead to characteristic neural circuit responses. However, the characteristics of neural circuits reconstructed by electrical signals remain poorly understood, which greatly limits the application of such electrical neuromodulation techniques for the treatment of spinal cord injury. Here, we develop a dual electrical stimulation system that combines epidural electrical and muscle stimulation to mimic feedforward and feedback electrical signals in spinal sensorimotor circuits. We demonstrate that a stimulus frequency of 10−20 Hz under dual stimulation conditions is required for structural and functional reconstruction of spinal sensorimotor circuits, which not only activates genes associated with axonal regeneration of motoneurons, but also improves the excitability of spinal neurons. Overall, the results provide insights into neural signal decoding during spinal sensorimotor circuit reconstruction, suggesting that the combination of epidural electrical and muscle stimulation is a promising method for the treatment of spinal cord injury.

Functional Electrostimulation System for a Prototype of a Human Hand Prosthesis Using Electromyography Signal Classification by Machine Learning Techniques

Functional electrical stimulation (FES) has been proven to be a reliable rehabilitation technique that increases muscle strength, reduces spasms, and enhances neuroplasticity in the long term. However, the available electrical stimulation systems on the market produce stimulation signals with no personalized voltage–current amplitudes, which could lead to muscle fatigue or incomplete enforced therapeutic motion. This work proposes an FES system aided by machine learning strategies that could adjust the stimulating signal based on electromyography (EMG) information. The regulation of the stimulated signal according to the patient’s therapeutic requirements is proposed. The EMG signals were classified using Long Short-Term Memory (LSTM) and a least-squares boosting ensemble model with an accuracy of 91.87% and 84.7%, respectively, when a set of 1200 signals from six different patients were used. The classification outcomes were used as input to a second regression machine learning algorithm that produced the adjusted electrostimulation signal required by the user according to their own electrophysiological conditions. The output of the second network served as input to a digitally processed electrostimulator that generated the necessary signal to be injected into the extremity to be treated. The results were evaluated in both simulated and robotized human hand scenarios. These evaluations demonstrated a two percent error when replicating the required movement enforced by the collected EMG information.

Rehabilitation exercise-driven symbiotic electrical stimulation system accelerating bone regeneration.

Electrical stimulation can effectively accelerate bone healing. However, the substantial size and weight of electrical stimulation devices result in reduced patient benefits and compliance. It remains a challenge to establish a flexible and lightweight implantable microelectronic stimulator for bone regeneration. Here, we use self-powered technology to develop an electric pulse stimulator without circuits and batteries, which removes the problems of weight, volume, and necessary rigid packaging. The fully implantable bone defect electrical stimulation (BD-ES) system combines a hybrid tribo/piezoelectric nanogenerator to provide biphasic electric pulses in response to rehabilitation exercise with a conductive bioactive hydrogel. BD-ES can enhance multiple osteogenesis-related biological processes, including calcium ion import and osteogenic differentiation. In a rat model of critical-sized femoral defects, the bone defect was reversed by electrical stimulation therapy with BD-ES and subsequent bone mineralization, and the femur completely healed within 6 weeks. This work is expected to advance the development of symbiotic electrical stimulation therapy devices without batteries and circuits.

Charge-Mode Neural Stimulator With a Capacitor-Reuse Residual Charge Detector and Active Charge Balancing for Epileptic Seizure Suppression.

This study proposes a charge-mode neural stimulator for electrical stimulation systems that utilizes a capacitor-reuse technique with a residual charge detector and achieves active charge balancing simultaneously. The design is mainly used for epilepsy suppression systems to achieve real-time symptom relief during seizures. A charge-mode stimulator is adopted in consideration of the complexity of circuit design, the high voltage tolerance of transistors, and system integration requirements in the future. The residual charge detector allows users to understand the current stimulus situation, enabling them to make optimal adjustments to the stimulation parameters. On the basis of the information on actual stimulation charge, active charge balancing can effectively prevent the accumulation of mismatched charges on electrode impedance. The capacitor- and phase-reuse techniques help realize high integration of the overall stimulator circuit in consideration of the commonality of the use of a capacitor and charging/discharging phase in the stimulation circuit and charge detector. The proposed charge-mode neural stimulator is implemented in a TSMC 0.18 µm 1P6M CMOS process with a core area of 0.2127 mm2. Measurement results demonstrate the accuracy of the stimulation's functionality and the programmable stimulus parameters. The effectiveness of the proposed charge-mode neural stimulator for epileptic seizure suppression is verified through animal experiments.

Enhanced cytotoxic activity of natural killer cells from increased calcium influx induced by electrical stimulation.

Natural killer (NK) cells play a crucial role in immunosurveillance independent of antigen presentation, which is regulated by signal balance via activating and inhibitory receptors. The anti-tumor activity of NK cells is largely dependent on signaling from target recognition to cytolytic degranulation; however, the underlying mechanism remains unclear, and NK cell cytotoxicity is readily impaired by tumor cells. Understanding the activation mechanism is necessary to overcome the immune evasion mechanism, which remains an obstacle in immunotherapy. Because calcium ions are important activators of NK cells, we hypothesized that electrical stimulation could induce changes in intracellular Ca2+ levels, thereby improving the functional potential of NK cells. In this study, we designed an electrical stimulation system and observed a correlation between elevated Ca2+ flux induced by electrical stimulation and NK cell activation. Breast cancer MCF-7 cells co-cultured with electrically stimulated KHYG-1 cells showed a 1.27-fold (0.5 V/cm) and 1.55-fold (1.0 V/cm) higher cytotoxicity, respectively. Electrically stimulated KHYG-1 cells exhibited a minor increase in Ca2+ level (1.31-fold (0.5 V/cm) and 1.11-fold (1.0 V/cm) higher), which also led to increased gene expression of granzyme B (GZMB) by 1.36-fold (0.5 V/cm) and 1.58-fold (1.0 V/cm) by activating Ca2+-dependent nuclear factor of activated T cell 1 (NFAT1). In addition, chelating Ca2+ influx with 5 μM BAPTA-AM suppressed the gene expression of Ca2+ signaling and lytic granule (granzyme B) proteins by neutralizing the effects of electrical stimulation. This study suggests a promising immunotherapeutic approach without genetic modifications and elucidates the correlation between cytolytic effector function and intracellular Ca2+ levels in electrically stimulated NK cells.