Using a Digital Twin of an Electrical Stimulation Device to Monitor and Control the Electrical Stimulation of Cells in vitro

Electrical stimulation for application in tissue engineering and regenerative medicine has received increasing attention in recent years. A variety of stimulation methods, waveforms and amplitudes have been studied. However, a clear choice of optimal stimulation parameters is still not available and is complicated by ambiguous reporting standards. In order to understand underlying cellular mechanisms affected by the electrical stimulation, the knowledge of the actual prevailing field strength or current density is required. Here, we present a comprehensive digital representation, a digital twin, of a basic electrical stimulation device for the electrical stimulation of cells in vitro. The effect of electrochemical processes at the electrode surface was experimentally characterised and integrated into a numerical model of the electrical stimulation. Uncertainty quantification techniques were used to identify the influence of model uncertainties on relevant observables. Different stimulation protocols were compared and it was assessed if the information contained in the monitored stimulation pulses could be related to the stimulation model. We found that our approach permits to model and simulate the recorded rectangular waveforms such that local electric field strengths become accessible. Moreover, we could predict stimulation voltages and currents reliably. This enabled us to define a controlled stimulation setting and to identify significant temperature changes of the cell culture in the monitored voltage data. Eventually, we give an outlook on how the presented methods can be applied in more complex situations such as the stimulation of hydrogels or tissue in vivo.

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Experimental Migraine Models and Their Relevance in Migraine Therapy

Cephalalgia ◽

10.1111/j.1468-2982.2005.01082.x ◽

2006 ◽

Vol 26 (6) ◽

pp. 642-659 ◽

Cited By ~ 31

Author(s):

U Arulmani ◽

S Gupta ◽

A Maassen VanDenBrink ◽

D Centurión ◽

CM Villalón ◽

...

Keyword(s):

Electrical Stimulation ◽

Trigeminal Ganglion ◽

In Vitro Models ◽

In Vivo Model ◽

Trigeminal System ◽

Sagittal Sinus ◽

Migraine Pathophysiology ◽

Stimulation Of

Although the understanding of migraine pathophysiology is incomplete, it is now well accepted that this neurovascular syndrome is mainly due to a cranial vasodilation with activation of the trigeminal system. Several experimental migraine models, based on vascular and neuronal involvement, have been developed. Obviously, the migraine models do not entail all facets of this clinically heterogeneous disorder, but their contribution at several levels (molecular, in vitro, in vivo) has been crucial in the development of novel antimigraine drugs and in the understanding of migraine pathophysiology. One important vascular in vivo model, based on an assumption that migraine headache involves cranial vasodilation, determines porcine arteriovenous anastomotic blood flow. Other models utilize electrical stimulation of the trigeminal ganglion/nerve to study neurogenic dural inflammation, while the superior sagittal sinus stimulation model takes into account the transmission of trigeminal nociceptive input in the brainstem. More recently, the introduction of integrated models, namely electrical stimulation of the trigeminal ganglion or systemic administration of capsaicin, allows studying the activation of the trigeminal system and its effect on the cranial vasculature. Studies using in vitro models have contributed enormously during the preclinical stage to characterizing the receptors in cranial blood vessels and to studying the effects of several putative antimigraine agents. The aforementioned migraine models have advantages as well as some limitations. The present review is devoted to discussing various migraine models and their relevance to antimigraine therapy.

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Regulation of lipolysis by somatotropin: functional alteration of adrenergic and adenosine signaling in bovine adipose tissue

Journal of Endocrinology ◽

10.1677/joe.0.1520465 ◽

1997 ◽

Vol 152 (3) ◽

pp. 465-475 ◽

Cited By ~ 18

Author(s):

K L Houseknecht ◽

D E Bauman

Keyword(s):

Adipose Tissue ◽

Signaling Proteins ◽

Heterotrimeric G Proteins ◽

Adrenergic Stimulation ◽

Cellular Mechanisms ◽

Lactating Cows ◽

Adipose Tissue Lipolysis ◽

Stimulation Of

To investigate the cellular mechanisms of somatotropin (ST) action on adipose tissue lipolysis, experiments were conducted using adipose tissue taken from lactating cows treated with excipient or ST (40 mg/day). Stimulation of lipolysis in vitro by the effectors isoproterenol with or without adenosine deaminase, dibutyryl cAMP with or without isobutylmethylxanthine, and forskolin was not altered by ST treatment. Conversely, the response to the antilipolytic effector, phenylisopropyladenosine (PIA), was significantly reduced in adipose tissue explants from ST or fasted cows. The different responses to adrenergic-stimulating agents (in vivo) and PIA (in vitro) were not due to differences in the abundance of α, β or γ subunits of the stimulatory (Gs) and inhibitory (Gi) subunits of the heterotrimeric G-proteins which bind to the β-adrenergic and adenosine receptors respectively. However, the functionality of Gi proteins, as assessed by their ability to be ADP-ribosylated by pertussis toxin, was significantly reduced in ST-treated but not fasted cows. These data highlight differential regulation of signaling proteins by ST and fasting, both of which result in enhanced in vivo response to adrenergic stimulation of lipolysis. Journal of Endocrinology (1997) 152, 465–475

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Peripheral neural input to neurons of the stellate ganglion in dog

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1982.242.3.r237 ◽

1982 ◽

Vol 242 (3) ◽

pp. R237-R243

Author(s):

Z. J. Bosnjak ◽

J. L. Seagard ◽

J. P. Kampine

Keyword(s):

Electrical Stimulation ◽

Action Potentials ◽

Stellate Ganglion ◽

Afferent Input ◽

In Vivo Studies ◽

Organ Bath ◽

Efferent Nerve ◽

Stimulation Of

In vitro and in vivo studies were conducted on the stellate ganglion (SG) of the dog by recording action potentials from its nerves and its neurons. For in vitro preparations, the SG and its nerve trunks were dissected from the animal and secured in an organ bath. Peripheral input to the SG was produced by electrical stimulation of the ventral ansa subclavia (VA), dorsal ansa subclavia (DA), and stellate cardiac nerve (SC) in 15 ganglion preparations studied in vitro. Electrical stimulation of the VA elicited action potentials recorded at the DA. This conducting pathway did not involve direct anatomic continuity, since the evoked potentials were blocked by injection of hexamethonium chloride into the SG. Most neurons in the SG received synaptic input from fibers of both central and peripheral origin. In 12 in vivo preparations, all nerves to the SG except the VA were cut. When peripheral sympathetic afferent input to the SG was increased, some of the postganglionic fibers of the dissected DA exhibited an increase in efferent nerve discharge. This response was also blocked by hexamethonium chloride. These results indicate that some of the functions of the SG might be independent of the central nervous system.

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Promoting osseointegration with electrical stimulation: a review

10.36227/techrxiv.14362838.v1 ◽

2021 ◽

Author(s):

Emily Pettersen ◽

Jenna Anderson ◽

Max Ortiz-Catalan

Keyword(s):

Electrical Stimulation ◽

Electric Fields ◽

Meta Analysis ◽

Implant Surface ◽

Power Sources ◽

Stimulation Parameters ◽

Bone Quantity ◽

Major Factors

Electrical stimulation has shown to be a promising approach for promoting osseointegration in bone-anchored implants, where osseointegration defines the biological bonding between an implant surface and bone tissue. Bone-anchored implants are used in the rehabilitation of hearing and limb loss, and extensively in edentulous patients. Inadequate osseointegration is one of the major factors of implant failure that could be prevented by accelerating or enhancing the osseointegration process by artificial means. In this article, we reviewed the efforts to enhance the biofunctionality at the implant-bone interface with electrical stimulation using various approaches such as different electrode configurations, power sources, and waveform-dependent stimulation parameters tested in different in vitro and in vivo models. We reviewed and compared studies from the last 45 years and found nonuniform protocols with disparities in cell type and animal model, implant location, experimental timeline, implant material, evaluation assays, and type of electrical stimulation. The reporting of stimulation parameters was also found to be inconsistent and incomplete throughout the literature. Studies using in vitro models showed that osteoblasts were sensitive to the magnitude of the electric field and duration of exposure, and such variables similarly affected bone quantity around implants in in vivo investigations. Most studies showed benefits of electrical stimulation in the underlying processes leading to osseointegration, and therefore we found the idea of promoting osseointegration by using electric fields to be supported by the available evidence. However, such an effect has not been demonstrated conclusively nor optimally in humans. We found that optimal stimulation parameters have not been thoroughly investigated and this remains an important step towards the clinical translation of this concept. In addition, there is a need for reporting standards to enable meta-analysis for evidence-based treatments.

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Load-elongation characteristics of in vivo human tendon and aponeurosis

Journal of Experimental Biology ◽

10.1242/jeb.203.4.751 ◽

2000 ◽

Vol 203 (4) ◽

pp. 751-756 ◽

Cited By ~ 2

Author(s):

C.N. Maganaris ◽

J.P. Paul

Keyword(s):

Electrical Stimulation ◽

Tibialis Anterior ◽

Material Testing ◽

Tetanic Stimulation ◽

Tibialis Anterior Tendon ◽

Human Tendon ◽

Tendon Strain ◽

Stimulation Of

In the present study, we measured the in vivo load-elongation characteristics of the human tibialis anterior tendon and its central aponeurosis. Measurements were taken in five men using dynamometry, muscle electrical stimulation and ultrasonography. Percutaneous tetanic stimulation of the muscle at successive voltages corresponding to 20, 40, 60, 80 and 100 % of maximum isometric dorsiflexion moment was applied. During electrical stimulation, we recorded the displacements of the tibialis anterior tendon origin and its aponeurosis proximal end using B-mode ultrasonography. Aponeurosis displacement was calculated by subtracting tendon displacement from the displacement of the aponeurosis proximal end. Tendon and aponeurosis displacements increased curvilinearly from 1.3 to 4 mm and from 3.7 to 12 mm, respectively, as a function of dorsiflexion load. Scaling of the displacements recorded to the resting lengths (measured over the skin) yielded strain values that increased curvilinearly with load, from 0.8 to 2.5% in the tendon and from 2.1 to 7% in the aponeurosis. Tendon strain was smaller by between 61 and 64% compared with aponeurosis strain at any given contraction level. These findings are in line with reports from in vitro isolated material testing and have important implications for muscle modelling.

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Promoting osseointegration with electrical stimulation: a review

10.36227/techrxiv.14362838 ◽

2021 ◽

Author(s):

Emily Pettersen ◽

Jenna Anderson ◽

Max Ortiz-Catalan

Keyword(s):

Electrical Stimulation ◽

Electric Fields ◽

Meta Analysis ◽

Implant Surface ◽

Power Sources ◽

Stimulation Parameters ◽

Bone Quantity ◽

Major Factors

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In vivo exercise followed by in vitro contraction additively elevates subsequent insulin-stimulated glucose transport by rat skeletal muscle

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00758.2009 ◽

2010 ◽

Vol 298 (5) ◽

pp. E999-E1010 ◽

Cited By ~ 46

Author(s):

Katsuhiko Funai ◽

George G. Schweitzer ◽

Carlos M. Castorena ◽

Makoto Kanzaki ◽

Gregory D. Cartee

Keyword(s):

Electrical Stimulation ◽

Insulin Sensitivity ◽

Glucose Transport ◽

Rat Skeletal Muscle ◽

Cellular Mechanisms ◽

Subsequent Increase ◽

Rat Serum ◽

Prior Exercise

The cellular mechanisms whereby prior exercise enhances insulin-stimulated glucose transport (GT) are not well understood. Previous studies suggested that a prolonged increase in phosphorylation of Akt substrate of 160 kDa (AS160) may be important for the postexercise increase in insulin sensitivity. In the current study, the effects of in vivo exercise and in vitro contraction on subsequent insulin-stimulated GT were studied separately and together. Consistent with results from previous studies, prior exercise resulted in an increase in AS160642Thr phosphorylation immediately after exercise in rat epitrochlearis muscles, and this increase remained 3 h postexercise concomitant with enhanced insulin-stimulated GT. For experiments with in vitro contraction, isolated rat epitrochlearis muscles were electrically stimulated to contract in the presence or absence of rat serum. As expected, insulin-stimulated GT measured 3 h after electrical stimulation in serum, but not after electrical stimulation without serum, exceeded resting controls. Immediately after electrical stimulation with or without serum, phosphorylation of both AS160 (detected by phospho-Akt substrate, PAS, antibody, or phospho-642Thr antibody) and its paralog TBC1D1 (detected by phospho-237Ser antibody) was increased. However, both AS160 and TBC1D1 phosphorylation had reversed to resting values at 3 h poststimulation with or without serum. Increasing the amount of exercise (from 1 to 2 h) or electrical stimulation (from 5 to 10 tetani) did not further elevate insulin-stimulated GT. In contrast, the combination of prior exercise and electrical stimulation had an additive effect on the subsequent increase in insulin-stimulated GT, suggesting that these exercise and electrical stimulation protocols may amplify insulin-stimulated GT through distinct mechanisms, with a persistent increase in AS160 phosphorylation potentially important for increased insulin sensitivity after exercise, but not after in vitro contraction.

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EFFECTS OF ELECTRICAL STIMULATION OF THE NEUROHYPOPHYSIS ON LABOUR IN THE RAT

Journal of Endocrinology ◽

10.1677/joe.0.0650163 ◽

1975 ◽

Vol 65 (2) ◽

pp. 163-176 ◽

Cited By ~ 24

Author(s):

K. BOER ◽

D. W. LINCOLN ◽

D. F. SWAAB

Keyword(s):

Electrical Stimulation ◽

Continuous Observation ◽

Birth Intervals ◽

Implanted Electrodes ◽

Uterine Contractions ◽

Stimulation Parameters ◽

Spontaneous Labour ◽

And Control ◽

Second Peak ◽

Stimulation Of

SUMMARY Labour was studied in 69 primiparous and multiparous rats by continuous observation and by the recording of intra-uterine activity. The effect of electrical stimulation of the neurohypophysis with stimulation parameters selected to create a pulsatile release of oxytocin was investigated. Stimulation was applied to the neurohypophysis through chronically implanted electrodes every 5 min, in 45 min sessions, from noon on Day 21 of gestation and at 3 h intervals thereafter. Electrical stimulation successfully promoted (or induced) the onset and facilitated the course of labour. Stimulation at 12.00 h on Day 21, or at a subsequent stimulation session 3, 6, 9 or more hours later, promoted an immediate increase in the frequency and amplitude of uterine contractions. Overt signs of abdominal straining followed within 5–30 min and the first pup was delivered shortly thereafter. These 'induced' deliveries were almost identical to those displayed by control rats; labour continued to completion despite the termination of the stimulation session after 45 min. By contrast, one third of the stimulated animals displayed an interrupted pattern of labour in which events virtually ceased for 30–60 min when stimulation was terminated. Stimulation, however, only advanced labour by 1–2 h in relation to control animals; this was not statistically significant. Stimulation accelerated the delivery of the first 5 pups in each litter. In both stimulated and control animals, the birth intervals declined over these first few deliveries to reach the lowest values of 5–6 min throughout the remainder of labour. The most common litter size was 12 pups. The distribution of labour on Day 21 and 22 was bimodal. Seventy per cent of the animals gave birth between 12.00 and 18.00 h on Day 21, a few gave birth during the following night and the remainder formed a second peak on Day 22. All litters of less than 6 pups were born during this later period. The implications of these results in the context of spontaneous labour are discussed. We conclude that endogenous oxytocin (with perhaps other neurohypophysial hormones) released in pulses of 1–3 mu. every 5 min can promote a pattern of labour on Day 21 of gestation that is almost indistinguishable from that which occurs naturally.

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Comonitoring of adenosine and dopamine using the Wireless Instantaneous Neurotransmitter Concentration System: proof of principle

Journal of Neurosurgery ◽

10.3171/2009.7.jns09787 ◽

2010 ◽

Vol 112 (3) ◽

pp. 539-548 ◽

Cited By ~ 42

Author(s):

Young-Min Shon ◽

Su-Youne Chang ◽

Susannah J. Tye ◽

Christopher J. Kimble ◽

Kevin E. Bennet ◽

...

Keyword(s):

Electrical Stimulation ◽

Carbon Fiber ◽

High Frequency ◽

High Frequency Stimulation ◽

Frequency Stimulation ◽

Dopamine Efflux ◽

Proof Of Principle ◽

Stimulation Of

Object The authors of previous studies have demonstrated that local adenosine efflux may contribute to the therapeutic mechanism of action of thalamic deep brain stimulation (DBS) for essential tremor. Real-time monitoring of the neurochemical output of DBS-targeted regions may thus advance functional neurosurgical procedures by identifying candidate neurotransmitters and neuromodulators involved in the physiological effects of DBS. This would in turn permit the development of a method of chemically guided placement of DBS electrodes in vivo. Designed in compliance with FDA-recognized standards for medical electrical device safety, the authors report on the utility of the Wireless Instantaneous Neurotransmitter Concentration System (WINCS) for real-time comonitoring of electrical stimulation–evoked adenosine and dopamine efflux in vivo, utilizing fast-scan cyclic voltammetry (FSCV) at a polyacrylonitrile-based (T-650) carbon fiber microelectrode (CFM). Methods The WINCS was used for FSCV, which consisted of a triangle wave scanned between −0.4 and +1.5 V at a rate of 400 V/second and applied at 10 Hz. All voltages applied to the CFM were with respect to an Ag/AgCl reference electrode. The CFM was constructed by aspirating a single T-650 carbon fiber (r = 2.5 μm) into a glass capillary and pulling to a microscopic tip using a pipette puller. The exposed carbon fiber (the sensing region) extended beyond the glass insulation by ~ 50 μm. Proof of principle tests included in vitro measurements of adenosine and dopamine, as well as in vivo measurements in urethane-anesthetized rats by monitoring adenosine and dopamine efflux in the dorsomedial caudate putamen evoked by high-frequency electrical stimulation of the ventral tegmental area and substantia nigra. Results The WINCS provided reliable, high-fidelity measurements of adenosine efflux. Peak oxidative currents appeared at +1.5 V and at +1.0 V for adenosine, separate from the peak oxidative current at +0.6 V for dopamine. The WINCS detected subsecond adenosine and dopamine efflux in the caudate putamen at an implanted CFM during high-frequency stimulation of the ventral tegmental area and substantia nigra. Both in vitro and in vivo testing demonstrated that WINCS can detect adenosine in the presence of other easily oxidizable neurochemicals such as dopamine comparable to the detection abilities of a conventional hardwired electrochemical system for FSCV. Conclusions Altogether, these results demonstrate that WINCS is well suited for wireless monitoring of high-frequency stimulation-evoked changes in brain extracellular concentrations of adenosine. Clinical applications of selective adenosine measurements may prove important to the future development of DBS technology.

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Enhancing osteoblast function through pulsed electrical stimulation: implications for peri-implant healing and osseointegration

10.21203/rs.3.rs-384578/v1 ◽

2021 ◽

Author(s):

Emily Pettersen ◽

Furqan A. Shah ◽

Max Ortiz-Catalan

Keyword(s):

Electrical Stimulation ◽

Titanium Implant ◽

Dependent Manner ◽

Nervous Stimulation ◽

Osteoblast Function ◽

Stimulation Parameters ◽

Wide Range ◽

The Impact

Abstract Electrical stimulation has been suggested as a mean for promoting the bonding of bone tissue to an implant, known as osseointegration. Previous work has investigated the impact of electrical stimulation in different models, both in vitro and in vivo, using various electrode configurations for delivering the electric field and with a wide range of stimulation parameters. However, there is no consensus on optimal electrode configuration nor stimulation parameters. Here, we investigated a novel approach of delivering electrical stimulation to a titanium implant using parameters clinically tested in a different application, namely peripheral nerve stimulation. We propose an in vitro model comprising of Ti6Al4V implants precultured with MC3T3-E1 preosteoblasts, stimulated for 72 h at two different pulse amplitudes (10 µA and 20 µA) and at two different frequencies (50 Hz and 100 Hz). We found that pulsed electrical stimulation enhances cell viability (and/or proliferation) and collagen production in an approximately dose-dependent manner. Our findings suggest that pulsed electrical stimulation with characteristics similar to peripheral nervous stimulation has the potential to accelerate osteoblast function and may provide a promising approach to improving peri-implant bone healing, particularly to neuromusculoskeletal interfaces in which implanted electrodes are readily available.

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