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Electrical stimulation has received increasing attention for decades for its application in regenerative medicine. Applications range from bone growth stimulation over cartilage regeneration to deep brain stimulation. Despite all research efforts, translation into clinical use has not yet been achieved in all fields. Recent critical assessments have identified limited documentation and monitoring of preclinical in vitro and in vivo experiments as possible reasons hampering clinical translation. In this work, we present experimental and numerical methods to determine the crucial quantities of electrical stimulation such as the electric field or current density. Knowing the stimulation quantities contributes to comprehending the biological response to electrical stimulation and to finally developing a reliable dose-response curve. To demonstrate the methods, we consider a direct contact electrical stimulation experiment that stands representative for a broad class of stimulation experiments. Electrochemical effects are addressed and methods to integrate them into numerical simulations are evaluated. A focus is laid on affordable lab equipment and reproducible open-source software solutions. Finally, clear guidelines to ensure replicability of electrical stimulation experiments are formulated., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Electric stimulation of neural tissues has been an effective clinical intervention to address a variety of pathological issues such as profound deafness, retinal diseases, and Parkinson's disease. However, the knowledge about the exact mechanism of neural excitation, especially activation sites is still ambiguous. Nevertheless, in silico models utilize two approaches namely activating function and sub-threshold potential to predict the activation sites of neural tissues. This paper studies the applicability of these two approaches to model the electric stimulation of pyramidal neuron and spiral ganglion neurons using finite element models. The simulation results suggest that the activating function could be prone to geometrical irregularities of the neural tissues, yet realistically predicts the activation sites on the myelinated neurons. In contrast, the sub-threshold potential predicts the activation of unmyelinated axons by considering the electrophysiological properties of neural tissues. The present study suggests that it is necessary to choose an appropriate method to estimate the neural activation sites while modeling the extracellular stimulation of neural tissues.

Since several years, the number of total hip arthroplasty revision surgeries is substantially growing. One of the main reasons for this procedure to become necessary is the loosening or damage of the prothesis, which is facilitated by bone necrosis at the implant-bone interface. Electrostimulation is one promising technique, which can accelerate the growth of bone cells and, therefore, enhance the anchorage of the implant to the bone. We present computational models of an electrostimulative total hip revision system to enhance bone regeneration. In this study, the influence of uncertainty in the conductivity of bone tissue on the electric field strength and the beneficial stimulation volume for an optimized electrode geometry and arrangement is investigated. The generalized polynomial chaos technique is used to quantify the uncertainty in the stimulation volumes with respect to the uncertain conductivity of cancellous bone, bone marrow, and bone substitute, which is used to fill defective areas. The results suggest that the overall beneficial stimulation areas are only slightly sensitive to the uncertainty in conductivity of bone tissue. However, in the proximity of tissue boundaries, larger uncertainties, especially in the transition between beneficial and understimulation areas, can be expected.

Unlabelled: Regarding potential endosteal cochlear implant electrodes, the primary goal of this paper is to compare different intra- and extra-cochlear stimulation sites in terms of current strengths needed for stimulating the auditory nerve. Our study was performed during routine cochlear implantation using needle electrodes for electric stimulation and by visually recording electrically elicited stapedius reflexes (ESRT) as a measure for the stimulus transfer. Of course this rather simple setup only allows rough estimations, which, however, may provide further arguments whether or not to proceed with the concept of an endosteal electrode. In addition, a mathematical model is being developed. In a pilot study, intra-operative electric stimuli were applied via a needle electrode commonly used for the promontory stimulation test. Thus, stapedius reflex thresholds (ESRTs), electrically elicited via the needle from different points inside and outside the cochlea served as indicators for the suitability of different electrode positions towards the modiolus. Tests were performed on 11 CI-recipients. In addition, the extension of electrical fields from different stimulation sites is simulated in a mathematical cochlea model. In most patients ESRT measurements could be performed and evaluated. Thus an "endosteal" stimulation seems possible, although the current intensities must be higher than at intraluminal stimulation sites. Moreover, our model calculations confirm that the extension of electric fields is less favourable with increasing distance from the electrode to the ganglion nerve cells. In terms of hearing, the concept of an endosteal electrode should only be promoted, if its superiority for hearing preservation can be proven, e.g. in animal experiments. However, for other indications like the electric suppression of tinnitus, further research seems advisable., Levels of Evidence: N/A.

Since the 1980s electrostimulation is used to accelerate the healing of fractures and bone defects. In prior works this effect has been implemented in a numerical model of an electrostimulative hip revision cup which was optimized using a multi-objective evolutionary algorithm. The aim of our simulations is to design an implant which provides optimal electric fields in the acetabular region enhancing the reconstruction of the pelvic bone in such way as to improve the fixation of the prosthesis in the surrounding bone. In the present work we will show that this multi-objective algorithm can also be used to identify a small amount of configurations of the implant that will be able to stimulate a wide range of pelvic bones with different acetabular defects.

Introduction: Deep brain stimulation (DBS) is a highly effective treatment option in Parkinson's disease. However, the underlying mechanisms of action, particularly effects on neuronal plasticity, remain enigmatic. Adult neurogenesis in the subventricular zone-olfactory bulb (SVZ-OB) axis and in the dentate gyrus (DG) has been linked to various non-motor symptoms in PD, e.g., memory deficits and olfactory dysfunction. Since DBS affects several of these non-motor symptoms, we analyzed the effects of DBS in the subthalamic nucleus (STN) and the entopeduncular nucleus (EPN) on neurogenesis in 6-hydroxydopamine (6-OHDA)-lesioned hemiparkinsonian rats. Methods: In our study, we applied five weeks of continuous bilateral STN-DBS or EPN-DBS in 6-OHDA-lesioned rats with stable dopaminergic deficits compared to 6-OHDA-lesioned rats with corresponding sham stimulation. We injected two thymidine analogs to quantify newborn neurons early after DBS onset and three weeks later. Immunohistochemistry identified newborn cells co-labeled with NeuN, TH and GABA within the OB and DG. As a putative mechanism, we simulated the electric field distribution depending on the stimulation site to analyze direct electric effects on neural stem cell proliferation. Results: STN-DBS persistently increased the number of newborn dopaminergic and GABAergic neurons in the OB but not in the DG, while EPN-DBS does not impact neurogenesis. These effects do not seem to be mediated via direct electric stimulation of neural stem/progenitor cells within the neurogenic niches. Discussion: Our data support target-specific effects of STN-DBS on adult neurogenesis, a putative modulator of non-motor symptoms in Parkinson's disease. [ABSTRACT FROM AUTHOR]

Background: Electrical stimulation is used for enhanced bone fracture healing. Electrochemical processes occur during the electrical stimulation at the electrodes and influence cellular reactions. Our approach aimed to distinguish between electrochemical and electric field effects on osteoblast-like MG-63 cells. We applied 20 Hz biphasic pulses via platinum electrodes for 2 h. The electrical stimulation of the cell culture medium and subsequent application to cells was compared to directly stimulated cells. The electric field distribution was predicted using a digital twin. Results: Cyclic voltammetry and electrochemical impedance spectroscopy revealed partial electrolysis at the electrodes, which was confirmed by increased concentrations of hydrogen peroxide in the medium. While both direct stimulation and AC-conditioned medium decreased cell adhesion and spreading, only the direct stimulation enhanced the intracellular calcium ions and reactive oxygen species. Conclusion: The electrochemical by-product hydrogen peroxide is not the main contributor to the cellular effects of electrical stimulation. However, undesired effects like decreased adhesion are mediated through electrochemical products in stimulated medium. Detailed characterisation and monitoring of the stimulation set up and electrochemical reactions are necessary to find safe electrical stimulation protocols. [ABSTRACT FROM AUTHOR]

Biophysical stimulation by electric fields can promote bone formation in bone defects of critical size. Even though, long-term effects of alternating electric fields on the differentiation of osteoblasts are not fully understood. Human preosteoblasts were stimulated over 31 days to gain more information about these cellular processes. An alternating electric field with 0.7 Vrms and 20 Hz at two distances was applied and viability, mineralization, gene expression, and protein release of differentiation factors were analyzed. The viability was enhanced during the first days of stimulation. A higher electric field resulted in upregulation of typical osteogenic markers like osteoprotegerin, osteopontin, and interleukin-6, but no significant changes in mineralization. Upregulation of the osteogenic markers could be detected with a lower electric field after the first days of stimulation. As a significant increase in the mineralized matrix was identified, an enhanced osteogenesis due to low alternating electric fields can be assumed. [ABSTRACT FROM AUTHOR]

Increasing research has incorporated bioactive glass nanoparticles (BGN) and electric field (EF) stimulation for bone tissue engineering and regeneration applications. However, their interplay and the effects of different EF stimulation regimes on osteogenic differentiation of human mesenchymal stem cells (hMSC) are less investigated. In this study, we introduced EF with negligible magnetic field strength through a well-characterized transformer-like coupling (TLC) system, and applied EF disrupted (4/4) or consecutive (12/12) regime on type I collagen (Col) coatings with/without BGN over 28 days. Additionally, dexamethasone was excluded to enable an accurate interpretation of BGN and EF in supporting osteogenic differentiation. Here, we demonstrated the influences of BGN and EF on collagen topography and maintaining coating stability. Coupled with the release profile of Si ions from the BGN, cell proliferation and calcium deposition were enhanced in the Col-BGN samples after 28 days. Further, osteogenic differentiation was initiated as early as d 7, and each EF regime was shown to activate distinct pathways. The disrupted (4/4) regime was associated with the BMP/Smad4 pathways that up-regulate Runx2/OCN gene expression on d 7, with a lesser effect on ALP activity. In contrast, the canonical Wnt/β-Catenin signaling pathway activated through mechanotransduction cues is associated with the consecutive (12/12) regime, with significantly elevated ALP activity and Sp7 gene expression reported on d 7. In summary, our results illustrated the synergistic effects of BGN and EF in different stimulation regimes on osteogenic differentiation that can be further exploited to enhance current bone tissue engineering and regeneration approaches. The unique release mechanisms of silica from bioactive glass nanoparticles (BGN) were coupled with pulsatile electric field (EF) stimulation to support hMSC osteogenic differentiation, in the absence of dexamethasone. Furthermore, the interplay with consecutive (12/12) and disrupted (4/4) stimulation regimes was investigated. The reported physical, mechanical and topographical effects of BGN and EF on the collagen coating, hMSC and the distinct progression of osteogenic differentiation (canonical Wnt/β-Catenin and BMP/Smad) triggered by respective stimulation regime were not explicitly reported previously. These results provide the fundamentals for further exploitations on BGN composites with metal ions and rotation of EF regimes to enhance osteogenic differentiation. The goal is sustaining continual osteogenic differentiation and achieving a more physiologically-relevant state and bone constructs in vitro. [Display omitted] [ABSTRACT FROM AUTHOR]

An extensive research field in regenerative medicine is electrical stimulation (ES) and its impact on tissue and cells. The mechanism of action of ES, particularly the role of electrical parameters like intensity, frequency, and duration of the electric field, is not yet fully understood. Human MG-63 osteoblasts were electrically stimulated for 10 min with a commercially available multi-channel system (IonOptix). We generated alternating current (AC) electrical fields with a voltage of 1 or 5 V and frequencies of 7.9 or 20 Hz, respectively. To exclude liquid-mediated effects, we characterized the AC-stimulated culture medium. AC stimulation did not change the medium's pH, temperature, and oxygen content. The H2O2 level was comparable with the unstimulated samples except at 5 V_7.9 Hz, where a significant increase in H2O2 was found within the first 30 min. Pulsed electrical stimulation was beneficial for the process of attachment and initial adhesion of suspended osteoblasts. At the same time, the intracellular Ca2+ level was enhanced and highest for 20 Hz stimulated cells with 1 and 5 V, respectively. In addition, increased Ca2+ mobilization after an additional trigger (ATP) was detected at these parameters. New knowledge was provided on why electrical stimulation contributes to cell activation in bone tissue regeneration. [ABSTRACT FROM AUTHOR]

Electrical stimulation of biological samples such as tissues and cell cultures attracts growing attention due to its capability of enhancing cell activity, proliferation, and differentiation. Eventually, a profound knowledge of the underlying mechanisms paves the way for innovative therapeutic devices. Capacitive coupling is one option of delivering electric fields to biological samples that has advantages regarding biocompatibility. However, its biological mechanism of interaction is not well understood. Experimental findings could be related to voltage-gated channels, which are triggered by changes of the transmembrane potential. Numerical simulations by the finite element method provide a possibility to estimate the transmembrane potential. Since a full resolution of the cell membrane within a macroscopic model would lead to prohibitively expensive models, we suggest the adaptation of an approximate finite element method. Starting from a basic 2.5D model, the chosen method is validated and applied to realistic experimental situations. To understand the influence of the dielectric properties on the modelling outcome, uncertainty quantification techniques are employed. A frequency-dependent influence of the uncertain dielectric properties of the cell membrane on the modelling outcome is revealed. This may have practical implications for future experimental studies. Our methodology can be easily adapted for computational studies relying on experimental data. [ABSTRACT FROM AUTHOR]

Presently, total joint replacement (TJR) is a standard procedure in orthopedic surgery. Adequate osseointegration of the implant components still remains a clinical issue. However, active stimulation of bone tissue to enhance bone ongrowth at the implant surfaces has not been widely investigated so far. For the last several years, invasive electromagnetically induced osseotherapy has been employed in clinical practice, e.g., for the treatment of avascular necrosis, femoral neck fractures, and pseudarthrosis. In the present study, the approach of exploiting the electric stimulation effect was transferred to the field of TJR. Therefore, a commercially available total hip stem was instrumented with an electrode on its surface in order to generate an electric field supporting the regeneration of the surrounding bone tissue. The objective was to conduct numerical simulations validated by experimental investigations as a proof of concept for an instrumented electro-stimulative total hip stem. The results revealed that the calculated electric field around a total hip stem fulfills the requirements to stimulate adjacent bone tissue when using clinically applied electric voltages. The derived numerical and experimental data of electric potentials and corresponding electric fields are encouraging for the implementation of active electrical stimulation in uncemented total hip stems to enhance their osseointegration. [ABSTRACT FROM AUTHOR]

Electric stimulation of the auditory nerve by cochlear implants has been a successful clinical intervention to treat the sensory neural deafness. In this pathological condition of the cochlea, type-1 spiral ganglion neurons in Rosenthal's canal play a vital role in the action potential initiation. Various morphological studies of the human temporal bones suggest that the spiral ganglion neurons are surrounded by heterogeneous structures formed by a variety of cells and tissues. However, the existing simulation models have not considered the tissue heterogeneity in the Rosenthal's canal while studying the electric field interaction with spiral ganglion neurons. Unlike the existing models, we have implemented the tissue heterogeneity in the Rosenthal's canal using a computationally inexpensive image based method in a two-dimensional finite element model. Our simulation results suggest that the spatial heterogeneity of surrounding tissues influences the electric field distribution in the Rosenthal's canal, and thereby alters the transmembrane potential of the spiral ganglion neurons. In addition to the academic interest, these results are especially useful to understand how the latest tissue regeneration methods such as gene therapy and drug-induced resprouting of peripheral axons, which probably modify the density of the tissues in the Rosenthal's canal, affect the cochlear implant functionality. [ABSTRACT FROM PUBLISHER]

In this paper, we present a Pareto classifier for a multiobjective evolutionary algorithm used to optimize the numerical model of an electrostimulative acetabular revision system. This classifier is based on the hyper-radial visualization method and enables us to automatically choose the most efficient stimulation electrode arrangement from a Pareto amount of optimal solutions to treat the pelvic bone after a hip revision surgery. It is based on two criteria: 1) the average performance concerning all optimization goals and 2) the general strength of tradeoffs in each goal function to achieve this performance. [ABSTRACT FROM AUTHOR]

Cartilage regeneration is a clinical challenge. In recent years, hydrogels have emerged as implantable scaffolds in cartilage tissue engineering. Similarly, electrical stimulation has been employed to improve matrix synthesis of cartilage cells, and thus to foster engineering and regeneration of cartilage tissue. The combination of hydrogels and electrical stimulation may pave the way for new clinical treatment of cartilage lesions. To find the optimal electric properties of hydrogels, theoretical considerations and corresponding numerical simulations are needed to identify well-suited initial parameters for experimental studies. We present the theoretical analysis of a hydrogel in a frequently used electrical stimulation device for cartilage regeneration and tissue engineering. By means of equivalent circuits, finite element analysis, and uncertainty quantification, we elucidate the influence of the geometric and dielectric properties of cell-seeded hydrogels on the capacitive-coupling electrical field stimulation. Moreover, we discuss the possibility of cellular organisation inside the hydrogel due to forces generated by the external electric field. The introduced methodology is easily reusable by other researchers and allows to directly develop novel electrical stimulation study designs. Thus, this study paves the way for the design of future experimental studies using electrically conductive hydrogels and electrical stimulation for tissue engineering. [ABSTRACT FROM AUTHOR]

The intrinsic regeneration potential of hyaline cartilage is highly limited due to the absence of blood vessels, lymphatics, and nerves, as well as a low cell turnover within the tissue. Despite various advancements in the field of regenerative medicine, it remains a challenge to remedy articular cartilage defects resulting from trauma, aging, or osteoarthritis. Among various approaches, tissue engineering using tailored electroactive scaffolds has evolved as a promising strategy to repair damaged cartilage tissue. In this approach, hydrogel scaffolds are used as artificial extracellular matrices, and electric stimulation is applied to facilitate proliferation, differentiation, and cell growth at the defect site. In this regard, we present a simulation model of electroactive hydrogels to be used for cartilage–tissue engineering employing open-source finite-element software FEniCS together with a Python interface. The proposed mathematical formulation was first validated with an example from the literature. Then, we computed the effect of electric stimulation on a circular hydrogel sample that served as a model for a cartilage-repair implant. [ABSTRACT FROM AUTHOR]

• Articular cartilage has a poor regeneration capacity due to its avascular nature. • Cartilage repair using electrically stimulated hydrogel scaffolds is a promising approach. • A simulation model on electromechanics of electroactive hydrogels is presented. • The model serves as basis for designing optimized experiments for cartilage-tissue repair. The self-repair capability of articular cartilage is limited because of non-vascularization and low turnover of its extracellular matrix. Regenerating hyaline cartilage remains a significant clinical challenge as most non-surgical and surgical treatments provide only mid-term relief. Eventually, further pain and mobility loss occur for many patients in the long run due to further joint deterioration. Repair of articular cartilage tissue using electroactive scaffolds and biophysical stimuli like electrical and osmotic stimulation may have the potential to heal cartilage defects occurring due to trauma, osteoarthritis, or sport-related injuries. Therefore, the focus of the current study is to present a computational model of electroactive hydrogels for the cartilage-tissue repair as a first step towards an optimized experimental design. The multiphysics transport model that mainly includes the Poisson–Nernst–Planck equations and the mechanical equation is used to find the electrical stimulation response of the polyelectrolyte hydrogels. Based upon this, a numerical model on electromechanics of electroactive hydrogels seeded with chondrocytes is presented employing the open-source software FEniCS, which is a Python library for finite-element analysis. We analyzed the ionic concentrations and electric potential in a hydrogel sample and the cell culture medium, the osmotic pressure created due to ionic concentration variations and the resulting hydrogel displacement. The proposed mathematical model was validated with examples from literature. The presented model for the electrical and osmotic stimulation of a hydrogel sample can serve as a useful tool for the development and analysis of a cartilaginous scaffold employing electrical stimulation. By analyzing various parameters, we pave the way for future research on a finer scale using open-source software. [ABSTRACT FROM AUTHOR]