Search Results (12)

Electric fields (EFs) are widely employed to promote tissue regeneration and accelerate wound healing. Despite extensive study, the cellular responses elicited by EFs are complex and not well understood. The present work focuses on cell migration—a process essential to organismal development, immune surveillance, and repair—and seeks to achieve its precise, closed-loop regulation. Effective control is impeded by (i) the nonlinear and stochastic nature of migratory dynamics and (ii) safety constraints that restrict the admissible EF magnitude. To address these challenges, we reformulate a neural network (NN) feedback controller previously developed for single-cell membrane-potential regulation and adapt it to guide population-level cell migration. A projection operator is embedded into the NN weight-update law to prevent maladaptive learning that arises when the control signal saturates at its EF limit. Numerical simulations confirm that the modified controller maintains accurate trajectory tracking under saturation and outperforms the original NN design. Finally, we demonstrate a proof-of-concept by implementing the controller in vitro to direct the electrotactic migration of naïve macrophages in 2D culture under a unidirectional EF. For the in vitro experiments, we compare performance to the standard proportional–integral–derivative (PID) controller. Full article

Microscale systems have been underexplored in contemporary regenerative therapies developed to treat vision loss. The pairing of in vitro cell systems with optical fluorescent imaging provides unique opportunities to examine the infiltration of donor stem cells needed for successful transplantation therapies. A parallel eye device was developed to provide electric field (EF) stimulation to guide the migration of cells within 3D eye facsimiles synthesized from different ocular biomaterials. Cell infiltration within facsimiles was rapidly resolved using confocal microscopy to eliminate dependence on the cryostat sectioning commonly used for cell study. Moreover, EF stimulated galvanotaxis of donor cells within different depths of eye facsimiles. Optical imaging provided rapid resolution of z-stack images at physiologically appropriate depths below 500 microns. This study demonstrates that paired microscale–optical systems can be developed to elucidate understudied transplantation processes and improve future outcomes in patients. Full article

It has increasingly been recognized that electrical currents play a pivotal role in cell migration and tissue repair, in a process named “galvanotaxis”. In this review, we summarize the current evidence supporting the potential benefits of electric stimulation (ES) in the physiology of peripheral nerve repair (PNR). Moreover, we discuss the potential of piezoelectric materials in this context. The use of these materials has deserved great attention, as the movement of the body or of the external environment can be used to power internally the electrical properties of devices used for providing ES or acting as sensory receptors in artificial skin (e-skin). The fact that organic materials sustain spontaneous degradation inside the body means their piezoelectric effect is limited in duration. In the case of PNR, this is not necessarily problematic, as ES is only required during the regeneration period. Arguably, piezoelectric materials have the potential to revolutionize PNR with new biomedical devices that range from scaffolds and nerve-guiding conduits to sensory or efferent components of e-skin. However, much remains to be learned regarding piezoelectric materials, their use in manufacturing of biomedical devices, and their sterilization process, to fine-tune their safe, effective, and predictable in vivo application. Full article

Accumulating evidence suggests that an important role is played by electric signals in modifying cell behaviour during developmental, regenerative and pathological processes. However, their role in asthma has not yet been addressed. Bronchial fibroblasts have recently been identified having important roles in asthma development. Therefore, we adapted an experimental approach based on the lineages of human bronchial fibroblasts (HBF) derived from non-asthmatic (NA) donors and asthmatic (AS) patients to elucidate whether their reactivity to direct current electric fields (dcEF) could participate in the asthmatic process. The efficient responsiveness of NA HBF to an electric field in the range of 2–4 V/cm was illustrated based on the perpendicular orientation of long axes of the cells to the field lines and their directional movement towards the anode. These responses were related to the activity of TGF-β signalling, as the electrotaxis and re-orientation of NA HBF polarity was impaired by the inhibitors of canonical and non-canonical TGF-β-dependent pathways. A similar tendency towards perpendicular cell-dcEF orientation was observed for AS HBF. However, their motility remained insensitive to the electric field applied at 2–4 V/cm. Collectively, these observations demonstrate the sensitivity of NA HBF to dcEF, as well as the inter-relations between this parameter and the canonical and non-canonical TGF-β pathways, and the differences between the electrotactic responses of NA and AS HBF point to the possible role of their dcEFs in desensitisation in the asthmatic process. This process may impair the physiologic behaviour of AS HBF functions, including cell motility, ECM deposition, and contractility, thus promoting bronchial wall remodelling, which is a characteristic of bronchial asthma. Full article

Several cues for a directional migration of colorectal cancer cells were identified as being crucial in tumor progression. However, galvanotaxis, the directional migration in direct-current electrical fields, has not been investigated so far. Therefore, we asked whether direct-current electrical fields could be used to mobilize colorectal cancer cells along field vectors. For this purpose, five patient-derived low-passage cell lines were exposed to field strengths of 150–250 V/m in vitro, and migration along the field vectors was investigated. To further study the role of voltage-gated calcium channels on galvanotaxis and intracellular signaling pathways that are associated with migration of colorectal cancer cells, the cultures were exposed to selective inhibitors. In three out of five colorectal cancer cell lines, we found a preferred cathodal migration. The cellular integrity of the cells was not impaired by exposure of the cells to the selected field strengths. Galvanotaxis was sensitive to inhibition of voltage-gated calcium channels. Furthermore, signaling pathways such as AKT and MEK, but not STAT3, were also found to contribute to galvanotaxis in our in vitro model system. Overall, we identify electrical fields as an important contributor to the directional migration of colorectal cancer cells. Full article

Articular cartilage injuries are a common source of joint pain and dysfunction. As articular cartilage is avascular, it exhibits a poor intrinsic healing capacity for self-repair. Clinically, osteochondral grafts are used to surgically restore the articular surface following injury. A significant challenge remains with the repair properties at the graft-host tissue interface as proper integration is critical toward restoring normal load distribution across the joint. A key to addressing poor tissue integration may involve optimizing mobilization of fibroblast-like synoviocytes (FLS) that exhibit chondrogenic potential and are derived from the adjacent synovium, the specialized connective tissue membrane that envelops the diarthrodial joint. Synovium-derived cells have been directly implicated in the native repair response of articular cartilage. Electrotherapeutics hold potential as low-cost, low-risk, non-invasive adjunctive therapies for promoting cartilage healing via cell-mediated repair. Pulsed electromagnetic fields (PEMFs) and applied direct current (DC) electric fields (EFs) via galvanotaxis are two potential therapeutic strategies to promote cartilage repair by stimulating the migration of FLS within a wound or defect site. PEMF chambers were calibrated to recapitulate clinical standards (1.5 ± 0.2 mT, 75 Hz, 1.3 ms duration). PEMF stimulation promoted bovine FLS migration using a 2D in vitro scratch assay to assess the rate of wound closure following cruciform injury. Galvanotaxis DC EF stimulation assisted FLS migration within a collagen hydrogel matrix in order to promote cartilage repair. A novel tissue-scale bioreactor capable of applying DC EFs in sterile culture conditions to 3D constructs was designed in order to track the increased recruitment of synovial repair cells via galvanotaxis from intact bovine synovium explants to the site of a cartilage wound injury. PEMF stimulation further modulated FLS migration into the bovine cartilage defect region. Biochemical composition, histological analysis, and gene expression revealed elevated GAG and collagen levels following PEMF treatment, indicative of its pro-anabolic effect. Together, PEMF and galvanotaxis DC EF modulation are electrotherapeutic strategies with complementary repair properties. Both procedures may enable direct migration or selective homing of target cells to defect sites, thus augmenting natural repair processes for improving cartilage repair and healing. Full article

Galvanotaxis, the migration along direct current electrical fields, may contribute to the invasion of brain cancer cells in the tumor-surrounding tissue. We hypothesized that pharmacological perturbation of the epidermal growth factor (EGF) receptor and downstream phosphatidylinositol 3-kinase (PI3K)/AKT pathway prevent galvanotactic migration. In our study, patient-derived glioblastoma and brain metastases cells were exposed to direct current electrical field conditions. Velocity and direction of migration were estimated. To determine the effects of EGF receptor antagonist afatinib and AKT inhibitor capivasertib, assays of cell proliferation, apoptosis and immunoblot analyses were performed. Both inhibitors attenuated cell proliferation in a dose-dependent manner and induced apoptosis. We found that most of the glioblastoma cells migrated preferentially in an anodal direction, while brain metastases cells were unaffected by direct current stimulations. Afatinib presented only a mild attenuation of galvanotaxis. In contrast, capivasertib abolished the migration of glioblastoma cells without genetic alterations in the PI3K/AKT pathway, but not in cells harboring PTEN mutation. In these cells, an increase in the activation of ERK1/2 may in part substitute the inhibition of the AKT pathway. Overall, our data demonstrate that glioblastoma cells migrate in the electrical field and the PI3K/AKT pathway was found to be highly involved in galvanotaxis. Full article

Electrical stimulation (ES) is an attractive field among clinicians in the topic of wound healing, which is common yet complicated and requires multidisciplinary approaches. The conventional dressing and skin graft showed no promise on complete wound closure. These urge the need for the exploration of electrical stimulation to supplement current wound care management. This review aims to provide an overview of electrical stimulation in wound healing. The mechanism of galvanotaxis related to wound repair will be reviewed at the cellular and molecular levels. Meanwhile, different modalities of externally applied electricity mimicking a physiologic electric field will be discussed and compared in vitro, in vivo, and clinically. With the emerging of tissue engineering and regenerative medicine, the integration of electroconductive biomaterials into modern miniaturised dressing is of interest and has become possible with the advancing understanding of smart biomaterials. Full article

Microbial attachment to surfaces is ubiquitous in nature. Most species of bacteria attach and adhere to surfaces via special appendages such as pili and fimbriae, the roles of which have been extensively studied. Here, we report an experiment on pilus-less mutants of Caulobacter crescentus weakly attached to polyethylene surface. We find that some individual cells transiently but repeatedly adhere to the surface in a stick-slip fashion in the presence of an electric field parallel to the surface. These bacteria move significantly slower than the unattached ones in the same field of view undergoing electrophoretic motion. We refer this behavior of repeated and transient attachment as “quasi-attachment”. The speed of the quasi-attached bacteria exhibits large variation, frequently dropping close to zero for short intervals of time. We propose a polymeric tethering model to account for the experimental findings. This study sheds light on bacteria–surface interaction, which is significant in broader contexts such as infection and environmental control. Full article

A wide body of evidence suggests that voltage-gated sodium channels (VGSCs) are expressed de novo in several human carcinomas where channel activity promotes a variety of cellular behaviours integral to the metastatic cascade. These include directional motility (including galvanotaxis), pH balance, extracellular proteolysis, and invasion. Contrary to the substantial in vitro data, however, evidence for VGSC involvement in the cancer process in vivo is limited. Here, we critically assess, for the first time, the available in vivo evidence, hierarchically from mRNA level to emerging clinical aspects, including protein-level studies, electrolyte content, animal tests, and clinical imaging. The evidence strongly suggests that different VGSC subtypes (mainly Nav1.5 and Nav1.7) are expressed de novo in human carcinoma tissues and generally parallel the situation in vitro. Consistent with this, tissue electrolyte (sodium) levels, quantified by clinical imaging, are significantly higher in cancer vs. matched non-cancer tissues. These are early events in the acquisition of metastatic potential by the cancer cells. Taken together, the multi-faceted evidence suggests that the VGSC expression has clinical (diagnostic and therapeutic) potential as a prognostic marker, as well as an anti-metastatic target. The distinct advantages offered by the VGSC include especially (1) its embryonic nature, demonstrated most clearly for the predominant neonatal Nav1.5 expression in breast and colon cancer, and (2) the specifically druggable persistent current that VGSCs develop under hypoxic conditions, as in growing tumours, which promotes invasiveness and metastasis. Full article

Electric fields have been studied extensively in biomedical engineering (BME) for numerous regenerative therapies. Recent studies have begun to examine the biological effects of electric fields in combination with other environmental cues, such as tissue-engineered extracellular matrices (ECM), chemical gradient profiles, and time-dependent temperature gradients. In the nervous system, cell migration driven by electrical fields, or galvanotaxis, has been most recently studied in transcranial direct stimulation (TCDS), spinal cord repair and tumor treating fields (TTF). The cell migratory response to galvano-combinatory fields, such as magnetic fields, chemical gradients, or heat shock, has only recently been explored. In the visual system, restoration of vision via cellular replacement therapies has been limited by low numbers of motile cells post-transplantation. Here, the combinatory application of electrical fields with other stimuli to direct cells within transplantable biomaterials and/or host tissues has been understudied. In this work, we developed the Gal-MµS device, a novel microfluidics device capable of examining cell migratory behavior in response to single and combinatory stimuli of electrical and chemical fields. The formation of steady-state, chemical concentration gradients and electrical fields within the Gal-MµS were modeled computationally and verified experimentally within devices fabricated via soft lithography. Further, we utilized real-time imaging within the device to capture cell trajectories in response to electric fields and chemical gradients, individually, as well as in combinatory fields of both. Our data demonstrated that neural cells migrated longer distances and with higher velocities in response to combined galvanic and chemical stimuli than to either field individually, implicating cooperative behavior. These results reveal a biological response to galvano-chemotactic fields that is only partially understood, as well as point towards novel migration-targeted treatments to improve cell-based regenerative therapies. Full article

Electrotaxis, or galvanotaxis, refers to the migration pattern of cells induced in response to electrical potential. Electrotaxis has not been explored in detail in bacterial cells; information regarding the impact of current on pathogenic bacteria is severely lacking. Using microfluidic platforms and optical microscopy, we designed a series of single- and multi-cue experiments to assess the impact of varying electrical currents and acetic acid concentrations on bacterial motility dynamics in pathogenic multi-drug resistant (MDR) strains of Pseudomonas aeruginosa and Escherichia coli. The use of the microfluidic platform allows for single-cue experiments where electrical current is supplied at a range that is biocidal to bacteria and multi-cue experiments where acetic acid is combined with current to enhance disinfection. These strategies may offer substantial therapeutic benefits, specifically for the treatment of biofilm infections, such as those found in the wound environment. Our results showed that an application of current in combination with acetic acid has profound inhibitory effects on MDR strains of P. aeruginosa and E. coli, even with brief applications. Specifically, E. coli motility dynamics and cell survival were significantly impaired starting at a concentration of 0.125 mA of direct current (DC) and 0.31% acetic acid, while P. aeruginosa was impaired at 0.70 mA and 0.31% acetic acid. As these strains are relevant wound pathogens, it is likely that this strategy would be effective against similar strains in vivo and could represent a new approach to hasten wound healing. Full article