Endogenous Electric Fields Research Articles

Graphene oxide-based injectable conductive hydrogel dressing with immunomodulatory for chronic infected diabetic wounds

The main challenges of chronic wounds represented by diabetic wounds are that the infection is not easily controlled and the healing is difficult, mainly due to the high-glucose microenvironment, M1 macrophage aggregation, and persistent inflammation. Previous studies inspired by endogenous electric fields have demonstrated that conductive materials can promote cell proliferation, migration, etc., to promote wound healing. However, no study has been conducted on the effect of conductive materials on local immunity. To this end, this study designed a graphene oxide-based conductive hydrogel to repair infected diabetic wounds. Self-healing injectable conductive hydrogels were synthesized by dynamic Schiff-base reaction and electrostatic interactions between oxidized hyaluronic acid, N-carboxyethyl chitosan, graphene oxide, and polymyxin B. The study found that the hydrogel has good biocompatibility and antibacterial properties. In addition, in vivo experiments confirmed that the hydrogel could modulate macrophage polarization to improve the local inflammatory microenvironment, promote neovascularization, and significantly accelerate the healing of diabetic wounds. Most notably, graphene oxide-based conductive hydrogels can modulate local immunity in diabetic wounds to promote healing. This study provides new guidelines for expanding research on conductive materials and new directions for promoting healing in infected diabetic wounds.

A Biocompatible Self-Powered Piezoelectric Poly(vinyl alcohol)-Based Hydrogel for Diabetic Wound Repair.

Acute and chronic wounds, caused by trauma, tumors, diabetic foot ulcers, etc., are usually difficult to heal, while applying exogenous electrical stimulation to enhance the endogenous electric field in the wound has been proven to significantly accelerate wound healing. However, traditional electrical stimulation devices require an additional external power supply, making them poor in portability and comfort. In this work, a self-powered piezoelectric poly(vinyl alcohol) (PVA)/polyvinylidene fluoride (PVDF) composite hydrogel is constructed by establishing a distinctive preparation process of freezing/thawing-solvent replacement-annealing-swelling. The hydrogen bonding in the hydrogel is remarkably enhanced by the annealing-swelling process, which is stronger between PVA/PVDF molecules than that between PVA molecules, promoting transformation of the α-phase into the electroactive β-phase PVDF and facilitating formation of a much more crystalline structure with high cross-linking density. Hence, an obvious piezoelectric response with high piezoelectric coefficient and electrical signal output with superior stability and sensitivity and excellent mechanical strength and stretchability was achieved for hydrogels. PVA/PVDF composite hydrogels with good cytocompatibility significantly promote proliferation, migration, and secretion of extracellular matrix proteins and growth factors of fibroblasts, possibly through activating the AKT and ERK1/2 signaling pathways. In a wound model of diabetic rats, piezoelectric hydrogels could not only rapidly attract wound exudate and maintain the wet environment of the wound bed but also convert the mechanical energy generated by rats' physical activities into electrical energy, so as to provide local piezoelectric stimulation to the wound bed evenly and symmetrically in real time. Such an effect significantly promotes re-epithelialization and collagen deposition and increases angiogenesis and secretion of growth factors in wound tissue. Besides, it regulates the macrophage phenotype from the M1 subtype (pro-inflammatory subtype) to the M2 subtype (anti-inflammatory subtype) and reduces the expression levels of inflammatory factors, thus accelerating wound healing. The development of such a novel piezoelectric hydrogel provides new therapeutic strategies for chronic wound healing.

Autophagy promotes directed migration of HUVEC in response to electric fields through the ROS/SIRT1/FOXO1 pathway

Endogenous electric fields (EFs) have been confirmed to facilitate angiogenesis through guiding directional migration of endothelial cells (ECs), but the underlying mechanisms remain obscure. Recent studies suggest that the directed migration of ECs in angiogenesis is correlated with autophagy, and the latter of which could be augmented by EFs. We hypothesize that autophagy may participate in the EFs-guided migration of ECs during angiogenesis. Herein, we showed that EFs induced human umbilical vein endothelial cells (HUVEC) migration toward the cathode with enhanced autophagy. Genetic ablation of autophagy by silencing the autophagy-related gene (Atg) 5 abolished the EFs-directed migration of HUVEC, indicating that autophagy is definitely required for EFs-guided migration of cells. Mechanistically, we identified the intracellular reactive oxygen species (ROS) as a crucial mediator in EFs-triggered autophagy through augmenting the silencing information regulator 2 related enzyme1 (SIRT1)/forkhead box protein O1 (FOXO1) signaling. Either ROS scavenging or SIRT1 knockdown eliminated the EFs-triggered autophagy in HUVEC. Further study showed that SIRT1 promoted FOXO1 deacetylation, facilitating its nuclear accumulation and transcriptional activity, and thereby activating autophagy in EFs-treated HUVECs. In conclusion, our study demonstrated a pivotal role for autophagy in EFs-induced directed migration of HUVECs through the ROS/SIRT1/FOXO1 pathway, and provided a novel theoretical foundation for angiogenesis.

Core Concept Of Bioelectronic Medicine And Their Theranostic Application In Cancer

Bioelectronic medicine is a way of treating in which the electrical communication networks of the body are altered to treat disease. Bioelectric circuitry in every cell creates a resting membrane potential as well as endogenous electric fields that regulate cell function and communication. The theory that cancer is caused by bioelectrical circuitry malfunctions in cells is now widely acknowledged. This opens up the possibility of using bioelectronic medicine to develop new cancer treatments by influencing the disease's bioelectrical properties. To meet societal and technical obstacles, today's individuals aspire to better their quality of life. So, in the midst of all of this, bioelectronic medicine has altered the way we practice medicine and has proven to dramatically enhance healthcare outcomes. This technique employs a variety of procedures, such as neuromodulation, to treat a specific disease, ailment, or damage. Interfacing electronics with nerves to specifically target the biological processes underlying diseases. In cancer, screening and early detection are crucial for the patient's therapy to be successful and for the patient's survival percentage to grow. For illness diagnosis, therapy, and follow-up, the development of analytical methods for non-invasive detection through the analysis of cancer biomarkers is crucial. Tumor biomarkers are substances or processes that indicate the existence of cancer in the body in clinical situations. These biomarkers can be detected using biosensors, which are popular alternatives to traditional approaches due to their speed, accuracy, and point-of-care applicability. Here we have discussed the consequences of current cancer treatments and bioelectronic medicine a combat for cancer diagnosis and treatment.

Bioelectric Signaling: Role of Bioelectricity in Directional Cell Migration in Wound Healing.

In wound healing, individual cells' behaviors coordinate movement toward the wound center to restore small or large barrier defects. The migration of epithelial cells as a continuous sheet structure is one of the most important processes by which the skin barrier is restored. How such multicellular and tissue level movement is initiated upon injury, coordinated during healing, and stopped when wounds healed has been a research focus for decades. When skin is wounded, the compromised epithelial barrier generates endogenous electric fields (EFs), produced by ion channels and maintained by cell junctions. These EFs are present across wounds, with the cathodal pole at the wound center. Epithelial cells detect minute EFs and migrate directionally in response to electrical signals. It has long been postulated that the naturally occurring EFs facilitate wound healing by guiding cell migration. It is not until recently that experimental evidence has shown that large epithelial sheets of keratinocytes or corneal epithelial cells respond to applied EFs by collective directional migration. Although some of the mechanisms of the collective cell migration are similar to those used by isolated cells, there are unique mechanisms that govern the coordinated movement of the cohesive sheet. We will review the understanding of wound EFs and how epithelial cells and other cells important to wound healing respond to the electric signals individually as well as collectively. Mounting evidence suggests that wound bioelectrical signaling is an important mechanism in healing. Critical understanding and proper exploitation of this mechanism will be important for better wound healing and regeneration.

Transcriptional Analysis of Mice Melanoma B16-F10 Cells in Response to Directed Current Electric Fields.

The endogenous electric field (EF) is widely observed among tissues. It is supposed to be an important environmental factor in tumor metastasis. To explore the role of endogenous EFs in tumor metastasis, the migration of mouse melanoma B16-F10 cells in directed current EFs (dcEFs) was investigated. The transcriptome of melanoma B16-F10 cells in response to EF stimulation was analyzed using RNA sequencing. The results demonstrated that the mouse melanoma B16-F10 cells migrated toward the cathode in applied dcEFs. Directional migration occurred in a voltage-dependent manner. Approximately 3000 upregulated and 2613 downregulated genes were identified under dcEF. Some genes correlated with cell migration, such as Serpine1, Ctgf, Fosb, and Fos, were upregulated. The signaling pathways involved in cell motility were significantly altered. Some genes, highly related to tumorigenesis, invasion, and metastasis, are upregulated in response to EF stimulation. Endogenous EFs may play a role in tumorigenesis and metastasis in vivo. © 2022 Bioelectromagnetics Society.

Electroconductive Polythiophene Nanocomposite Fibrous Scaffolds for Enhanced Osteogenic Differentiation via Electrical Stimulation.

Biophysical cues are key distinguishing characteristics that influence tissue development and regeneration, and significant efforts have been made to alter the cellular behavior by means of cell-substrate interactions and external stimuli. Electrically conductive nanofibers are capable of treating bone defects since they closely mimic the fibrillar architecture of the bone matrix and deliver the endogenous and exogenous electric fields required to direct cell activities. Nevertheless, previous studies on conductive polymer-based scaffolds have been limited to polypyrrole, polyaniline, and poly(3,4-ethylenedioxythiophene) (PEDOT). In the present study, chemically synthesized polythiophene nanoparticles (PTh NPs) are incorporated into polycaprolactone (PCL) nanofibers, and subsequent changes in physicochemical, mechanical, and electrical properties are observed in a concentration-dependent manner. In murine preosteoblasts (MC3T3-E1), we examine how substrate properties modified by adding PTh NPs contribute to changes in the cellular behavior, including viability, proliferation, differentiation, and mineralization. Additionally, we determine that external electrical stimulation (ES) mediated by PTh NPs positively affects such osteogenic responses. Together, our results provide insights into polythiophene's potential as an electroconductive composite scaffold material.

Endogenous Electric-Field-Coupled Electrospun Short Fiber via Collecting Wound Exudation.

Endogenous electric fields (EF) are the basis of bioelectric signal conduction and the priority signal for damaged tissue regeneration. Tissue exudation directly affects the characteristics of endogenous EF. However, current biomaterials lead to passive repair of defect tissue due to limited management of early wound exudates and inability to actively respond to coupled endogenous EF. Herein, the 3D bionic short-fiber scaffold with the functions of early biofluid collection, response to coupled endogenous EF, is constructed by guiding the short fibers into a 3D network structure and subsequent multifunctional modification. The scaffold exhibits rapid reversible water absorption, reaching maximum after only 30 s. The stable and uniform distribution of polydopamine-reduced graphene oxide endows the scaffold with stable electrical and mechanical performances even after long-term immersion. Due to its unique - bionic structure and tissue affinity, the scaffold further acts as an "electronic skin," which transmits endogenous bioelectricity via absorbing wound exudates, promoting the treatment of diabetic wounds. Furthermore, under the endogenous EF, the cascade release of vascular endothelial growth factor accelerates the healing process. Thus, the versatile scaffold is expected to be an ideal candidate for repairing different defect tissues, especially electrosensitive tissues.

Effect on electrode configuration in electrical wound healing

Endogenous electric field is known to play significant part in wound closure and healing of wounds which takes place through its process of protein synthesis and migration of cells to the centre of the wounds due to wound currents. Many clinical studies have showed that electrical stimulation with bio-mimicking exogeneous current through electrodes tends to accelerate wound-healing by promoting electro-taxis of cells under an applied external electrical field (EF). Finite element analysis (FEA) of a circular wound model of diameter 2 cm along with multiple skin layers like stratum corneum, epidermis, dermis, and subcutis layer with defined thickness and properties were modelled using COMSOL Multiphysics®5.3. The endogenous voltage of wounded skin along with its EF distribution is modeled across half the wound bed and shows a higher EF near the wound periphery (x = 10000 µm) which gradually decreases towards its center (x = 0). In the present study simulation was carried out with varying electrode configuration to provide an optimal EF gradient for effective electrotaxis. Potential distribution across 4 micro electrodes arrays (MEAs) (with decreasing applied voltage towards center) along with corresponding EF distribution shows similar gradient as that of endogenous EF unlike through conventional 2 pair of electrodes thereby successfully mimicking the endogenous EF with MEAs would lead to accelerated wound healing.

Constructing a coplanar heterojunction through enhanced π-π conjugation in g-C3N4 for efficient solar-driven water splitting

Adjusting the electronic structure of graphitic carbon nitride (g-C3N4) photocatalyst through π-π conjugation is an effective method to achieve efficient photogenerated carrier separation. One key challenge of π-π conjugation control is to tune the degree of such conjugation without destroying the g-C3N4 structure. Herein we report a conceptual design that achieves a coplanar heterojunction by enhancing the π-π conjugation via the doping of crystalline g-C3N4 using a conjugated double bond ring molecule, 1,3,5-benzenetriol, during calcination process. The selection of the dopant enables the facile creation of a unique coplanar heterojunction which not only retains the pristine network structure of g-C3N4, but remarkably promotes separation and transfer of photogenerated carriers through the enhanced π-conjugated endogenous electric field. As a result, the new g-C3N4 photocatalyst efficiently photocatalytically produces hydrogen from water under visible light irradiation with a high H2 production rate up to 94.94 µmol/h, and a notable external quantum efficiency of 16.4% at 420 nm.

Electroactive electrospun nanofibers for tissue engineering

The ability of electrospun nanofibers to mimic the structure and composition of certain components of the extracellular matrix (ECM) has been widely used in the construction of tissue regeneration scaffolds. As the biophysical cues of the ECM, bioelectric communication mediated by endogenous electrical fields and currents also plays an important role in the repair and regeneration of defected tissues. To this end, it is compelling to develop electroactive electrospun nanofibers for tissue engineering. Here, we briefly summarize the commonly developed electroactive electrospun nanofibers and their progress in tissue engineering, especially for heart repair, nerve injury treatment, wound healing, skeletal muscle and bone regeneration. We also discuss their potential applications as biosensors and drug delivery platforms. Afterwards, we specifically focus on the future direction of the design and functionalization of electroactive electrospun nanofibers for tissue engineering. At last, we propose several promising strategies to make the scaffolds more intelligent, portable, monitorable, and safe.

Electrical stimulation mediated the neurite outgrowth of PC-12 cells on the conductive polylactic acid/reduced graphene oxide/polypyrrole composite nanofibers

The synergistic effect of endogenous electric field and electrical stimulation (ES) has promising application in the repair and regeneration of injured peripheral nerve. Conducting polymers-based (especially polypyrrole (PPy)) nanofibers have received more attention due to the promotive effects on cell behaviors under ES. However, the conductivity of PPy is unstable and the inferior hydrophilicity hinders its broad applications. Herein, the stable conductive polylactic acid/reduced graphene oxide/polypyrrole (PLA/rGO/PPy) composite nanofibers were prepared by incorporating rGO into PLA, by the following in-situ PPy polymerized on the surface of the PLA/rGO nanofibers. The results show that PPy on the surface of composite nanofibers are dense and continuous, the wettability is significantly improved. With the presence of PPy and rGO, the conductivity and stability of PLA/rGO/PPy composite nanofibers increase, and the conductivity of PLA/rGO 3.5/PPy composite nanofibers was the highest conductivity (1.46 × 10−1 S/cm). The proliferation and differentiation of PC-12 cells seeded on the surface of PLA/rGO3.5/PPy composite nanofibers reach the highest level under 400 mV/cm. These results are beneficial for improving biomaterial properties and provide guidance to ES application in peripheral nerve repair.

Accelerated Skin Wound Healing by Electrical Stimulation.

When the integrity of the skin got damaged, an endogenous electric field will be generated in the wound and a series of physiological reactions will be initiated to close the wound. The existence of the endogenous electric field of the wound has a promoting effect on all stages of wound healing. For wounds that cannot heal on their own, the exogenous electric field can assist the treatment. In this review, the effects of exogenous electrical stimulation on wound healing, such as the inflammation phase, blood flow, cell proliferation and migration, and the wound scarring is overviewed. This article also reviews the new electrical stimulation methods that have emerged in recent years, such as small power supplies, nanogenerators (NGs), and other physical, chemical or biological strategies. These new electrical stimulation methods and devices are safe, low-cost, stable, and small in size. The challenge and perspective are discussed for the future trends of the electrical stimulation treatment in accelerating skin wound healing.

Bioengineering Clinically Relevant Cardiomyocytes and Cardiac Tissues from Pluripotent Stem Cells.

The regenerative capacity of cardiomyocytes is insufficient to functionally recover damaged tissue, and as such, ischaemic heart disease forms the largest proportion of cardiovascular associated deaths. Human-induced pluripotent stem cells (hiPSCs) have enormous potential for developing patient specific cardiomyocytes for modelling heart disease, patient-based cardiac toxicity testing and potentially replacement therapy. However, traditional protocols for hiPSC-derived cardiomyocytes yield mixed populations of atrial, ventricular and nodal-like cells with immature cardiac properties. New insights gleaned from embryonic heart development have progressed the precise production of subtype-specific hiPSC-derived cardiomyocytes; however, their physiological immaturity severely limits their utility as model systems and their use for drug screening and cell therapy. The long-entrenched challenges in this field are being addressed by innovative bioengingeering technologies that incorporate biophysical, biochemical and more recently biomimetic electrical cues, with the latter having the potential to be used to both direct hiPSC differentiation and augment maturation and the function of derived cardiomyocytes and cardiac tissues by mimicking endogenous electric fields.

Modulation of intercolumnar synchronization by endogenous electric fields in cerebral cortex.

Neurons synaptically interacting in a conductive medium generate extracellular endogenous electric fields (EFs) that reciprocally affect membrane potential. Exogenous EFs modulate neuronal activity, and their clinical applications are being profusely explored. However, whether endogenous EFs contribute to network synchronization remains unclear. We analyzed spontaneously generated slow-wave activity in the cerebral cortex network in vitro, which allowed us to distinguish synaptic from nonsynaptic mechanisms of activity propagation and synchronization. Slow oscillations generated EFs that propagated independently of synaptic transmission. We demonstrate that cortical oscillations modulate spontaneous rhythmic activity of neighboring synaptically disconnected cortical columns if layers are aligned. We provide experimental evidence that these EF-mediated effects are compatible with electric dipoles. With a model of interacting dipoles, we reproduce the experimental measurements and predict that endogenous EF-mediated synchronizing effects should be relevant in the brain. Thus, experiments and models suggest that electric-dipole interactions contribute to synchronization of neighboring cortical columns.

Remotely controlled self-powering electrical stimulators for osteogenic differentiation using bone inspired bioactive piezoelectric whitlockite nanoparticles

Endogenous electric fields naturally exist in our body and plays a vital role especially in the development and regeneration of bones. Therefore, piezoelectric bone implants are gaining ample attention due to its inherent electrical signal generation, but generally they lack bioactivity, resorption, and ECM like composition. To address this, we evoke ‘piezoelectricity’ in whitlockite (Ca 18 Mg 2 (HPO 4 ) 2 (PO 4 ) 12 ) nanoparticles (WH NPs) for the first time in literature. WH NPs are the second most-abundant inorganic bone mineral and reported for intermediate resorption compared to hydroxyapatite and tricalcium phosphate. Systematic electrical studies reveal that WH NPs annealed at 750 °C (PWH-750) exhibit superior ferroelectric and dielectric characteristics and produce electrical signals analogous to native tissues when triggered using FDA approved low-intensity pulsed ultrasound (LIPUS) noninvasively. The energy generation performance of Piezoelectric WH based self powered nanogenerators are analyzed and demonstrated to power the commercial LED upon LIPUS stimulation. The in vitro studies with pre-osteoblast MC3T3-E1 cells co-cultured with piezoelectric WH NPs exhibit increased ALP activity, calcium mineralization, and osteogenic gene expression along with significant upregulation of Piezo1, and TRPV4 expressions. This confirms the enhanced osteogenic differentiation compared to the control WH nanoparticles due to the remotely activated self powering capacity of piezoelectric WH NPs and thereby produce bioelectric signals analogous to native tissues. Thus, the study evidences the development of a potential bioactive piezoelectric ceramic with extensive applicability for future clinical translation. • Development of piezoelectric whitlockite nanoparticles for self-powered electrical cell stimulation. • The study also reports the development of the unique piezoelectric nanogenerator (PENG) based on biocompatible WH NPs. • LIPUS mediated electric field produced by the piezoelectric WH NPs promotes osteoblast proliferation and differentiation. • The study confirms the enhanced osteogenic differentiation via Piezo1 and TRPV4 mechanosensitive ion channels. • A new perspective in the field of regenerative medicine through self-powered electrical stimulation to cells.

Toward Hijacking Bioelectricity in Cancer to Develop New Bioelectronic Medicine

AbstractBioelectronic medicine is a treatment modality that uses electricity to treat disease by altering the body's electrical communication systems. All cells are electrically active, in that they possess bioelectric circuitry generating a resting membrane potential and endogenous electric fields that influence cell functions and communication. There is now an accepted paradigm that cancer is characterized by malfunctions in cells’ bioelectrical circuitry. This yields opportunities for bioelectronic medicine as novel treatments for cancer by manipulating its bioelectrical properties. To highlight the possibilities a bioelectrical approach can offer cancer therapy, the relevance of bioelectrical activity in cancer is reviewed and also how such activity can be hijacked in novel treatments. This includes sensing or measuring the electrical activity of cells for diagnostic and prognostic applications, controlling or altering bioelectricity including both ionic and faradaic current processes, and eliciting morphological changes using electric fields. Importantly, key links between cellular ionic and faradaic processes that contribute to cancer phenotypes are presented, which if considered and understood as a whole, can bring broad‐reaching improvements to cancer therapy.

Theoretical analysis of the electrochemical systems used for the application of direct current/voltage stimuli on cell cultures

Endogenous electric fields drive many essential functions relating to cell proliferation, motion, differentiation and tissue development. They are usually mimicked in vitro by using electrochemical systems to apply direct current or voltage stimuli to cell cultures. The many studies devoted to this topic have given rise to a wide variety of experimental systems, whose results are often difficult to compare. Here, these systems are analysed from an electrochemical standpoint to help harmonize protocols and facilitate optimal understanding of the data produced.The theoretical analysis of single-electrode systems shows the necessity of measuring the Nernst potential of the electrode and of discussing the results on this basis rather than using the value of the potential gradient. The paper then emphasizes the great complexity that can arise when high cell voltage is applied to a single electrode, because of the possible occurrence of anode and cathode sites. An analysis of two-electrode systems leads to the advice to change experimental practices by applying current instead of voltage. It also suggests that the values of electric fields reported so far may have been considerably overestimated in macro-sized devices. It would consequently be wise to revisit this area by testing considerably lower electric field values.

Physiological electric fields induce directional migration of mammalian cranial neural crest cells

During neurulation, cranial neural crest cells (CNCCs) migrate long distances from the neural tube to their terminal site of differentiation. The pathway traveled by the CNCCs defines the blueprint for craniofacial construction, abnormalities of which contribute to three-quarters of human birth defects. Biophysical cues like naturally occurring electric fields (EFs) have been proposed to be one of the guiding mechanisms for CNCC migration from the neural tube to identified position in the branchial arches. Such endogenous EFs can be mimicked by applied EFs of physiological strength that has been reported to guide the migration of amphibian and avian neural crest cells (NCCs), namely galvanotaxis or electrotaxis. However, the behavior of mammalian NCCs in external EFs has not been reported. We show here that mammalian CNCCs migrate towards the anode in direct current (dc) EFs. Reversal of the field polarity reverses the directedness. The response threshold was below 30 ​mV/mm and the migration directedness and displacement speed increased with increase in field strength. Both CNCC line (O9-1) and primary mouse CNCCs show similar galvanotaxis behavior. Our results demonstrate for the first time that the mammalian CNCCs respond to physiological EFs by robust directional migration towards the anode in a voltage-dependent manner.

Toward Controlled Electrical Stimulation for Wound Healing Based on a Precision Layered Skin Model.

Bioelectricity performs vital functions in the human body. When skin is damaged, the endogenous electric field will orient toward the center of wounds, guiding the migration of relevant cells and stimulating the secretion of growth factors. A large number of experiments have indicated that external electric stimuli have significant positive influences on wound healing. However, the mechanism of this therapy remains unclear, and the current selection of parameters for electric stimuli tends to be arbitrary or empirical, making it inefficient and ineffective. From the perspective of bioelectricity and electrochemistry, the mechanism of electric stimuli is investigated in detail based on a sectioned multilayer model in this work, and an electric stimuli window is obtained in terms of frequency, duty cycle, voltage, and electric charge and verified experimentally. This model provides general guidance for the optimization of electrical stimuli therapy for wound healing.