Endogenous Electric Fields Research Articles

Galvanin is an electric-field sensor for directed cell migration.

Directed cell migration is critical for the rapid response of immune cells, such as neutrophils, following tissue injury or infection. Endogenous electric fields, generated by the disruption of the transepithelial potential across the skin, help to guide the movement of immune and skin cells toward the wound site. However, the mechanisms by which cells sense these physical cues remain largely unknown. Through a CRISPR-based screen, we identified Galvanin, a previously uncharacterized single-pass transmembrane protein that is required for human neutrophils to change their direction of migration in response to an applied electric field. Our results indicate that Galvanin rapidly relocalizes to the anodal side of a cell on exposure to an electric field, and that the net charge on its extracellular domain is necessary and sufficient to drive this relocalization. The spatial pattern of neutrophil protrusion and retraction changes immediately upon Galvanin relocalization, suggesting that it acts as a direct sensor of the electric field that then transduces spatial information about a cell's electrical environment to the migratory apparatus. The apparent mechanism of cell steering by sensor relocalization represents a new paradigm for directed cell migration.

Endogenous electric field coupling Mxene sponge for diabetic wound management: haemostatic, antibacterial, and healing

Improper management of diabetic wound effusion and disruption of the endogenous electric field can lead to passive healing of damaged tissue, affecting the process of tissue cascade repair. This study developed an extracellular matrix sponge scaffold (K1P6@Mxene) by incorporating Mxene into an acellular dermal stroma-hydroxypropyl chitosan interpenetrating network structure. This scaffold is designed to couple with the endogenous electric field and promote precise tissue remodelling in diabetic wounds. The fibrous structure of the sponge closely resembles that of a natural extracellular matrix, providing a conducive microenvironment for cells to adhere grow, and exchange oxygen. Additionally, the inclusion of Mxene enhances antibacterial activity(98.89%) and electrical conductivity within the scaffold. Simultaneously, K1P6@Mxene exhibits excellent water absorption (39 times) and porosity (91%). It actively interacts with the endogenous electric field to guide cell migration and growth on the wound surface upon absorbing wound exudate. In in vivo experiments, the K1P6@Mxene sponge reduced the inflammatory response in diabetic wounds, increased collagen deposition and arrangement, promoted microvascular regeneration, Facilitate expedited re-epithelialization of wounds, minimize scar formation, and accelerate the healing process of diabetic wounds by 7 days. Therefore, this extracellular matrix sponge scaffold, combined with an endogenous electric field, presents an appealing approach for the comprehensive repair of diabetic wounds.

MXene-coated piezoelectric poly-L-lactic acid membrane accelerates wound healing by biomimicking low-voltage electrical pulses

Electrical stimulation therapy is effective in promoting wound healing by rescuing the decreased endogenous electrical field, where self-powered and miniaturized devices such as nanogenerators become the emerging trends. While high-voltage and unidirectional electric field may pose thermal effect and damage to the skin, nanogenerators with lower voltages, pulsed or bidirectional currents, and less invasive electrodes are preferred. Herein, we construct a polydopamine (PDA)-modified poly-L-lactic acid (PLLA) /MXene (PDMP/MXene) nanofibrous composite membrane that generates piezoelectric voltages matching the transepithelial potential (TEP) to accelerate wound healing. PDA coating not only enhances the piezoelectricity of PLLA by dipole attraction and alignment, but also increases its hydrophilicity and facilitates subsequent MXene adhesion for electrical conductivity and stability in physiological environment. When applied as wound dressings in mice, the PDMP/MXene membranes act as a nanogenerators with reduced internal resistances and satisfactory piezoelectric performances that resemble bioelectric potentials (~10 mV) responding to physical activities. The membrane significantly accelerates wound closure by facilitating fibroblast migration, collagen deposition and angiogenesis, and suppressing the expression of inflammatory responses. This piezoelectric fibrous membrane therefore provides a convenient solution for speeding up wound healing by sustained low voltage mimicking bioelectricity, better cell affinity.

Bioelectret Materials and Their Bioelectric Effects for Tissue Repair: A Review.

Biophysical and clinical medical studies have confirmed that biological tissue lesions and trauma are related to the damage of an intrinsic electret (i.e., endogenous electric field), such as wound healing, embryonic development, the occurrence of various diseases, immune regulation, tissue regeneration, and cancer metastasis. As exogenous electrical signals, such as conductivity, piezoelectricity, ferroelectricity, and pyroelectricity, bioelectroactives can regulate the endogenous electric field, thus controlling the function of cells and promoting the repair and regeneration of tissues. Materials, once polarized, can harness their inherent polarized static electric fields to generate an electric field through direct stimulation or indirect interactions facilitated by physical signals, such as friction, ultrasound, or mechanical stimulation. The interaction with the biological microenvironment allows for the regulation and compensation of polarized electric signals in damaged tissue microenvironments, leading to tissue regeneration and repair. The technique shows great promise for applications in the field of tissue regeneration. In this paper, the generation and change of the endogenous electric field and the regulation of exogenous electroactive substances are expounded, and the latest research progress of the electret and its biological effects in the field of tissue repair include bone repair, nerve repair, drug penetration promotion, wound healing, etc. Finally, the opportunities and challenges of electret materials in tissue repair were summarized. Exploring the research and development of new polarized materials and the mechanism of regulating endogenous electric field changes may provide new insights and innovative methods for tissue repair and disease treatment in biological applications.

The role of TGF-β in the electrotactic reaction of mouse 3T3 fibroblasts in vitro.

Endogenous electric fields (EFs) serve as a crucial signal to guide cell movement in processes such as wound healing, embryonic development, and cancer metastasis. However, the mechanism underlying cell electrotaxis remains poorly understood. A plausible hypothesis suggests that electrophoretic or electroosmotic forces may rearrange charged components of the cell membrane, including receptors for chemoattractants which induce asymmetric signaling and directional motility. This study aimed to explore the role of Transforming Growth Factor Beta (TGFβ) signaling in the electrotactic reaction of 3T3 fibroblasts. Our findings indicate that inhibiting canonical and several non-canonical signaling pathways originating from the activated TGF-β receptor does not hinder the directed migration of 3T3 cells to the cathode. Furthermore, suppression of TGF-β receptor expression does not eliminate the directional migration effect of 3T3 cells in the electric field. Additionally, there is no observed redistribution of the TGF-β receptor in the electric field. However, our studies affirm the significant involvement of Phosphoinositide 3-Kinase (PI3K) in electrotaxis, suggesting that in our model, its activation is likely associated with factors independent of TGFβ action.

Ferroelectric catalytic BaTiO3‐based composite insoles to promote healing of infected wounds: Analysis of antibacterial efficacy and angiogenesis

AbstractOur feet are often subjected to moist and warm environments, which can promote the growth of harmful bacteria and the development of severe infection in wounds located in the foot. As a result, there is a need for new and innovative strategies to safely sterilize feet, when shoes are worn, to prevent any potential foot‐related diseases. In this paper, we have produced a non‐destructive, biocompatible and convenient‐to‐use insole by embedding a BaTiO3 (BT) ferroelectric material into a conventional polydimethylsilane (PDMS) insole material to exploit a ferroelectric catalytic effect to promote the antibacterial and healing of infected wounds via the ferroelectric charges generated during walking. The formation of reactive oxygen species generated through a ferroelectric catalytic effect in the PDMS‐BT composite is shown to increase the oxidative stress on bacteria and decrease both the activity of bacteria and the rate of formation of bacterial biofilms. In addition, the ferroelectric field generated by the PDMS‐BT insole can enhance the level of transforming growth factor‐beta and CD31 by influencing the endogenous electric field of a wound, thereby promoting the proliferation, differentiation of fibroblasts and angiogenesis. This work therefore provides a new route for antimicrobial and tissue reconstruction by integrating a ferroelectric biomaterial into a shoe insole, with significant potential for health‐related applications.

A Wearable Self-Charging Electroceutical Device for Bacteria-Infected Wound Healing.

The prolonged wound-healing process caused by pathogen infection remains a major public health challenge. The developed electrical antibiotic administration typically requires metal electrodes wired to a continuous power supply, restricting their use beyond clinical environments. To obviate the necessity for antibiotics and an external power source, we have developed a wearable synergistic electroceutical device composed of an air self-charging Zn battery. This battery integrates sustained tissue regeneration and antibacterial modalities while maintaining more than half of the initial capacity after ten cycles of chemical charging. In vitro bacterial/cell coculture with the self-charging battery demonstrates inhibited bacterial activity and enhanced cell function by simulating the endogenous electric field and dynamically engineering the microenvironment with released chemicals. This electroceutical device provides accelerated healing of a bacteria-infected wound by stimulating angiogenesis and modulating inflammation, while effectively inhibiting bacterial growth at the wound site. Considering the simple structure and easy operation for long-term treatment, this self-charging electroceutical device offers great potential for personalized wound care.

Electric fields reverse the differentiation of keratinocyte monolayer by down-regulating E-cadherin through PI3K/AKT/Snail pathway

Re-epithelialization is an important step in skin wound healing, referring to the migration, proliferation, and differentiation of keratinocytes around the wound. During this process, the edges of the wound begin to form new epithelial cells, which migrate from the periphery of the wound towards the center, gradually covering the entire wound area. These newly formed epithelial cells proliferate and differentiate, ultimately forming a protective layer over the exposed dermal surface. Wound endogenous electric fields (EFs) are known as the dominant factor to facilitate the epidermal migration to wound center. However, the precise mechanisms by which EFs promote epidermal migration remains elusive. Here, we found that in a model of cultured keratinocyte monolayer in vitro, EFs application reversed the differentiation of cells, as indicated by the reduction of the early differentiation markers K1 and K10. Genetic manipulation confirmed that EFs reversed keratinocyte differentiation through down-regulating the E-cadherin-mediated adhesion. By RNA-sequencing analysis, we screened out Snail as the transcription suppressor of E-cadherin. Snail knockdown abolished the down-regulation of E-cadherin and the reversal of differentiation induced by EFs. KEGG analysis identified PI3K/AKT signaling for Snail induction under EFs. Inhibition of PI3K by LY294002 diminished the EFs-induced AKT activation and Snail augmentation, largely restoring the level of E-cadherin reduced by EFs. Finally, in model of full-thickness skin wounds in pigs, we found that weakening of the wound endogenous EFs by the direction-reversed exogenous EFs resulted in an up-regulation of E-cadherin and earlier differentiation in newly formed epidermis in vivo. Our research suggests that electric fields (EFs) decrease E-cadherin expression by suppressing the PI3K/AKT/Snail pathway, thereby reversing the differentiation of keratinocytes. This discovery provides us with new insights into the role of electric fields in wound healing. EFs intervene in intracellular signaling pathways, inhibiting the expression of E-cadherin, which results in a lower differentiation state of keratinocytes. In this state, keratinocytes exhibit increased migratory capacity, facilitating the migration of epidermal cells and wound reepithelialization.

A Wound Exudate‐Activated Yarn Battery for Antimicrobial Electrical Fabric Dressing

AbstractExcessive inflammation poses a major challenge to wound care, with massive exudation and bacterial infection being the prominent factors contributing to the inflammation. Current biomaterials can achieve passive or interactive wound repair through exudate absorption and anti‐infection. However, they cannot actively modulate the cellular behavior associated with skin wound repair. Inspired by the endogenous electric field (EF), the present study develops an antimicrobial and self‐powered electrical fabric dressing (EFD). An EFD with multifunctional properties of wound exudate collection, anti‐infection, and self‐powered electrical stimulation (ES) is assembled via weaving a series of hydrophilically modified cotton yarn‐based batteries. Upon contact with the wound, EFD absorbs the wound exudate owing to its high hydrophilicity and utilizes it as the natural electrolyte to activate the battery. With the endogenous power supply, the ES‐promoted polarization of macrophage, as well as the migration and proliferation of fibroblasts, enhancing the active wound repair process. Moreover, the dressings exhibit excellent antibacterial properties, attributable to the synergistic effects of the cationic polymer brushes on the cotton yarn and the anodic by‐product (magnesium hydroxide) during discharging. Thus, the wound exudate‐activated EFD can effectively manage wound exudates, prevent bacterial infection, and provide self‐powered electrotherapy to facilitate active wound tissue repair.

Electrical aligned polyurethane nerve guidance conduit modulates macrophage polarization and facilitates immunoregulatory peripheral nerve regeneration

Biomaterials can modulate the local immune microenvironments to promote peripheral nerve regeneration. Inspired by the spatial orderly distribution and endogenous electric field of nerve fibers, we aimed to investigate the synergistic effects of electrical and topological cues on immune microenvironments of peripheral nerve regeneration. Nerve guidance conduits (NGCs) with aligned electrospun nanofibers were fabricated using a polyurethane copolymer containing a conductive aniline trimer and degradable L-lysine (PUAT). In vitro experiments showed that the aligned PUAT (A-PUAT) membranes promoted the recruitment of macrophages and induced their polarization towards the pro-healing M2 phenotype, which subsequently facilitated the migration and myelination of Schwann cells. Furthermore, NGCs fabricated from A-PUAT increased the proportion of pro-healing macrophages and improved peripheral nerve regeneration in a rat model of sciatic nerve injury. In conclusion, this study demonstrated the potential application of NGCs in peripheral nerve regeneration from an immunomodulatory perspective and revealed A-PUAT as a clinically-actionable strategy for peripheral nerve injury.

Effects of Electric Field‐Modulated Conductive Hydrogel on Osseoperception and Osseointegration of Dental Implants

AbstractAchieving optimal implant restoration hinges on both robust osseointegration as the structural foundation and favorable osseoperception for advanced masticatory function. The significance of nerve innervation in the peri‐implant environment as the cornerstone of osseointegration and osseoperception is often underestimated. Despite the integral role of endogenous electric fields (EFs) in the human body, particularly in electrosensitive tissues like nerve tissue, the current approach involving external electrical stimulation is invasive and not clinically applicable. The present study introduces a conductive hydrogel designed to respond to endogenous EFs, aiming to foster nerve regeneration around dental implants to coordinate both osseointegration and osseoperception. The hydrogel promotes neurite outgrowth by upregulating intracellular Ca2+ concentration and activating subsequent pathways. Furthermore, the enhanced release of neuropeptides from neurocells improves the osteogenesis of osteoblasts. The impact of the conductive hydrogel on osseointegration and osseoperception is also thoroughly investigated in vivo. This conductive hydrogel represents a unique strategy for enhancing osseointegration and osseoperception within the endogenous EFs of the peri‐implant environment. This advancement opens the door to achieving the physiological and psychological integration of dental implants.

Bioelectronic Direct Current Stimulation at the Transition Between Reversible and Irreversible Charge Transfer.

Many biological processes rely on endogenous electric fields (EFs), including tissue regeneration, cell development, wound healing, and cancer metastasis. Mimicking these biological EFs by applying external direct current stimulation (DCS) is therefore the key to many new therapeutic strategies. During DCS, the charge transfer from electrode to tissue relies on a combination of reversible and irreversible electrochemical processes, which may generate toxic or bio-altering substances, including metal ions and reactive oxygen species (ROS). Poly(3,4-ethylenedioxythiophene) (PEDOT) based electrodes are emerging as suitable candidates for DCS to improve biocompatibility compared to metals. This work addresses whether PEDOT electrodes can be tailored to favor reversible biocompatible charge transfer. To this end, different PEDOT formulations and their respective back electrodes are studied using cyclic voltammetry, chronopotentiometry, and direct measurements of H2O2 and O2. This combination of electrochemical methods sheds light on the time dynamics of reversible and irreversible charge transfer and the relationship between capacitance and ROS generation. The results presented here show that although all electrode materials investigated generate ROS, the onset of ROS can be delayed by increasing the electrode's capacitance via PEDOT coating, which has implications for future bioelectronic devices that allow longer reversibly driven pulse durations during DCS.

Accelerating wound healing with flexible zinc ion microbatteries coupled with endogenous electrical fields

Wound healing is an important physiological process in living organisms, involving the migration and proliferation of cells in the endogenous electric field (EEF). Continuous and stable electrical stimulation by an external power supply can effectively mimic the EEF, accelerating the biological processes involved in wound healing. However, the clumsiness of conventional external power supplies and the unstable voltage output of novel power supplies greatly limit the application of electric fields for wound healing. Here we demonstrate the use of a flexible and wearable microbattery for wound healing. The annular electrode is designed to generate an annular electric field in the same direction as the EEF of the wound, allowing for faster, more uniform fibroblast migration, proliferation, and transdifferentiation processes, thus accelerating wound healing. Studies on rats show that skin wounds given a stable electric field using aqueous Zn-MnO2 microbatteries with an operating voltage of 1.5 V healed completely within 6 days, while the blank control group took 10 days or longer. Further, the series connection of microbatteries can match wounds of different areas, enabling rapid healing. These advantages make flexible microbatteries highly promising for practical applications in the biomedical field.

Wearable Magnetoelectric Stimulation for Chronic Wound Healing by Electrospun CoFe2O4@CTAB/PVDF Dressings.

Magnetoelectric stimulation is a promising therapy for various disorders due to its high efficacy and safety. To explore its potential in chronic skin wound treatment, we developed a magnetoelectric dressing, CFO@CTAB/PVDF (CCP), by electrospinning cetyltrimethylammonium bromide-modified CoFe2O4 (CFO) particles with polyvinylidene fluoride. Cetyltrimethylammonium bromide (CTAB) serves as a dispersion surfactant for CFO, with its quaternary ammonium cations imparting antibacterial and hydrophilic properties to the dressing. Electrospinning polarizes polyvinylidene fluoride (PVDF) molecules and forms a fibrous membrane with flexibility and breathability. With a wearable electromagnetic induction device, a dynamic magnetic field is established to induce magnetostrictive deformation of CFO nanoparticles. Consequently, a piezoelectric potential is generated on the surface of PVDF nanofibers to enhance the endogenous electrical field in the wound, achieving a cascade coupling of electric-magnetic-mechanical-electric effects. Bacteria and cell cultures show that 2% CTAB effectively balances antibacterial property and fibroblast activity. Under dynamic magnetoelectric stimulation, the CCP dressing demonstrates significant upregulation of TGF-β, FGF, and VEGF, promoting L929 cell adhesion and proliferation. Moreover, it facilitates the healing of diabetic rat skin wounds infected with Staphylococcus aureus within 2 weeks. Histological and molecular biology evaluations confirm the anti-inflammatory effect of CTAB and the accelerated formation of collagen and vessel by electrical stimulation. This work provides insights into the application of magnetoelectric stimulation in the healing of chronic wounds.

All-in-One Self-Powered Microneedle Device for Accelerating Infected Diabetic Wound Repair.

Diabetic wound healing remains a significant clinical challenge due to the complex microenvironment and attenuated endogenous electric field. Herein, a novel all-in-one self-powered microneedle device (termed TZ@mMN-TENG) is developed by combining the multifunctional microneedle carried tannin@ZnO microparticles (TZ@mMN) with the self-powered triboelectric nanogenerator (TENG). In addition to the delivery of tannin and Zn2+, TZ@mMN also effectively conducts electrical stimulation (ES) to infected diabetic wounds. As a self-powered device, the TENG can convert biomechanical motion into exogenous ES to accelerate the infected diabetic wound healing. In vitro experiment demonstrated that TZ@mMN shows excellent conductive, high antioxidant ability, and effective antibacterial properties against both Staphylococcus aureus and Escherichia coli (>99% antibacterial rates). Besides, the TZ@mMN-TENG can effectively promote cell proliferation and migration. In the diabetic rat full-thickness skin wound model infected with Staphylococcus aureus, the TZ@mMN-TENG can eliminate bacteria, accelerate epidermal growth (regenerative epidermis: ≈303.3 ± 19.1µm), enhance collagen deposition, inhibit inflammation (lower TNF-α and IL-6 expression), and promote angiogenesis (higher CD31 and VEGF expression) to accelerate infected wound repair. Overall, the TZ@mMN-TENG provides a promising strategy for clinical application in diabetic wound repair.

A Self‐Powered Wound Dressing Based on “Lock‐ON/OFF” Drug Release Combined Electric Stimulus Therapy for Accelerated Infected Wound Healing

AbstractTo facilitate the on‐demand release of hydrophilic antibiotics for accelerated repair of infected wounds, a self‐powered wound dressing incorporating a “Lock‐ON/OFF” electric field (EF)‐driven drug release mechanism combined with electrical stimulation (ES) therapy is presented. When subjected to mechanical stress, the drug exhibits controlled, slow‐release behavior, achieving a remarkable cumulative release rate of 88.57%—89 times higher than the non‐mechanical stress group. Conversely, in the absence of mechanical stress, the drug remains unreleased, maintaining a 0% cumulative release rate in a fully closed state. The dressing utilizes its piezoelectric effect to establish an electric field, enabling precise control of hydrophilic drug release by regulating the electrostatic balance between the drug carrier and the drug. Moreover, the piezoelectric field acts as an exogenous electric field, remodeling the endogenous electric field of the wound, and accelerating wound closure. Combining EF‐driven drug release with ES result in a 1.26 fold improvement in wound healing compared to ES alone. This study addresses precision therapy limitations in fully automated diagnosis and treatment, paving the way for advancements in remote diagnosis, wireless therapy, and on‐demand precision medicine.

Reconfiguring the endogenous electric field of a wound through a conductive hydrogel for effective exudate management to enhance skin wound healing.

The ionic environment has a strong influence on the bioelectricity of skin, which is also present in the wound healing process. Inspired by this, we proposed a mechanism for hydrogel-based dressings to respond to endogenous electric fields through exudate absorption and conducted a verification study using a typical hydrogel, namely, polyacrylamide and sodium alginate (PAM-SA) hydrogels, as an example. Theoretical calculations showed that the PAM-SA hydrogels could absorb and orient the various electrolytes of exudate in the hydrogel at the wound site, contributing to the reconstruction of the electric field at the wound site. During the treatment process, this effect significantly accelerated the healing process of the rat epidermis, which exceeded the conventional dressing in terms of healing speed and efficacy, and the wounds on the complete layer of rat skin (wound area: 1.13 cm2) could be rapidly repaired within 10 days. Revealing the electrophysiological behavior of PAM-SA dressings during wound healing can help further improve the design model, the optimization concept, and development paths for the bioelectrical structures of modern dressings and bioelectrical stimulation in wound healing.

Paxillin/HDAC6 regulates microtubule acetylation to promote directional migration of keratinocytes driven by electric fields

Endogenous electric fields (EFs) have been demonstrated to facilitate wound healing by directing the migration of epidermal cells. Despite the identification of numerous molecules and signaling pathways that are crucial for the directional migration of keratinocytes under EFs, the underlying molecular mechanisms remain undefined. Previous studies have indicated that microtubule (MT) acetylation is linked to cell migration, while Paxillin exerts a significant influence on cell motility. Therefore, we postulated that Paxillin could enhance EF-induced directional migration of keratinocytes by modulating MT acetylation. In the present study, we observed that EFs (200 mV/mm) induced migration of human immortalized epidermal cells (HaCaT) towards the anode, while upregulating Paxillin, downregulating HDAC6, and increasing the level of microtubule acetylation. Our findings suggested that Paxillin plays a pivotal role in inhibiting HDAC6-mediated microtubule acetylation during directional migration under EF regulation. Conversely, downregulation of Paxillin decreased microtubule acetylation and electrotaxis of epidermal cells by promoting HDAC6 expression, and this effect could be reversed by the addition of tubacin, an HDAC6-specific inhibitor. Furthermore, we observed that EFs also mediated the polarization of Paxillin and acetylated α-tubulin, which is critical for directional migration. In conclusion, our study revealed that MT acetylation in EF-guided keratinocyte migration is regulated by the Paxillin/HDAC6 signaling pathway, providing a novel theoretical foundation for the molecular mechanism of EF-guided directional migration of keratinocytes.

A Bioresorbable and Conductive Scaffold Integrating Silicon Membranes for Peripheral Nerve Regeneration.

Peripheral nerve injury represents one of the most common types of traumatic damage, severely impairing motor and sensory functions, and posttraumatic nerve regeneration remains a major challenge. Electrical cues are critical bioactive factors that promote nerve regrowth, and bioartificial scaffolds incorporating conductive materials to enhance the endogenous electrical field have been demonstrated to be effective. The utilization of fully biodegradable scaffolds can eliminate material residues, and circumvent the need for secondary retrieval procedures. Here, a fully bioresorbable and conductive nerve scaffold integrating N-type silicon (Si) membranes is proposed, which can deliver both structural guidance and electrical cues for the repair of nerve defects. The entire scaffold is fully biodegradable, and the introduction of N-type Si can significantly promote the proliferation and production of neurotrophic factors of Schwann cells and enhance the calcium activity of dorsal root ganglion (DRG) neurons. The conductive scaffolds enable accelerated nerve regeneration and motor functional recovery in rodents with sciatic nerve transection injuries. This work sheds light on the advancement of bioresorbable and electrically active materials to achieve desirable neural interfaces and improved therapeutic outcomes, offering essential strategies for regenerative medicine.

Reducing Sialylation Enhances Electrotaxis of Corneal Epithelial Cells.

Corneal wound healing is a complex biological process that integrates a host of different signals to coordinate cell behavior. Upon wounding, there is the generation of an endogenous wound electric field that serves as a powerful cue to guide cell migration. Concurrently, the corneal epithelium reduces sialylated glycoforms, suggesting that sialylation plays an important role during electrotaxis. Here, we show that pretreating human telomerase-immortalized corneal epithelial (hTCEpi) cells with a sialyltransferase inhibitor, P-3FAX-Neu5Ac (3F-Neu5Ac), improves electrotaxis by enhancing directionality, but not speed. This was recapitulated using Kifunensine, which inhibits cleavage of mannoses and therefore precludes sialylation on N-glycans. We also identified that 3F-Neu5Ac enhanced the responsiveness of the hTCEpi cell population to the electric field and that pretreated hTCEpi cells showed increased directionality even at low voltages. Furthermore, when we increased sialylation using N-azidoacetylmannosamine-tetraacylated (Ac4ManNAz), hTCEpi cells showed a decrease in both speed and directionality. Importantly, pretreating enucleated eyes with 3F-Neu5Ac significantly improved re-epithelialization in an ex vivo model of a corneal injury. Finally, we show that in hTCEpi cells, sialylation is increased by growth factor deprivation and reduced by PDGF-BB. Taken together, our results suggest that during corneal wound healing, reduced sialylated glycoforms enhance electrotaxis and re-epithelialization, potentially opening new avenues to promote corneal wound healing.