Effects of electrical stimulation on skin surface

Abstract

Abstract: Skin is the largest organ in the body, and directly contact with the external environment. Articles on the role of micro-current and skin have emerged in recent years. The function of micro-current is various, including introducing various drugs into the skin locally or throughout the body, stimulating skin wounds healing through various currents, suppressing pain caused by various diseases, and promoting blood circulation for postoperative muscle rehabilitation, etc. This article reviews these efforts. Compared with various physical and chemical medical therapies, micro-current stimulation provides a relatively safe, non-invasive therapy with few side effects, giving modern medicine a more suitable treatment option. At the same time, the cost of the electrical stimulation generating device is relatively low, which makes it have wider space to and more clinical application value. The current micro-current stimulation technology has become more and more mature, but there are still many problems in its research. The design of the experiment and the selection of the current parameters not standardized and rigorous. Now, clear regulations are needed to regulate this field. Micro-current skin therapy has become a robust, reliable, and well-structured system.

Keywords: Drug delivery; Electrical stimulation; Transdermal; Transdermal drug delivery system; Wound healing.

Fig. 1

a Structure of skin [15]. b Structure of the hair follicle: 1 – infundibulum; 2 – isthmus [16]. c Cross section of the hair follicle: Lanugo hairs are non- medullated and nonpigmented, present during intrauterine life [16]. d Protein levels of cytokines in BM-MSC-conditioned medium. (A) Antibody-based protein array analysis human dermal fibroblast (FB)- or BM-MSC-conditioned medium under hypoxic conditions. Similar results were obtained from three independent experiments and results from one of them are shown [18]. e Effect of BM-MSC-conditioned medium on wound closure. Representative images of wounds before treatment or 7 days after treatment with vehicle control medium (vehicle-M) (left), concentrated fibroblast (FB-M)- or BM-MSC-conditioned medium (MSC-M) (right) [18]

Fig. 2

a Different routes of drug transport through skin [22]. b Percutaneous penetration of lipid vesicular carrier [22]. c Bulge region of a human hair follicle [21]. d Stem/progenitor cell populations that contribute to cutaneous wound healing [21]. e Cross-sectional view of polymer membrane permeation-controlled TDD systems [15]

Fig. 3

a Cross-section of a typical matrix patch, in this case the rivastigmine transdermal patch (Exelon® patch, Novartis Pharma AG, Basel, Switzerland) [24]. b Types of transdermal drug delivery systems [25]. c In the experimental group, heparin after pulse current was observed in both the stratum corneum and the epidermis, and fluorescence was also observed in some areas of the dermis. Total magnification × 100 (right). In the control group, no fluorescence was observed in the epidermal layer and the dermal layer. Total magnification × 100 (left) [28]. d Histology of rat skin treated or untreated with pulsed current iontophoresis. Rat skin treated by pulsed current iontophoresis, total magnification × 200 (left), control (right) [28]. e Iontophoresis using a Ag/AgCl electrode system [27]

Fig. 4

a SEM photographs of transdermal patches A: EC/PVP (3:2) before permeation studies; A1: EC/PVP (3:2) after permeation studies; B: ERL/ERS (4:1) before permeation studies; B1: ERL/ERS (4:1) after permeation studies [30]. b Comparison of transdermal iontophoretic skin permeation profiles of LHRH by three different application pattems with a current intensity of 0.6 mA [3]. c Schematic illustration of different concentration gradients across skin during various durations of current application. The transdermal iontophoretic skin permeation of LHRH is proportional to the concentration gradient, whose equilibrium concentration gradient is time-dependent [3]. d Current (filled circle) and voltage (open square) profiles 1 h after the initiation of lysine iontophoresis with 50% square-wave, unipolar, pulsed DC at frequencies of (up) 2500 Hz, (down) 250 Hz [31]

Fig. 5

a Deposited amount of AA obtained with AA Formula 1 (5%) and AA Formula 2 (10%) at each current profile (0.2 mA/cm²) for 5 min iontophoresis (n = 6) [6]. b Comparison of the deposition of 0.2% EA solution at pH 4.0 and pH 7.0 at 0.3 mA/cm², applied for 10 min and 20 min iontophoresis. (l) Scanning electron microscope image of flufenamic acid-loaded FA-PLGA nanoparticles [6]. c Negative polarity current profiles, galvanic DC [6]. d Negative polarity current profiles, from left to right are galvanic direct current and pulse current (DC + PC), and SPC [6]. e Scanning electron microscope image of flufenamic acid-loaded FA-PLGA nanoparticles [44]. f Effect of lidocaine on porcine epidermis. Light micrograph of a 1 μm thick plastic section showing alteration of pig epidermis produced by iontophoresis of 4% aqueous lidocaine hydrochloride (3 mA for 45 min) in vivo. Note the dense cytoplasmic staining, the darkly stained flattened nuclei in the upper stratum spinosum and the stratum granulosum and the vacuolation of cells of the basal layer [32]. g Light micrograph showing control porcine skin [32]

Fig. 6

a Schematic of the stratum corneum with LDR, a localized region (radius = 30–500 μm) where electric energy is dissipated, and which is characterized by a drop in resistance [47]. b A complete set of results from one experiment. The pulse parameters were U_skin = 83 V and τ_pulse = 95 ms [47]. c Model for the electrothermally induced changes at stratum corneum. (A) Stratum corneum before high-voltage pulse, (B) during electric current flow with propagating heat front starting at the center of maximal current density, and (C) partial recovery of the stratum corneum after pulse at sites where the phase transition of the lipid structure was not reached [47]. d Key features of skin, skin barriers and hypothetical aqueous pathways [48]

Fig. 7

a Photograph of SKH-1 hairless mouse being treated with parallel plate electrode under isoflurane inhalation anesthesia. (Inset) Close-up of one of the plates of parallel plate electrode showing it recessed by 0.5 mm to allow a space for a conductive agar gel to be placed on it [7]. b Typical response of a melanoma to three applications of 100 pulses (300 ns, 40 kV/cm, 0.5 Hz) 30 min apart on day 0 followed by a single application on day 4 using a 5 mm diameter parallel plate electrode on mouse #102. Collection of seven matched sets of images of the same tumor all taken on the day indicated in the lower left corner of the transillumination image [7]. c Blood flow in melanoma before and after nsPEF application. (A) 3-D reconstruction of volume of melanoma; (B) power Doppler reconstruction of blood flow before field application. (C) 3-D reconstruction of volume of the same melanoma shown in (A) generated about 15 min after 100 pulses (300 ns, 40 kV/cm, 0.5 Hz). (D) Power Doppler reconstruction of blood flow in the same tumor shown in (B) generated about 15 min after 100 pulses (300 ns, 40 kV/cm, 0.5 Hz) [7]. d Location of electropores with respect to electric field. (A) One electropore at pole of each hemisphere when induced electric field strength, E, is equal to the minimum transmembrane electric field strength needed to cause dielectric breakdown, ET. (B) Additional electropores induced at greater distance from poles when E > ET. (C) Net negative charged entity inside spherical membrane is inhibited from diffusing through electropores if movement is against transmembrane electric field. (D) Net positive charged entity inside spherical membrane can diffuse out since movement is in same direction as electric field in vicinity of pore [49]. e Photographs of formalin-fixed, paraffin-embedded cross-sections of porcine buccal mucosae. Hematoxylin and eosin staining: (A) Control, untreated. (B) Control, passive permeation after an 8 h treatment period. Slightly enlargement of 2–3 cell layers (arrows) [50]

Fig. 8

a Inflammatory phase after a cutaneous cut; hemostasis and invasion of inflammatory cells [53]. b Proliferative phase; organization of the thrombus, secretion of growth factors, synthesis of collagen III and the beginning of angiogenesis [53]. c Remodeling phase; regenerative processes fade and are followed by reorganization of the connective tissue and contractile response [53]. d Generation of skin wound electric fields. When wounded, the potential drives current flow through the newly formed low resistance pathway generating an electric field whose negative vector points toward the wound center at the lower portion of the epidermis and away from the wound on the upper portion below the stratum corneum [57]

Fig. 9

a Observations made near a wound in rat cornea. (A) Neuron outgrowths are strongly aligned by the endogenous electric field and exhibit a more random orientation when the field is reduced by ouabain addition. (B) The rate of corneal wound healing is reduced in the presence of ouabain. (C) The frequency and orientation of division planes is influenced by the field strength. Aminophylline increases the transcorneal potential and stimulates an increase in the rate of cell division and orientation of the axis of division perpendicular to the field [57]. b Diagram of the setup for current supply to the wounds. The newt was placed in a three-compartment chamber with only the feet immersed in pools of pond water. This minimized shunting of the supplied current (left). The benzocaine-soaked pads for keeping the head and trunk moist and the animal anesthetized are omitted for the sake of clarity (right). A view of one current-supplying electrode and the two microelectrodes used for potential measurements [57]. c The diagram illustrates the interaction between electric fields. The electric field can be directly attached to the endogenous electric field of the wound, where applying EF (brown arrow) in the default direction of wound healing will enhance wound-induced endogenous EF (red arrow), thus increasing the wound healing rate. In contrast, reversing the direction of EF (blue arrow) against the default wound healing direction will suppress the endogenous EF in the wound (red arrow), thus reducing or even stop the normal wound healing behaviors [10]. d Directional angiogenesis is a vascular-like structure of a rat placed in a 3D armature chamber with the aortic ring growing toward the anode. On the left is the aortic ring after embedding; on the right is day 3, after 200 mV/mm EF treatment. Rod is 500 μm [10]

Fig. 10

a An EF directs migration of corneal epithelial cells in a monolayer model of wound healing (150 mV/mm) [59]. b Stratified corneal epithelium migrate in situ to heal a wound (towards the left) [59]. c Electric fields applied with polarity opposite to the default healing direction direct the wound edge to migrate away from the wound [59]. d Electrical stimulation experiments of fibroblasts cultured in the absence of (control) and (experimental) electric fields. It can be observed that fibroblasts differentiate along the electric field line [59]. e Polarized EGF receptors, dp-ERK (activated mitogen-activated protein kinase) and actin polymerization. Dp-ERK1/2 and F-actin are surface plots that represent fluorescence intensity [60]. f Light micrograph (hematoxylin and eosin, 100) of full-thickness wound in guinea pig 7 day after incision, control, cathodal ES, and anodal ES, respectively, from left to right. Cathodal and anodal DC ES (sensory intensity) was applied for 1 h per day, every other day, for 7 days. The number of fibroblasts (dark fusiform cells, F) was significantly higher in cathodal ES group compared with control group [63]

Fig. 11

a Representative immunohistochemistry (IHC) of SP expression. Dotted lines indicate epidermal-dermal junction. Scale bar is 100 μm [65]. b IHC of PGP9.5 expression [65]. c Confocal microscopy imaging (A and A’) of colocalization of E-cadherin and vimentin-positive cells at day 6 after injury; insets provide its higher magnification [72]. d Effect of ES on fibroblast a-SMA expression. Dermal fibroblasts were seeded on conductive PPy/HE/PLLA membranes followed by exposure to 50 or 200 mV/mm for various periods. The cells were then detached from the conductive mesgmbranes, washed, seeded on coverslips, and cultured up to 70% confluence. The cells were then stained using relevant monoclonal antibodies. Cytoplasmically immunolabelled myofibroblasts are presented [64]. e A constant direct current. B double peak unidirectional current, that is, high-voltage pulse current [HPVC] or intermittent low-intensity direct current. C proves double-symmetric current, also called low-voltage pulse current. D biophasic symmetrical, which is a TENS. E balanced asymmetrical biophasic [69]. f Dermal fibroblasts exposed to 200 mV/mm highly contracted the collagen gel matrix. Following exposure to ES, the fibroblasts were added to a collagen type I gel and cultured. The diameter of each collagen gel was measured at 48 h and 72 h. Representative photos show the action of the ES-exposed and non- exposed cells on collagen gel contraction [64]. g Skin blood flow in a typical subject measured by the laser doppler flow imager before treatment (a), after 20 min wound heating (b) and just at the end of electrical stimulation (c). The whiter the color, the greater the blood flow. Blue represents the lowest blood flow [71]

Fig. 12

a Diagram showing the gate control theory of pain as originally described by Melzack and Wall, 1965 [82]. b Details of the experimental proce-dure, illustrating the placement of the TENS electrodes, skin thermistor probes, and the recording of muscle activity [83]. c Schematic illustration of a typical pain syn­drome and its elements [87]

Fig. 13

a Bar graphs represent the analgesia produced by TENS and morphine in the tail flick test for animals that are intact and those that were spinalized. Fifty-hertz electrical stimulation produced an increase in the tail flick latency similar to that of systemic morphine. Spinal transection reduced the amount of inhibition by electrical stimulation or morphine by approximately 50% [82]. b Bar graphs represent the analgesia produced by 50 Hz electrical stimulation or morphine in the tail flick test in intact animals. Animals pretreated with PCPA to deplete the neurotransmitter serotonin (5-HT) showed a significant reduction in the amount of analgesia produced by either electrical stimulation or morphine. Control animals did not receive electrical stimulation or morphine but were still spinalized or pretreated with PCPA [82]. c Depiction of the wave-forms commonly found in most present-day TENS devices [87]

Fig. 14

a Diagram of a motor unit, which is composed of the motor nerve, its branches, and all of the muscle fibers it innervates [95]. b Illustration of a NMES circuit [95]. c Examples of electrical waveforms commonly used in NMES. A, bursted biphasic (“Russian”) current; B, pulsed symmetric biphasic current; C, pulsed asymmetric biphasic current [95]. d Capillaries visualized byalkaline phosphatase in rabbit extensor digitorum [12]. e Transverse sections of rabbit EDL muscles stained for succinic dehydrogenase: (a) control and (b) stimulated for 14 days at 5 Hz continuously; (c) control and (d) stimulated for 21 days at 10 Hz intermittently [12]

Fig. 15

a Longitudinal nerve sections. Representative sections were taken from transected and surgically repaired tibial nerves from Thy1-GFP transgenic rats in which the gastrocnemius muscle was sham-stimulated (A) or subjected to daily EMS (B). The hashed line is the suture line. Higher magnification views of the boxed areas within the distal nerve stump are shown in (C) and (D) [101]. b Isoforce GT-330 (OG Giken), which was used to measure maximum muscle strength of both legs during CKC exercise (left). Cross-sectional areas of extensor and flexor muscles of injured and intact leg were measured in horizontal CT image (right) [102]. c A user is absorbed in his reading, not noticing the lamppost. Actuated navigation automatically steers him around the obstacle [108]. d Placement of the EMS electrodes and wearable control unit [109]. e Anatomic figure of the left forearm. Two electrode sleeves are placed on the skin. The electrodes cover several muscles. There are three active EMS channels: 3 + 4 → 12, 7 → 15, and 8 → 16. The blue electrodes are deactivated [110]

Fig. 16

a Two sleeves worn at the forearm. The upper sleeve has 22 electrodes, the lower sleeve has 18 electrodes [110]. b Example of overriding the conventional behavior: (a) As participants expected this door to open to the conventional side, they turned the handle right, (b) Affordance +  + induced a left turning motion instead [113]. c Changing behavior according to the object’s state: (a) this cold cup affords grasping, (b) when hot it repels the user’s hand, but (c) its handle continues to afford grasping [113]. d An audience member guiding the artist’s brushstrokes by pressing a button on a connected tablet to activate one of the sets of EMS pads worn by the artist [114]. e Muscle-Propelled Force Feedback allows for miniaturized force feedback devices by electrically stimulating the user’s muscles, instead of using mechanical actuators [112]. f Impacto allows users to feel the impact of blocking the avatar’s hit by thrusting the user’s arm backwards by operating the user’s biceps (a). The same impacto unit allows simulating the sensation of attacking. In both cases the impacto unit activates the user’s biceps. This time, this causes the user’s hand to stop in mid-air, as if it had hit the opponent (b) [13]. g Additional solenoid unit mounted to the back of the hand featuring a surface tip allows the user to attack using jabs and uppercuts [13]