Reverse Iontophoresis: Noninvasive Assessment of Topical Drug Bioavailability.

Assessing drug disposition in the skin after the application of a topical formulation is difficult. It is hypothesized that reverse iontophoresis (RI), which can extract charged/polar molecules for monitoring purposes, may provide a noninvasive approach for the assessment of local drug bioavailability. The passive and RI extraction of salicylic acid (SA) and nicotine (NIC) from porcine skin in vitro was assessed after a simple solution of the former and a transdermal patch of the latter had been applied for 24 and 8 h, respectively. Immediately after this "passive skin loading", the amount of drug in the stratum corneum (SC) and "viable" tissue (VT) was measured either (a) after tape-stripping and subsequent solvent extraction of both skin layers or (b) following RI extraction over 4 h. Parallel experiments were then performed in vivo in healthy volunteers; in this case, the VT was not sampled and the skin loading period for NIC was only 4 h. RI extraction of both drugs was significantly higher (in vitro and in vivo) than that achieved passively, and the cumulative RI extraction profiles as a function of time were mathematically analyzed using a straightforward compartmental model. Best-fit estimates of drug amounts in the SC and VT (ASC,0 and AVT,0, respectively) at the end of "loading" and two first-order rate constants describing transfer between the model compartments were then determined. The in vitro predictions of ASC,0 and AVT,0 were in excellent agreement with the experimental results, as was the value of the former in vivo. The rate constants derived from the in vitro and in vivo results were also similar. In summary, the results provide proof-of-concept that the RI method has the potential to noninvasively assess relevant metrics of drug bioavailability in the skin.

Transcutaneous Delivery of Dexamethasone Sodium Phosphate Via Microneedle-Assisted Iontophoretic Enhancement - A Potential Therapeutic Option for Inflammatory Disorders.

AIM: This study aimed to fabricate dexamethasone sodium phosphate loaded microneedle arrays (MNA) and investigate their efficiency in combination with iontophoresis for the treatment of hind paw oedema in rats. METHODS: Drug loaded polyvinyl alcohol, polyvinyl pyrrolidone and D-sorbitol-based MNA11 were fabricated by vacuum micromolding. Physicochemical, morphological, thermal, in-silico, in-vitro insertion ability (on parafilm) and drug release studies were performed. Ex-vivo permeation, in-vivo insertion and anti-inflammatory studies were performed in combination with iontophoresis. RESULTS: MNA11 displayed sharp-tipped projections and acceptable physicochemical features. Differential scanning calorimetry results indicated that drug loaded MNA11 were amorphous solids. Drug interacted with PVP and PVA predominately via hydrogen bonding. Parafilm displayed conspicuously engraved complementary structure of MNA11. Within 60 min, 91.50 ± 3.1% drug released from MNA11. A significantly higher i.e., 95.06 ± 2.5% permeation of drug was observed rapidly (within 60 min) from MNA11-iontophoresis combination than MNA11 i.e., 84.07 ± 3.5% within 240 min. Rat skin treated using MNA11 and MNA11-iontophoresis showed disruptions / microchannels in the epidermis without any damage to underlying anatomical structures. MNA11-iontophoresis combination led to significant reduction (83.02 ± 3.9%) in paw oedema as compared to MNA11 alone (72.55 ± 4.1%). CONCLUSION: MNA11-iontophoresis combination can act as a promising candidate to deliver drugs transcutaneously for treating inflammatory diseases.

Development of an Effective Psoriasis Treatment by Combining Tacrolimus-Encapsulated Liposomes and Iontophoresis.

Psoriasis is a chronic T-cell-mediated autoimmune skin disease. Tacrolimus (FK506) is commonly used treatment for psoriasis. However, since the molecular weight of FK506 is more than 500 Da, its skin penetration is limited, so that there is a need to improve the penetrability of FK506 to allow for more effective treatment. To this end, we employed iontophoresis (ItP), which is a physical, intradermal drug delivery technology that relies on the use of weak electric current. Previous findings suggest that activation of cell signaling by the weak electric current applied during ItP may affect the expression of inflammatory cytokines, leading to aggravation of psoriasis. In this study, we analyzed the effect of ItP on the expression of various inflammatory cytokines in the skin, and subsequently examined the therapeutic effect of ItP using negatively-charged liposomes encapsulating FK506 (FK-Lipo) in a rat psoriasis model induced by imiquimod. We found that ItP (0.34 mA/cm2, 1 h) did not affect mRNA levels of inflammatory cytokines or epidermis thickness, indicating that ItP is a safe technology for psoriasis treatment. ItP of FK-Lipo suppressed the expression of inflammatory cytokines induced by imiquimod treatment to a greater extent than skin treated with FK506 ointment for 1 h. Furthermore, epidermis thickening was significantly suppressed only by ItP of FK-Lipo. Taken together, results of this study demonstrate the successful development of an efficient treatment for psoriasis by combining FK-Lipo and ItP, without disease aggravation associated with the weak electric current.

Comparison of the clinical efficacy of topical tretinoin 0.05% cream and tacrolimus 0.1% ointment plus iontophoresis in the management of palmoplantar psoriasis.

BACKGROUND: Palmoplantar psoriasis (PPP) is a localized variant of psoriasis that may be resistant to topical therapy, owing to the poor penetrability of topical agents at this anatomical site. Modalities that enhance localized cutaneous delivery of drugs could help to solve this problem. Iontophoresis is one such procedure that augments transdermal drug delivery, thus enabling better and expeditious therapeutic outcomes. OBJECTIVE: To compare the therapeutic efficacy and safety of iontophoresis with tretinoin 0.05% cream and tacrolimus 0.1% ointment in treating patients with PPP. METHODS: Sixty patients with PPP (28 males and 32 females, age range 8-76 years) were enrolled and randomly assigned to one of two groups comprising 30 patients each. One group (12 males and 18 females) received iontophoresis with tretinoin 0.05% cream; the other (16 males and 14 females) received iontophoresis treatment with tacrolimus 0.1% ointment. Both groups received treatment weekly from baseline until 4 weeks and then fortnightly at weeks 6 and 8. Clinical images were taken at each visit and improvement of psoriasis was evaluated using the erythema, scaling, induration and fissuring (ESIF) score. The percentage reduction in ESIF score was also assessed on completion of treatment and the grade of improvement noted for each patient. RESULTS: Twenty-seven patients in the iontophoresis with tretinoin 0.05% cream group and 29 in the iontophoresis treatment with tacrolimus 0.1% ointment group completed the study. The mean (SD) ESIF score in the former decreased significantly from 8.7 (2) at baseline to 3.2 (1.7) at the study endpoint (P < 0.001). Similarly, in the latter group, there was a substantial reduction in mean (SD) ESIF score from 8.2 (1.9) at baseline to 3.3 (1.1) at the study end (P < 0.001). No significant adverse effects were encountered in either treatment arm. CONCLUSIONS: Iontophoresis using tretinoin and tacrolimus was found to be effective and safe for the treatment of PPP. Although iontophoresis with tretinoin showed slightly better results than with tacrolimus, these were not statistically significant.

Evaluation test and analysis of a microneedle and iontophoresis based medical device "CELLADEEP Patch" in skin improvement on ex vivo human-derived skin tissue models.

BACKGROUND: Microneedles are tiny needles, typically ranging from tens to hundreds of micrometers in length, used in various medical procedures and treatments. The tested medical device named "CELLADEEP Patch" a dissolvable microneedle therapy system (MTS), made of hyaluronic acid and collagen. And the iontophoresis technique is also applied in the system. The study aimed to evaluate the effectiveness of the "CELLADEEP Patch" in skin improvement. METHODS: Ex vivo human-derived skin tissue models were used in this study and they were divided into three different groups, namely, the Untreated Group, the Negative Control Group, and the Test Group respectively. The Untreated Group received no treatment measures, the Negative Control Group was exposed to ultraviolet B radiation (UVB) irradiation, and the Test Group was exposed to UVB irradiation and treated with "CELLADEEP Patch". Skin moisture content, transdermal water loss, and skin elasticity were evaluated by three clinical devices. Additionally, histological staining and related mRNA expression levels were also analyzed. RESULTS: The results of skin moisture content, transdermal water loss, and skin elasticity evaluation consistently illustrated that the application of "CELLADEEP Patch" led to remarkable skin improvement. And the analysis of histological staining images also confirmed the effectiveness of the "CELLADEEP Patch", especially for increasing collagen density. Moreover, the upregulation of Collagen type 1 a (COL1A1) and hyaluronan synthase 3 mRNA expression and the decrease of Matrix metalloproteinase 1 (MMP-1) and Interleukin-1 beta (IL-1ß) mRNA expression reflected its wrinkle improvement, moisturizing and anti-inflammation function. CONCLUSION: "CELLADEPP Patch", the MTS combined with the iontophoresis technique, exhibits its effectiveness in moisturizing, skin elasticity improvement, and anti-inflammatory function when applied to ex vivo human-derived skin tissue models in experiments. The study has contributed to the understanding of the "CELLADEPP Patch" and laid the foundation for subsequent animal experiments and clinical trials.

Analysis of the effect of calcium ions on promoting the penetrability of riboflavin into the corneal stroma by iontophoresis.

PURPOSE: To investigate the effect of calcium ions on promoting the penetrability of riboflavin into the corneal stroma by iontophoresis and to analyse the possible mechanism. METHODS: Forty rabbits were divided into five groups randomly: 0.1% riboflavin-balanced salt solution (BSS) by iontophoresis group, 0.1% riboflavin-saline solution by iontophoresis group, 0.1% riboflavin-zinc gluconate solution by iontophoresis group, 0.1% riboflavin-calcium gluconate solution by iontophoresis group and classical riboflavin instillation after corneal de-epithelialization as the control group. The riboflavin concentrations in corneal stroma were determined and compared by high-performance liquid chromatography (HPLC) after removing epithelium and endothelium. RESULTS: Iontophoretic delivery of a 0.1% riboflavin-calcium gluconate solution was the closest to the effect of classical de-epithelialization. The other solvents were unsufficient at enhancing the permeability of the riboflavin. CONCLUSION: Calcium ions can promote the penetrability of riboflavin into the corneal stroma by iontophoresis.

[Method of comprehensive physiotherapy of dental patients after COVID-19]. / Metod kompleksnoi fizioterapii u stomatologicheskikh patsientov posle COVID-19.

Functional gastrointestinal disorders, which had an impact on the dentofacial system (pain, loose teeth and falling out of them) in patients who have had COVID-19, drew the close attention of specialists of different profiles. The pathogenesis of worsening post-COVID edentulism is insufficiently studied, as many issues of adequate therapy remain unsolved, in which the role of non-drug technologies in the treatment of dental patients who have suffered from COVID-19 is extremely high. OBJECTIVE: To describe the mechanism of action and clinical effectiveness of the developed combined physiotherapy method, including the induced technique of piracetam iontophoresis on the frontooccipital technic and acupuncture laser therapy in dental patients with complaints of edentulism progression after COVID-19 on the basis of the analysis of single studies on the post-COVID loss of teeth treatment. MATERIAL AND METHODS: A number of patients equal 120 who complained of tooth loss after COVID-19 during the past 6 months were examined. The following initial and end points were considered: dental bleeding and inflammation scores, vascular and endothelial dysfunction markers - levels of intercellular adhesion molecules and their receptors (SlCAM-1, SVCAM-1, VEGF-A, ET-1) before and after treatment. RESULTS: Negative correlation between VEGF-A (pg/ml) concentration in peripheral blood serum and sVCAM-1 (ng/ml) level in the examined patients (r=0.4830, p<0.05) and strong inverse correlation between slCAM-1 (ng/ml) level and sVCAM-1 (r=0.7696, p<0.01) have been established. More significant effects after application of the combined induced method on the head's structures and laser acupuncture have been noted than after acupuncture laser exposure and after inducing technique separately, namely in the form of dental inflammation score correction by 1.76 times (p<0.001), decrease of bleeding score by 2.6 (p<0.05), decrease of concentration of SVCAM-1 by 1.7 times and SlCAM-1 by 2 times (p<0.001), increase of endothelin level by 1.7 times as well as the initial low VEGF-A (pg/ml) by 1.5 times (p<0.01). CONCLUSION: The developed physiotherapeutic complex, which includes laser acupuncture physiotherapy and induced technique of 5% piracetam iontophoresis, can potentially be considered as a physioprophylactic and therapeutic model of post-COVID edentulism.

Epinephrine iontophoresis attenuates changes in skin blood flow and abolishes cutaneous contamination of near-infrared diffuse correlation spectroscopy estimations of muscle perfusion.

Near-infrared diffuse correlation spectroscopy (NIR-DCS) is an optical imaging technique for measuring relative changes in skeletal muscle microvascular perfusion (i.e., fold change above baseline) during reactive hyperemia testing and exercise and is reported as a blood flow index (BFI). Although it is generally accepted that changes in BFI are primarily driven by changes in muscle perfusion, it is well known that large, hyperthermia-induced changes in cutaneous blood flow can uncouple this relationship. What remains unknown, is how much of an impact that changes in cutaneous perfusion have on NIR-DCS BFI and estimates of skeletal muscle perfusion under thermoneutral conditions, where changes in cutaneous blood flow are assumed to be relatively low. We therefore used epinephrine iontophoresis to pharmacologically block changes in cutaneous perfusion throughout a battery of experimental procedures. The data show that 1) epinephrine iontophoresis attenuates changes in cutaneous perfusion for up to 4-h posttreatment, even in the face of significant neural and local stimuli, 2) under thermoneutral conditions, cutaneous perfusion does not significantly impact NIR-DCS BFI during reactive hyperemia testing or moderate-intensity exercise, and 3) during passive whole body heat stress, when cutaneous vasodilation is pronounced, epinephrine iontophoresis preserves NIR-DCS measures of skeletal muscle BFI during moderate-intensity exercise. Collectively, these data suggest that cutaneous perfusion is unlikely to have a major impact on NIR-DCS estimates of skeletal muscle BFI under thermoneutral conditions, but that epinephrine iontophoresis can be used to abolish cutaneous contamination of the NIR-DCS BFI signal during studies where skin blood flow may be elevated but skeletal muscle perfusion is of specific interest.

Transdermal iontophoretic application of l-NAME is available in sweating research induced by heat stress in young healthy adults.

Iontophoretic transdermal administration of NG-nitro-l-arginine methyl ester hydrochloride [l-NAME, a nitric oxide synthase (NOS) inhibitor] has been used as a non-invasive evaluation of NOS-dependent mechanisms in human skin. However, the availability has yet to be investigated in sweating research. Prior observations using invasive techniques (e.g., intradermal microdialysis technique) to administer l-NAME have implicated that NOS reduces sweating induced by heat stress but rarely influences the response induced by the administration of cholinergic muscarinic receptor agonists. Therefore, we investigated whether the transdermal iontophoretic administration of l-NAME modulates sweating similar to those prior observations. Twenty young healthy adults (10 males, 10 females) participated in two experimental protocols on separate days. Before each protocol, saline (control) and 1% l-NAME were bilaterally administered to the forearm skin via transdermal iontophoresis. In protocol 1, 0.001% and 1% pilocarpine were iontophoretically administered at l-NAME-treated and untreated sites. In protocol 2, passive heating was applied by immersing the lower limbs in hot water (43 °C) until the rectal temperature increased by 0.8 °C above baseline. The sweat rate was continuously measured throughout both protocols. Pilocarpine-induced sweat rate was not significantly different between the control and l-NAME-treated sites in both pilocarpine concentrations (P ≥ 0.316 for the treatment effect and interaction of treatment and pilocarpine concentration). The sweat rate during passive heating was attenuated at the l-NAME-treated site relative to the control (treatment effect, P = 0.020). Notably, these observations are consistent with prior sweating studies administrating l-NAME into human skin using intradermal microdialysis techniques. Based on the similarity of our results with already known observations, we conclude that transdermal iontophoresis of l-NAME is a valid non-invasive technique for the investigation of the mechanisms of sweating related to NOS during heat stress.

Microneedle Mediated Iontophoretic Delivery of Tofacitinib Citrate.

PURPOSE: To investigate in vitro transdermal delivery of tofacitinib citrate across human skin using microporation by microneedles and iontophoresis alone and in combination. METHODS: In vitro permeation studies were conducted using vertical Franz diffusion cells. Microneedles composed of polyvinyl alcohol and carboxymethyl cellulose were fabricated and successfully characterized using scanning electron microscopy. The microchannels created were further characterized using histology, dye binding study, scanning electron microscopy, and confocal microscopy studies. The effect of microporation on delivery of tofacitinib citrate was evaluated alone and in combination with iontophoresis. In addition, the effect of current density on iontophoretic delivery was also investigated. RESULTS: Total delivery of tofacitinib citrate via passive permeation was found out to be 11.04 ± 1 µg/sq.cm. Microporation with microneedles resulted in significant enhancement where a 28-fold increase in delivery of tofacitinib citrate was observed with a total delivery of 314.7±33.32 µg/sq.cm. The characterization studies confirmed the formation of microchannels in the skin where successful disruption of stratum corneum was observed after applying microneedles. Anodal iontophoresis at 0.1 and 0.5 mA/sq.cm showed a total delivery of 18.56 µg/sq.cm and 62.07 µg/sq.cm, respectively. A combination of microneedle and iontophoresis at 0.5 mA/sq.cm showed the highest total delivery of 566.59 µg/sq.cm demonstrating a synergistic effect. A sharp increase in transdermal flux was observed for a combination of microneedles and iontophoresis. CONCLUSION: This study demonstrates the use of microneedles and iontophoresis to deliver a therapeutic dose of tofacitinib citrate via transdermal route.

Iontophoresis on Porcine and Human Gingiva.

PURPOSE: Iontophoresis is a noninvasive method that enhances drug delivery using an electric field. This method can improve drug delivery to the tissues in the oral cavity. The effects of iontophoresis on gingival drug delivery have not been investigated. The objectives of this study were to (a) determine the flux enhancement of model permeants across porcine and human gingiva during iontophoresis, (b) examine the transport mechanisms of gingival iontophoresis, and (c) evaluate the potential of iontophoretically enhanced delivery for three model drugs lidocaine, ketorolac, and chlorhexidine. METHODS: Passive and iontophoretic fluxes were determined with porcine and human gingiva using a modified Franz diffusion cell and model drugs and permeants. To investigate the transport mechanisms of iontophoresis, the enhancement from the direct-field effect was determined by positively and negatively charged model permeants. The electroosmosis enhancement effect was determined with neutral permeants of different molecular weight. The alteration of the gingival barrier due to electropermeabilization was evaluated using electrical resistance measurements. RESULTS: Significant flux enhancement was observed during gingival iontophoresis. The direct-field effect was the major mechanism governing the iontophoretic transport of the charged permeants. Electroosmosis was from anode to cathode. The effective pore radius of the iontophoretic transport pathways in the porcine gingiva was ~0.68 nm. Irreversible electropermeabilization was observed after 2 and 4 h of iontophoresis under the conditions studied. CONCLUSION: Iontophoresis could enhance drug delivery and reduce transport lag time, showing promise for gingival drug delivery.

Improved Transdermal Delivery of Rabies Vaccine using Iontophoresis Coupled Microneedle Approach.

AIM: This study was aimed to develop rabies vaccine incorporated microneedle (MN) patches and evaluate the immunogenicity of prepared formulations in combination with iontophoresis. METHODS: Patches comprising of polyvinyl pyrrolidone, hyaluronic acid and polyethylene glycol 400 were engineered by vacuum micromolding technique. Physical evaluation of patches included determination of folding endurance, % swelling and morphological features. In vitro release study was performed in skin simulant agarose gel using model drug (methylene blue) loaded patches. In vitro insertion ability was assessed using stratum corneum simulant parafilm. In vivo insertion study was performed in rats. Immunogenicity was evaluated in dogs by determining immunoglobulin G (IgG) and rabies virus neutralizing antibodies (RVNA) titer. RESULTS: Patches displayed uniformly distributed microprojections with pointed tips and smooth surface, ~ 70% swelling, remained intact for ~ 200 foldings and successfully penetrated the parafilm. The area covered by model drug across agarose gel was almost double following treatment with MN-iontophoresis combination (MNdi) compared to MN alone (MNdo). Histological examination of rat skin treated with vaccine laden MN (MNvo) and MN-iontophoresis combination (MNvi) confirmed the formation of grooves in epidermis without any damage to the deep vasculature. A ~ 73% and ~ 206% increase (compared to untreated counterpart) was observed in the IgG titer of MNvo and MNvi treated dogs, respectively. The RVNA titer was increased by ~ 1.2 and ~ 2.2 times (compared to threshold value) after MNvo and MNvi treatment, respectively. CONCLUSION: MN-iontophoresis combination provided relatively potent immunogenic response over the conventional intramuscular injection, hence, can be used for administering vaccines transcutaneously.

Reversible skin microvascular hyporeactivity in patients with immune-mediated thrombocytopenic thrombotic purpura.

BACKGROUND: Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare disease characterized by arteriolar and capillary microthrombosis precipitating organ failure. However, the contribution of endothelial dysfunction on impaired microvascular blood flow in iTTP patients has been poorly explored. This pilot observational study aimed to explore endothelial-mediated vasoreactivity in iTTP patients at admission and its changes after plasma exchange therapy (PE). METHODS: We conducted a prospective observational study in patients (> 18-year old) admitted in ICU for iTTP. Using laser Doppler flowmetry and acetylcholine (Ach) iontophoresis in the forearm, we recorded the skin microvascular blood flow and the endothelium-mediated vasoreactivity at admission and after PE. Demographics, biological, clinical courses, and outcomes were also collected. As a control group, we used a previously published cohort of young diabetic patients after correction of ketoacidosis. RESULTS: Eighteen confirmed iTTP patients and 34 controls were included in the study, mainly female (72%) aged 43 ± 16-year-old. At admission, 55% had neurological abnormalities, 50% cardiac issues and 27.8% an acute kidney injury. Median platelet count was 19 G/mL [10-37]. Baseline microvascular blood flow was decreased in iTTP patients when compared to controls (5.97 ± 4.5 vs. 10.1 ± 6.3 PU, P = 0.03), associated with markedly impaired endothelial-mediated skin microvascular reactivity (AUC: 9627 ± 8122 vs. 16,475 ± 11,738, P = 0.03). Microvascular reactivity improved after the first PE session (AUC: 9627 ± 8122 vs 16,558 ± 10,699, P = 0.007, respectively, baseline and post-PE1) and much more after the second session (26,431 ± 23,181, P = 0.04 post-PE1 vs post-PE2). Hemolysis biomarkers (LDH and bilirubin) negatively correlated with skin microvascular flow and vasoreactivity. CONCLUSION: We highlighted a marked yet reversible skin endothelium-mediated microvascular hyporeactivity in iTTP patients that could participate in organ injury pathophysiology.

The Effect of Iontophoretic-Delivered Polyplex Vaccine on Melanoma Regression.

Although the strategy in cancer vaccination is to provide a therapeutic effect against an established tumor, there is an urgent need to develop prophylactic vaccines for non-viral cancers. In this study, we prepared polyplex nanoparticles through electrostatic interactions between a positively-charged modified tumor associated antigen, namely human derived melanoma gp10025-33 peptide (KVPRNQDWL-RRRR), and a negatively charged cytosine-phosphate-guanosine motif (CpG-ODN) adjuvant. We previously demonstrated successful transdermal delivery of various hydrophilic macromolecules by iontophoresis (IP) using weak electricity. Herein, we investigated the effectiveness of IP in the transdermal delivery of a prophylactic polyplex vaccine. IP was successful in establishing a homogenous distribution of the vaccine throughout skin. Efficacy of the vaccine was demonstrated against melanoma growth. A significant tumor regression effect was observed, which was confirmed by elevated mRNA expression levels of various cytokines, mainly interferon (IFN)-γ, as well as infiltration of cytotoxic CD8+ T cells. Additionally, we evaluated the therapeutic effect of the vaccine and we found a significant reduction in tumor burden. Stimulation of systemic immunity was confirmed by upregulation of IFN-γ. This is the first report to demonstrate the use of IP in the transdermal delivery of a prophylactic melanoma vaccine.

Predicting the Safety of Ocular Iontophoresis Using Reconstructed Human Corneal Epithelial Cells.

We aimed to investigate eye damage caused by ocular iontophoresis (IP) based on an in vitro eye irritation test using a reconstructed human corneal cell. In this study, the LabCyte CORNEA-MODEL was selected as the reconstructed corneal cell. The test procedure was performed according to Test Guideline No.492 of the Organisation for Economic Co-operation and Development, which was partially revised for the IP. From the relationship between the cell viability of the cornea model and the electric field intensity [current density (mA/cm2) × application time (min)] of the IP, we predicted that the intensity values of 465 mA/cm2 × min and 930 mA/cm2 × min caused reversible eye irritation and irreversible eye damage, respectively. However, further studies are required to improve the accuracy and reproducibility of the prediction. This report provides essential knowledge on the clinical safety of ocular IP.

Non-invasive Intradermal Delivery of Hyaluronic Acid via Iontophoresis.

Hyaluronic acid (HA) is a hydrophilic supra-macromolecule, with a molecular weight (MW) 1000000<. HA is recognized as a biomaterial for skin moisturization. HA solution is typically injected into the skin using a needle. However, needle injection is invasive and does not result in homogeneous distribution of HA over a large area of skin. Therefore, non-invasive and effective technologies for homogenous intradermal delivery of HA are needed. Recently, we demonstrated the use of iontophoresis (ItP) for non-invasive intradermal delivery of various macromolecules, such as small interfering RNA (siRNA) (MW: 12000) and antibodies (MW: 150000). Based on our previous studies, we hypothesized that HA can also be delivered non-invasively into the skin by ItP. In this study, we applied ItP to fluorescence-labeled HA (MW: 600000-1120000 and 1200000-1600000) on rat dorsal skin. Following treatment, fluorescence was observed to be widely distributed in the skin, demonstrating successful intradermal delivery of HA via ItP. In addition, the relative moisture content and elasticity of skin treated with ItP/HA was temporarily higher than that of control skin. This is the first report demonstrating successful non-invasive intradermal delivery of HA and improvement of skin conditions by high-molecular weight HA delivered by ItP. In conclusion, ItP would be a useful technology for non-invasive intradermal delivery of high-molecular weight HA for treatment of skin diseases and cosmetology applications.

Use of Iontophoresis Technology for Transdermal Delivery of a Minimal mRNA Vaccine as a Potential Melanoma Therapeutic.

mRNA vaccines have attracted considerable attention as a result of the 2019 coronavirus pandemic; however, challenges remain regarding use of mRNA vaccines, including insufficient delivery owing to the high molecular weights and high negative charges associated with mRNA. These characteristics of mRNA vaccines impair intracellular uptake and subsequent protein translation. In the current study, we prepared a minimal mRNA vaccine encoding a tumor associated antigen human gp10025-33 peptide (KVPRNQDWL), as a potential treatment for melanoma. Minimal mRNA vaccines have recently shown promise at improving the translational process, and can be prepared via a simple production method. Moreover, we previously reported the successful use of iontophoresis (IP) technology in the delivery of hydrophilic macromolecules into skin layers, as well as intracellular delivery of small interfering RNA (siRNA). We hypothesized that combining IP technology with a newly synthesized minimal mRNA vaccine can improve both transdermal and intracellular delivery of mRNA. Following IP-induced delivery of a mRNA vaccine, an immune response is elicited resulting in activation of skin resident immune cells. As expected, combining both technologies led to potent stimulation of the immune system, which was observed via potent tumor inhibition in mice bearing melanoma. Additionally, there was an elevation in mRNA expression levels of various cytokines, mainly interferon (IFN)-γ, as well as infiltration of cytotoxic CD8+ T cells in the tumor tissue, which are responsible for tumor clearance. This is the first report demonstrating the application of IP for delivery of a minimal mRNA vaccine as a potential melanoma therapeutic.

Is it safe for patients with metal implants to have iontophoresis treatment?

BACKGROUND: Iontophoresis passes electrical charge through skin to deliver drugs or reduce excessive sweating. Treatments can be performed by patients at home following initial instruction. A limitation of the technique is that patients are not permitted to have metal implants. These are hypothesized to increase the risk of electric shock, cause localized heating and/or corrosion. OBJECTIVES: To investigate whether metallic materials (titanium, stainless steel and copper) placed in the iontophoresis circuit would lead to an unfavourable outcome regarding corrosion or local heating of the metallic object. METHODS: This was carried out using mass loss and temperature change experiments, together with atomic force microscopy for stainless steel, to assess any surface roughness changes. The investigations were carried out under accelerated conditions (70 V compared with standard use 20-30 V). RESULTS: No changes in mass or clinically significant changes in temperature of any of the metallic objects (or surface roughness for stainless steel) were observed. CONCLUSIONS: This study suggests that patients with these metallic implants can safely undergo iontophoresis treatment. Further work is needed to review the impact on metallic implants with repeated exposure to the iontophoresis system to represent real-world evidence.

Development of a Semi-Dry Method for Measuring Drug Permeation into Skin Using an Electric Facial Care Device and Iontophoresis.

INTRODUCTION: Percutaneous drug delivery systems are attractive not only as a therapeutic strategy but also for cosmetic treatment. Iontophoresis is a well-recognized method for promoting transdermal absorption of ionized compounds. Franz cells are generally used to estimate drug permeation of skin by iontophoresis. However, methods using Franz cells are less versatile; for instance, the method is unsuited for use with a portable electric facial care device having a working probe of a certain size and weight. In this study, we constructed a semi-dry apparatus for use with an electric facial care device. METHODS: The apparatus has a multilayer structure consisting of mouse skin and 3 filter papers, modeled after the Franz cell. The skin permeation of the drug edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) was then measured using this apparatus. RESULTS: Edaravone permeation depended on working time, drug concentration, and ionization ratio of edaravone when iontophoresis was carried out with an electric facial care device. Furthermore, glycyrrhizic acid, α-tocopheryl phosphate, retinoic acid, and ascorbyl palmitate, which are recognized as functional cosmetic materials, also permeated the skin by applying iontophoresis with the device. CONCLUSION: These results suggest that the developed measuring apparatus is applicable for use with a portable electric facial care device and that iontophoresis using a portable electric facial care device is potentially useful in the cosmetic field.

The effect of lidocaine iontophoresis for the treatment of tinnitus: a systematic review.

PURPOSE: Tinnitus is a common symptom with multiple causes and treatment options. Previous studies have investigated the effect of lidocaine iontophoresis. The aim of this review is to systematically present the effects on tinnitus and to derive possible effects. METHODS: In accordance to the PRISMA statement, the search and analysis were performed. An abstract in German or English and a performed intervention with lidocaine iontophoresis for the treatment of tinnitus, independent of the study design, were considered as inclusion criteria. Due to the heterogeneity of the studies, only a narrative synthesis was performed. RESULTS: The search yielded 179 studies of which 170 were excluded. Six full-texts and three abstracts were included. In total, 957 patients were treated with lidocaine iontophoresis. The percent improvement in symptoms after lidocaine iontophoresis ranged from 4% to 62%. The qualitative assessment of the studies resulted in an overall "weak" rating for all of them. CONCLUSIONS: Due to the heterogeneity and the limited quality of the studies found, no clear statement can be made about the efficacy. The number of those who benefited from therapy varied widely. In addition, it cannot be ruled out that the effect was merely due to electrical stimulation of the cochlea.