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Competing Interests: Conflicts of interest None disclosed.

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-1β) 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., (© 2024 The Author(s). Skin Research and Technology published by John Wiley & Sons Ltd.)

A closed-loop system that can mini-invasively track blood glucose and intelligently treat diabetes is in great demand for modern medicine, yet it remains challenging to realize. Microneedles technologies have recently emerged as powerful tools for transdermal applications with inherent painlessness and biosafety. In this work, for the first time to the authors' knowledge, a fully integrated wearable closed-loop system (IWCS) based on mini-invasive microneedle platform is developed for in situ diabetic sensing and treatment. The IWCS consists of three connected modules: 1) a mesoporous microneedle-reverse iontophoretic glucose sensor; 2) a flexible printed circuit board as integrated and control; and 3) a microneedle-iontophoretic insulin delivery component. As the key component, mesoporous microneedles enable the painless penetration of stratum corneum, implementing subcutaneous substance exchange. The coupling with iontophoresis significantly enhances glucose extraction and insulin delivery and enables electrical control. This IWCS is demonstrated to accurately monitor glucose fluctuations, and responsively deliver insulin to regulate hyperglycemia in diabetic rat model. The painless microneedles and wearable design endows this IWCS as a highly promising platform to improve the therapies of diabetic patients., (© 2021 The Authors. Advanced Science published by Wiley-VCH GmbH.)

A microneedle array is an attractive option for a minimally invasive means to break through the skin barrier for efficient transdermal drug delivery. Here, we report the applications of solid polymer-based ion-conductive porous microneedles (PMN) containing interconnected micropores for improving iontophoresis, which is a technique of enhancing transdermal molecular transport by a direct current through the skin. The PMN modified with a charged hydrogel brings three innovative advantages in iontophoresis at once: (1) lowering the transdermal resistance by low-invasive puncture of the highly resistive stratum corneum, (2) transporting of larger molecules through the interconnected micropores, and (3) generating electroosmotic flow (EOF). In particular, the PMN-generated EOF greatly enhances the transdermal molecular penetration or extraction, similarly to the flow induced by external pressure. The enhanced efficiencies of the EOF-assisted delivery of a model drug (dextran) and of the extraction of glucose are demonstrated using a pig skin sample. Furthermore, the powering of the PMN-based transdermal EOF system by a built-in enzymatic biobattery (fructose / O 2 battery) is also demonstrated as a possible totally organic iontophoresis patch.

Background: Methyl nicotinate (MN) induces a local cutaneous erythema in the skin and may be valuable as a local provocation in the assessment of microcirculation and skin viability. The mechanisms through which MN mediates its vascular effect are not fully known. The aim of this study was to characterize the vasodilatory effects of topically applied MN and to study the involvement of nitric oxide (NO), local sensory nerves, and prostaglandin-mediated pathways., Methods: MN was applied on the skin of healthy subjects in which NO-mediated (L-NMMA), nerve-mediated (lidocaine/prilocaine), and cyclooxygenase-mediated (NSAID) pathways were selectively inhibited. Microvascular responses in the skin were measured using laser speckle contrast imaging (LSCI)., Results: NSAID reduced the MN-induced perfusion increase with 82% (P < .01), whereas lidocaine/prilocaine reduced it with 32% (P < .01). L-NMMA did not affect the microvascular response to MN., Conclusion: The prostaglandin pathway and local sensory nerves are involved in the vasodilatory actions of MN in the skin., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

A multifunctional system comprised of hyaluronic acid microneedles was developed as an effective transdermal delivery platform for rapid local delivery. The microneedles can regulate the filling amount on the tip, by controlling the concentration of hyaluronic acid solution. Ultrasonication induces dissolution of the HA microneedles via vibration of acoustic pressure, and AC iontophoresis improves the electrostatic force-driven diffusion of HA ions and rhodamine B. The effect of ultrasound on rhodamine release was analyzed in vitro using a gelatin hydrogel. The frequency and voltage dependence of the AC on the ion induction transfer was also evaluated experimentally. The results showed that the permeability of the material acts as a key material property. The delivery system based on ultrasonication and iontophoresis in microneedles increases permeation, thus resulting in shorter initial delivery time than that required by delivery systems based on passive or ultrasonication alone. This study highlights the significance of the combination between ultrasonic waves and iontophoresis for improving the efficiency of the microneedles, by shortening the reaction duration. We anticipate that this system can be extended to macromolecular and dependence delivery, based on drug response time.

Various jet injectors have been developed and used for the effective and efficient administration of drugs. Jet injections overcome the limitations of other drug delivery methods, such as ablation, iontophoresis, electroporation, sonophoresis, and microneedles, because jet injection is not limited by the diffusion rates of different drugs. However, controlling the jet pressure during drug delivery is difficult with most conventional jet injectors. Efficacy evaluation of such devices on laboratory animals is strongly required before initiating human clinical trials, but minimal research has been performed for the device developments. Therefore, we developed jet injector devices based on pyrotechnics using 2 types of explosives with different burning rates; we call these pyro-drive jet injectors. The liquid jet pressure profile suggests that the penetration depth and injection volume for soft materials and skin tissue are controllable. Here, we propose the pyro-drive jet injectors as another candidate well-controlled jet injector for laboratory animals in drug discovery testing as well as human clinical use., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Wearable biosensors are garnering substantial interest due to their potential to provide continuous, real-time physiological information via dynamic, noninvasive measurements of biochemical markers in biofluids, such as sweat, tears, saliva and interstitial fluid. Recent developments have focused on electrochemical and optical biosensors, together with advances in the noninvasive monitoring of biomarkers including metabolites, bacteria and hormones. A combination of multiplexed biosensing, microfluidic sampling and transport systems have been integrated, miniaturized and combined with flexible materials for improved wearability and ease of operation. Although wearable biosensors hold promise, a better understanding of the correlations between analyte concentrations in the blood and noninvasive biofluids is needed to improve reliability. An expanded set of on-body bioaffinity assays and more sensing strategies are needed to make more biomarkers accessible to monitoring. Large-cohort validation studies of wearable biosensor performance will be needed to underpin clinical acceptance. Accurate and reliable real-time sensing of physiological information using wearable biosensor technologies would have a broad impact on our daily lives.

Transdermal drug delivery has advantages of topical drug administration compared to the other conventional administration methods. However, the skin penetration of drugs is limited by the barrier properties of stratum corneum. The combinational strategy has been investigated to improve the skin permeability of the drug. For this study, we devised an improved device that can perform not only the single application of sonophoresis or iontophoresis but also the simultaneous application. The enhancement effect of sonophoresis was evaluated for various cosmeceutical drugs using a Franz diffusion cell. The enhancement ratio of niacinamide and retinol with sonophoresis was increased to 402% and 292%, respectively. The relationship was found between the enhancement effect of sonophoresis and the physicochemical properties of drugs. In particular, the simultaneous treatment of sonophoresis and iontophoresis enhanced skin penetration of glutamic acid to 240% using the fabricated device. The simultaneous application showed significantly higher enhancement ratio than application of sonophoresis or iontophoresis alone. Moreover, the improved device achieved skin penetration enhancement of various cosmeceutical drugs with lower intensity and a short application time. This combined strategy of transdermal physical enhancement methods is advantageous in terms of decline in energy density, thereby reducing the skin irritation. The miniaturized device with sonophoresis and iontophoresis is a promising approach due to enhanced transdermal drug delivery and feasibility of self-administration in cosmetic and therapeutic fields.

Purpose: Diabetic peripheral neuropathies are the common chronic complications of diabetes, but the diagnosis is insensitive by physical examination in busy outpatients. Here we evaluated the performance of SUDOSCAN in screening diabetic peripheral neuropathies in Chinese type 2 diabetic patients., Methods: The study enrolled 180 patients for annually screening. All patients underwent neurological symptoms assessment, clinical examination, nerve conduction studies and cardiovascular autonomic reflex tests. SUDOSCAN was tested and evaluated with electrochemical skin conductance in hands and feet, asymmetry ratio in hands and feet and predicted cardiac neuropathy., Results: Patients enrolled had an average age of 56.1 years, 9.8 years of diabetic duration. Patients with diabetic sensorimotor polyneuropathy showed significantly lower electrochemical skin conductance in feet and higher asymmetry ratio in feet compared with those without. Sensitivity and specificity of asymmetry ratio in feet for diagnosing diabetic sensorimotor polyneuropathy were 88.2% and 46.9% and area under ROC curve was 0.713. Patients with cardiovascular autonomic neuropathy showed significantly lower electrochemical skin conductance in hands and feet, and higher asymmetry ratio in feet and predicted cardiac neuropathy compared with those without. Sensitivity and specificity of electrochemical skin conductance in feet in diagnosing cardiovascular autonomic neuropathy were 85.6% and 76.1% with an area under ROC curve of 0.859., Conclusions: SUDOSCAN is a sensitive test to detect diabetic peripheral neuropathy in China and could be an effective screening tool in in busy outpatients and primary health care., Competing Interests: The authors declare that they have no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Despite major advancements in cancer treatments, there are still many limitations to therapy including off-target effects, drug resistance, and control of cancer-related symptoms. There are opportunities for local drug delivery devices to intervene at various stages of cancer to provide curative and palliative benefit. Iontophoretic devices that deliver drugs locally to a region of interest have been adapted for the treatment of cancer. These devices have shown promise in pre-clinical and clinical studies for retinoblastoma, skin, bladder, and pancreatic cancers. Herein, we review iontophoretic devices used in the management of cancer., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: fMRI blood oxygenation level-dependent (BOLD) signal has been widely used as a surrogate for neural activity. However, interpreting differences in BOLD fMRI based on underlying neuronal activity remains a challenge. Concurrent rsMRI data collection and electrophysiological recording in combination with microiontophoretically injected modulatory chemicals allows for improved understanding of the relationship between resting state BOLD and neuronal activity., New Methods: Simultaneous fMRI, multi-channel intracortical electrophysiology and focal pharmacological manipulation data to be acquired longitudinally in rats for up to 2 months. Our artifact replacing technique is optimized for combined LFP and rsMRI data collection., Results: Intracortical implantation of a multichannel microelectrode array resulted in minimal distortion and signal loss in fMRI images inside a 9.4T MRI scanner. rsMRI-induced electrophysiology artifacts were replaced using an in-house developed algorithm. Microinjection of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) enhanced dopaminergic neuronal activity in the ventral tegmental area (VTA) and altered LFP signal and fMRI functional connectivity in the striatum., Comparisons With Existing Method(s): Nanomanufacturing advances permit the production of MRI-compatible microelectrode arrays (with 16 or more channels), extending research beyond conventional methods limited to fewer channels. Our method permits longitudinal data collection of LFP and rsMRI and our algorithm effectively detects and replaces fMRI-induced electrophysiological noise, permitting rsMRI data collection concomitant with LFP recordings., Conclusions: Our model consists of longitudinal concurrent fMRI and multichannel intracortical electrophysiological recording during microinjection of pharmacological agents to modulate neural activity in the rat brain. We used commercial micro-electrodes and recording system and can be readily generalized to other labs., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Treatment of many posterior-segment ocular indications would benefit from improved targeting of drug delivery to the back of the eye. Here, we propose the use of iontophoresis to direct delivery of negatively charged nanoparticles through the suprachoroidal space (SCS) toward the posterior pole of the eye. Injection of nanoparticles into the SCS of the rabbit eye ex vivo without iontophoresis led to a nanoparticle distribution mostly localized at the site of injection near the limbus and <15% of nanoparticles delivered to the most posterior region of SCS (>9 mm from the limbus). Iontophoresis using a novel microneedle-based device increased posterior targeting with >30% of nanoparticles in the most posterior region of SCS. Posterior targeting increased with increasing iontophoresis current and increasing application time up to 3 min, but further increasing to 5 min was not better, probably due to the observed collapse of the SCS within 5 min after injection ex vivo. Reversing the direction of iontophoretic flow inhibited posterior targeting, with just ~5% of nanoparticles reaching the most posterior region of SCS. In the rabbit eye in vivo, iontophoresis at 0.14 mA for 3 min after injection of a 100 μL suspension of nanoparticles resulted in ~30% of nanoparticles delivered to the most posterior region of the SCS, which was consistent with ex vivo findings. The procedure was well tolerated, with only mild, transient tissue effects at the site of injection. We conclude that iontophoresis in the SCS using a microneedle has promise as a method to target ocular drug delivery within the eye, especially toward the posterior pole., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The efficacy of novel scleral iontophoresis device for in situ delivery of lutein to the human retina was assessed by Resonance Raman spectroscopy (RRS) technique. Eight human donor eye globes were used for experiments, 6 of which underwent trans-scleral iontophoresis delivery of lutein and the other 2 were used as controls. The scleral iontophoresis applicator was filled with liposome-enriched 0.1% lutein solution and the generator's current was set at 2.5 mA and delivered for 4 min. A custom RRS setup was used for detecting lutein in the inner sclera, choroid, retinal periphery and macula of treated samples and controls. Forty minutes after iontophoresis, the inner sclera, choroid and retinal periphery were greatly enriched with lutein (P < .05); no lutein was found in the same ocular regions of non-treated samples. In the same period, the average concentration of lutein in the macula (4.8 ± 1.7 ng/mm 2 ) of treated samples was 1.3 times greater than controls (3.7 ± 1.0 ng/mm 2 ; P = .4). Scleral iontophoresis was shown to be effective in delivering lutein to the human retina. Future studies will aim at assessing if this therapeutic strategy is valuable to enrich the macular pigment in human subjects., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Eccrine sweat has rapidly emerged as a non-invasive, ergonomic, and rich source of chemical analytes with numerous technological demonstrations now showing the ability for continuous electrochemical sensing. However, beyond active perspirers (athletes, workers, etc.), continuous sweat access in individuals at rest has hindered the advancement of both sweat sensing science and technology. Reported here is integration of sudomotor axon reflex sweat stimulation for continuous wearable sweat analyte analysis, including the ability for side-by-side integration of chemical stimulants & sensors without cross-contamination. This integration approach is uniquely compatible with sensors which consume the analyte (enzymatic) or sensors which equilibrate with analyte concentrations. In vivo validation is performed using iontophoretic delivery of carbachol with ion-selective and impedance sensors for sweat analysis. Carbachol has shown prolonged sweat stimulation in directly stimulated regions for five hours or longer. This work represents a significant leap forward in sweat sensing technology, and may be of broader interest to those interested in on-skin sensing integrated with drug-delivery.

Perspiration-based wearable biosensors facilitate continuous monitoring of individuals' health states with real-time and molecular-level insight. The inherent inaccessibility of sweat in sedentary individuals in large volume (≥10 µL) for on-demand and in situ analysis has limited our ability to capitalize on this noninvasive and rich source of information. A wearable and miniaturized iontophoresis interface is an excellent solution to overcome this barrier. The iontophoresis process involves delivery of stimulating agonists to the sweat glands with the aid of an electrical current. The challenge remains in devising an iontophoresis interface that can extract sufficient amount of sweat for robust sensing, without electrode corrosion and burning/causing discomfort in subjects. Here, we overcame this challenge through realizing an electrochemically enhanced iontophoresis interface, integrated in a wearable sweat analysis platform. This interface can be programmed to induce sweat with various secretion profiles for real-time analysis, a capability which can be exploited to advance our knowledge of the sweat gland physiology and the secretion process. To demonstrate the clinical value of our platform, human subject studies were performed in the context of the cystic fibrosis diagnosis and preliminary investigation of the blood/sweat glucose correlation. With our platform, we detected the elevated sweat electrolyte content of cystic fibrosis patients compared with that of healthy control subjects. Furthermore, our results indicate that oral glucose consumption in the fasting state is followed by increased glucose levels in both sweat and blood. Our solution opens the possibility for a broad range of noninvasive diagnostic and general population health monitoring applications., Competing Interests: The authors declare no conflict of interest.

Application of transdermal reverse iontophoresis for diagnostic purpose is a relatively new concept but its short span of research is full of ups and downs. In early nineties, when the idea was floated, it received a dubious welcome by the scientific community. Yet to the disbelief of many, 2001 saw the launching of GlucoWatch® G2 Biographer, the first device that could measure the blood sugar level noninvasively. Unfortunately, the device failed to match the expectation and was withdrawn in 2007. However, the concept stayed on. Research on reverse iontophoresis has diversified in many fields. Numerous in vitro and in vivo experiments confirmed the prospect of reverse iontophoresis as a noninvasive tool in therapeutic drug monitoring and clinical chemistry. This review provides an overview about the recent developments in reverse iontophoresis in the field of therapeutic drug monitoring., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The Food and Drug Administration (FDA) is issuing a final order to reclassify iontophoresis devices intended for any other purposes, which are preamendments class III devices (regulated under product code EGJ), into class II (special controls) and to amend the device identification to clarify that devices intended to deliver specific drugs are not considered part of this regulatory classification.

Fentanyl iontophoretic transdermal system (ITS) is a patient-controlled analgesia system used for the management of acute postoperative pain. The first-generation fentanyl ITS was an integrated one-piece system; however, corrosion that could limit reliability was detected in a small number of systems. A second-generation fentanyl ITS was designed to separate the hydrogels in the Drug Unit from the electronic circuit of the Controller during manufacture and storage, removing the primary cause of corrosion and thereby improving reliability. No evidence of corrosion has been observed in over 10,000 systems tested in real-time aging studies for the second generation fentanyl ITS. The second generation fentanyl ITS design features combine to ensure safe operation of the system with high reliability.

Poor delivery and systemic toxicity of many cytotoxic agents, such as the recent promising combination chemotherapy regimen of folinic acid (leucovorin), fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX), restrict their full utility in the treatment of pancreatic cancer. Local delivery of chemotherapies has become possible using iontophoretic devices that are implanted directly onto pancreatic tumors. We have fabricated implantable iontophoretic devices and tested the local iontophoretic delivery of FOLFIRINOX for the treatment of pancreatic cancer in an orthotopic patient-derived xenograft model. Iontophoretic delivery of FOLFIRINOX was found to increase tumor exposure by almost an order of magnitude compared with i.v. delivery with substantially lower plasma concentrations. Mice treated for 7 wk with device FOLFIRINOX experienced significantly greater tumor growth inhibition compared with i.v. FOLFIRINOX. A marker of cell proliferation, Ki-67, was stained, showing a significant reduction in tumor cell proliferation. These data capitalize on the unique ability of an implantable iontophoretic device to deliver much higher concentrations of drug to the tumor compared with i.v. delivery. Local iontophoretic delivery of cytotoxic agents should be considered for the treatment of patients with unresectable nonmetastatic disease and for patients with the need for palliation of local symptoms, and may be considered as a neoadjuvant approach to improve resection rates and outcome in patients with localized and locally advanced pancreatic cancer.

Purpose: Reverse iontophoresis (RI) is one of the potential techniques used to monitor the concentration of various analytes in body fluids non-invasively. Transdermal extraction of potassium is investigated using RI. In the present work, the effect of potassium on stratum corneum (SC) during RI, feasibility of RI for continuous monitoring of potassium, and use of potassium as internal standard in RI, are investigated., Methods: Tape stripping experiment is carried out to find potassium concentration in SC. RI is carried out continuously for 180 min without passive diffusion and after passive diffusion for 60 min. Skin impedance measurements are done at 20 Hz and 20 kHz., Results: Potassium is found to be in the range 300-650 nmol/cm(2) on SC by tape stripping experiment. Correlation coefficient between blood potassium and extracted potassium through RI after passive diffusion (R(2) = 0.5870) is more than without passive diffusion (R(2) = 0.5117). The skin impedance measurement shows that RI has more effect on SC than superficial layer of SC during RI., Conclusion: The present investigations conclude that it is possible to monitor potassium continuously through RI and using potassium as internal standard in RI., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: To determine the optimal electric current intensity of fluoride iontophoresis (FI) for remineralisation of early caries lesions in vitro., Materials and Methods: Sixty specimens were made from bovine incisors and immersed in a demineralising gel for 96 h. Specimens were divided into control (conventional fluoride application) and experimental (FI) groups. All of the specimens were covered with fluoride for 4 min every day. Different electric current intensities (100, 200, 300 and 400 μA) were applied in the FI groups using the FI device. The concentration of KOH-soluble fluoride was determined to evaluate the amount of CaF2 formed on the tooth surface. The reduction in lesion depth was measured by polarised light microscopy., Results: The concentration of KOH-soluble fluoride was the highest in the specimens of the 300 μA FI group. However, there was no significant difference in the reduction of lesion depth between the experimental groups and the control group., Conclusion: Variations in the electric current intensity influenced the amount of CaF2 formed on the enamel surface, with the greatest amount found for 300 μA.

Patient-controlled analgesia (PCA) is regularly used to manage pain following major surgery. The fentanyl hydrochloride iontophoretic transdermal system (ITS) was developed to overcome some of the limitations of intravenous (IV) PCA. The small, self-adhesive, needle-free disposable system is applied to the skin on the upper arm or chest and is controlled by patients clicking a button on the device. The authors identified patients who were underwent spinal surgery from 2 prior multicenter, randomized studies and analyzed their data. Of the 1296 patients in the original trials, 170 underwent spine surgery procedures: 90 were randomized to the fentanyl ITS (40 mcg/activation) and 80 to IV PCA morphine (1 mg/dose). More patients treated with the fentanyl ITS rated their method of pain control as "excellent" across all time points, but differences did not reach statistical significance. However, investigators' ratings of "excellent" satisfaction with study treatment were significantly higher for the fentanyl ITS. Discontinuation rates and overall adverse event rates were similar between groups. The only significant difference was that patients treated with the fentanyl ITS had a higher rate of application site reactions than infusion site reactions in the IV PCA morphine group; the reactions were typically mild-to-moderate erythema that resolved shortly after removal of the fentanyl ITS device and did not require further treatment. Ratings of satisfaction with pain control method were consistently higher for the fentanyl ITS than the IV PCA morphine. The 2 groups had a similar safety profile. These results suggest that the fentanyl ITS appears to be a safe, efficacious alternative to IV PCA in spine surgery patients., (Copyright 2015, SLACK Incorporated.)

We present a proof-of-concept demonstration of an all-printed temporary tattoo-based glucose sensor for noninvasive glycemic monitoring. The sensor represents the first example of an easy-to-wear flexible tattoo-based epidermal diagnostic device combining reverse iontophoretic extraction of interstitial glucose and an enzyme-based amperometric biosensor. In-vitro studies reveal the tattoo sensor's linear response toward physiologically relevant glucose levels with negligible interferences from common coexisting electroactive species. The iontophoretic-biosensing tattoo platform is reduced to practice by applying the device on human subjects and monitoring variations in glycemic levels due to food consumption. Correlation of the sensor response with that of a commercial glucose meter underscores the promise of the tattoo sensor to detect glucose levels in a noninvasive fashion. Control on-body experiments demonstrate the importance of the reverse iontophoresis operation and validate the sensor specificity. This preliminary investigation indicates that the tattoo-based iontophoresis-sensor platform holds considerable promise for efficient diabetes management and can be extended toward noninvasive monitoring of other physiologically relevant analytes present in the interstitial fluid.

The skin has evolved to resist the penetration of foreign substances and particles. Effective topical drug delivery into and/or through the skin is hindered by these epidermal barriers. A range of physical enhancement methods has been developed to selectively overcome this barrier. This review discusses recent advances in physical drug delivery by broadly separating the techniques into two main areas; indirect and direct approaches. Indirect approaches consist of electrical, vibrational or laser instrumentation that creates pores in the skin followed by application of the drug. Direct approaches consist of mechanical disruption of the epidermis using techniques such as microdermabrasion, biolistic injectors and microneedles. Although, in general, physical techniques are yet to be established in a clinical setting, the potential gains of enhancing delivery of compounds through the skin is of great significance and will no doubt continue to receive much attention.

The aims of this study were to investigate the most effective combination of physical forces from laser, electroporation, and reverse iontophoresis for noninvasive transdermal extraction of uric acid, and to develop a highly sensitive uric acid biosensor (UAB) for quantifying the uric acid extracted. It is believed that the combination of these physical forces has additional benefits for extraction of molecules other than uric acid from human skin. A diffusion cell with porcine skin was used to investigate the most effective combination of these physical forces. UABs coated with ZnO₂ nanoparticles and constructed in an array configuration were developed in this study. The results showed that a combination of laser (0.7 W), electroporation (100 V/cm(2)), and reverse iontophoresis (0.5 mA/cm(2)) was the most effective and significantly enhanced transdermal extraction of uric acid. A custom-designed UAB coated with ZnO₂ nanoparticles and constructed in a 1×3 array configuration (UAB-1×3-ZnO₂) demonstrated enough sensitivity (9.4 μA/mM) for quantifying uric acid extracted by the combined physical forces of laser, electroporation, and RI. A good linear relationship (R(2)=0.894) was demonstrated to exist between the concentration of uric acid (0.2-0.8 mM) inside the diffusion cell and the current response of the UAB-1×3-ZnO₂. In conclusion, a new approach to noninvasive transdermal extraction and quantification of uric acid has been established.

Iontophoresis (IOP) is a noninvasive method of delivering medication transcutaneously through the skin. The electrodes used in this method should tightly fit to rough and irregular surfaces and be biologically safe, easy to handle and prepare, and cost-effective. To satisfy these requirements, calcium alginate gel can be a candidate electrode for IOP. Using calcium alginate gel electrodes, we examined whether lidocaine can be effectively transported across an excised rat skin by squarewave alternating current (AC) application. A squarewave AC with either a 70% or 80% duty cycle was continuously applied to 0.5% calcium alginate gel electrodes containing 10% lidocaine at 10 V and 1 kHz for 60 min. Lidocaine concentration was measured using a spectrophotometer and the temperature of the gel was determined. The lidocaine concentrations for AC-IOP at the 70% and 80% duty cycles were significantly higher than that without AC-IOP. Furthermore, the group with the 80% duty cycle showed higher lidocaine concentrations than the group with the 70% duty cycle. The temperatures of all the groups were lower than 28 °C throughout the procedure. In conclusion, the calcium alginate gel can be used as a possible matrix for IOP electrodes.

It has recently been proposed that the combination of skin barrier impairment using microneedles (MNs) coupled with iontophoresis (ITP) may broaden the range of drugs suitable for transdermal delivery as well as enabling the rate of delivery to be achieved with precise electronic control. However, few reports exist on the combination of ITP with in situ drug-loaded polymeric MN delivery systems. Our in vitro permeation studies revealed that MN enhances transdermal drug delivery. The combination of dissolving MN and ITP did not further enhance the extent of delivery of the low molecular weight drug ibuprofen sodium after short application periods. However, the extent of peptide/protein delivery was significantly enhanced when ITP was used in combination with hydrogel-forming MN arrays. As such, hydrogel-forming MN arrays show promise for the electrically controlled transdermal delivery of biomacromolecules in a simple, one-step approach, though further technical developments will be necessary before patient benefit is realized.

Objectives: We describe a new iontophoresis solution, used in conjunction with a new iontophoresis system for achieving anesthesia of the tympanic membrane before myringotomy and insertion of pressure equalization tubes in an office setting., Methods: We selected 50 patients (86 ears) who met standard indications for myringotomy only or myringotomy and pressure equalization tube insertion for a single-site consecutive series trial (Institutional Review Board-approved; informed consent and assent) in the authors' clinical practice. Topical anesthesia was obtained with a new US Food and Drug Administration-cleared iontophoresis system (Acclarent, Inc, Menlo Park, California) and a novel iontophoresis solution mixture. The Wong-Baker FACES Pain Rating Scale was used to assess the tolerability of the iontophoresis system with the new solution and of the otologic procedure after topical anesthesia was obtained., Results: Iontophoresis success was obtained in 78 of 86 ears (90.7%). The average pain score for patients after iontophoresis was 1.07 on a 0-to-5 scale of increasing pain. The ear treatment was successful in 70 of 78 ears (89.7%). The average pain score for the surgical procedure was 1.19., Conclusions: This study demonstrates the safety and clinical effectiveness of the Acclarent iontophoresis system in conjunction with a new iontophoresis solution for anesthesia of the tympanic membrane in an office setting. This solution and device enable otologic procedures in children as young as 12 months of age without the use of a papoose, premedication, or general anesthesia.

Technological advances in drug discovery have resulted in increasing number of molecules including proteins and peptides as drug candidates. However, how to deliver drugs with satisfactory therapeutic effect, minimal side effects and increased patient compliance is a question posted before researchers, especially for those drugs with poor solubility, large molecular weight or instability. Microfabrication technology, polymer science and bioconjugate chemistry combine to address these problems and generate a number of novel engineered drug delivery systems. Injection routes usually have poor patient compliance due to their invasive nature and potential safety concerns over needle reuse. The alternative non-invasive routes, such as oral, mucosal (pulmonary, nasal, ocular, buccal, rectal, vaginal), and transdermal drug delivery have thus attracted many attentions. Here, we review the applications of the novel engineered systems for oral, mucosal and transdermal drug delivery.

The optimized preparation of Poly-(lactide-co-glycolic acid) (PLGA) nanospheres containing ubiquinone (UQ) for cosmetic products was pursued. By investigating various conditions for the preparation of UQ/PLGA nanospheres such as the molecular weight of PLGA, PLGA concentration, and UQ concentration, UQ/PLGA nanospheres with increased stability and slower drug release at a higher drug loading efficiency were prepared. Permeation tests on the prepared nanospheres using iontophoresis via electric dermal administration on membrane filters (200 nm pore size) and hairless mouse skin samples were also carried out. After iontophoresis, the nanospheres choked the membrane filter and remained on the horny layer of the hairless mouse skin, even after washing. Therefore, the prepared UQ/PLGA nanospheres and the established iontophoresis technique with the PLGA nanospheres in the present study can be applied to the future development of cosmetics.

Background: Palmar hyperhidrosis is characterized by excessive sweating on the palm. Although botulinum toxin is effective and safe treatment for palmar hyperhidrosis, some patients require inexpensive, easy-to-use therapeutic modalities., Objective: To evaluate the efficacy and safety of a portable "dry-type" iontophoretic device for treatment of palmar hyperhidrosis., Participants: Twenty-three volunteers with idiopathic palmar hyperhidrosis were enrolled; 20 completed the study., Methods: Participants were instructed to grasp the device with the left palm for 20 minutes once a day for 4 weeks. Follow-up evaluation was conducted during 4 weeks after termination of the treatment session. Sweat intensity, Investigator Global Assessment (IGA), patient satisfaction assessment (PSA), and hydration capacitance were measured for evaluation of efficacy. Adverse effects were investigated for evaluation of safety., Results: Statistically significantly greater improvement in IGA and hydration capacitance was achieved in the treated palm than in the untreated palm. Improvement in sweat intensity and PSA was not statistically significantly different in the treated and untreated palms. Two cases of mild local adverse effects were noted., Conclusion: The device is an effective therapeutic modality for palmar hyperhidrosis in addition to local injection of botulinum toxin, endoscopic sympathectomy, and conventional iontophoretic treatments., (© 2013 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc.)

Purpose: Iontophoretic mediated transdermal delivery of ferric pyrophosphate (FPP) in combination with microneedle pretreatment was investigated as a potential treatment for iron deficiency anemia (IDA)., Methods: In vitro transdermal delivery studies were performed using hairless rat skin and pharmacodynamic studies were performed in hairless anemic rat model. The hematological and biochemical parameters like hemoglobin, hematocrit and % serum transferrin were monitored in rats at healthy, anemic condition and post treatment. Micropores created by the microneedles were visualized in histological skin sections after staining with hemotoxylin and eosin. The recovery of micropores was investigated in vivo by measuring Transepidermal water loss (TEWL) at different time points., Results: The passive, microneedle and iontophoresis mediated delivery did not lead to significant improvement in hematological and biochemical parameters in anemic rats, when used individually. When iontophoresis (0.15 mA/cm(2) for 4 hours) was combined with microneedle pretreatment (for 2 min), therapeutically adequate amount of FPP was delivered and there was significant recovery of rats from IDA., Conclusions: Microneedle and iontophoresis mediated delivery of iron via transdermal route could be developed as a potential treatment for IDA. The transdermal controlled delivery of iron could become a potential, safe and effective alternative to parenteral iron therapy.

In vivo recordings from single neurons allow an investigator to examine the firing properties of neurons, for example in response to sensory stimuli. Neurons typically receive multiple excitatory and inhibitory afferent and/or efferent inputs that integrate with each other, and the ultimate measured response properties of the neuron are driven by the neural integrations of these inputs. To study information processing in neural systems, it is necessary to understand the various inputs to a neuron or neural system, and the specific properties of these inputs. A powerful and technically relatively simple method to assess the functional role of certain inputs that a given neuron is receiving is to dynamically and reversibly suppress or eliminate these inputs, and measure the changes in the neuron's output caused by this manipulation. This can be accomplished by pharmacologically altering the neuron's immediate environment with piggy-back multibarrel electrodes. These electrodes consist of a single barrel recording electrode and a multibarrel drug electrode that can carry up to 4 different synaptic agonists or antagonists. The pharmacological agents can be applied iontophoretically at desired times during the experiment, allowing for time-controlled delivery and reversible reconfiguration of synaptic inputs. As such, pharmacological manipulation of the microenvironment represents a powerful and unparalleled method to test specific hypotheses about neural circuit function. Here we describe how piggy-back electrodes are manufactured, and how they are used during in vivo experiments. The piggy-back system allows an investigator to combine a single barrel recording electrode of any arbitrary property (resistance, tip size, shape etc) with a multibarrel drug electrode. This is a major advantage over standard multi-electrodes, where all barrels have more or less similar shapes and properties. Multibarrel electrodes were first introduced over 40 years ago, and have undergone a number of design improvements until the piggy-back type was introduced in the 1980s. Here we present a set of important improvements in the laboratory production of piggy-back electrodes that allow for deep brain penetration in intact in vivo animal preparations due to a relatively thin electrode shaft that causes minimal damage. Furthermore these electrodes are characterized by low noise recordings, and have low resistance drug barrels for very effective iontophoresis of the desired pharmacological agents.

The purpose of this study was to determine the effect of microneedle (MN) technology and its combination with iontophoresis (ITP) on the in vivo transdermal delivery of salmon calcitonin (sCT). Maltose MNs (500 µm) were used to porate skin prior to application of the drug, with or without ITP. Micropores created by maltose MNs were characterized by histological sectioning and calcein imaging studies, which indicated uniformity of the created micropores. In vivo studies were performed in hairless rats to assess the degree of enhancement achieved by ITP (0.2 mA/cm² for 1 h), MNs (81 MNs), and their combination. In vivo studies indicate a serum maximal concentration of 0.61 ± 0.42 ng/mL, 1.79 ± 0.72 ng/mL, and 5.51 ± 0.32 ng/mL for ITP, MNs, and combination treatment, respectively. MN treatment alone increased serum concentration 2.5-fold and the combination treatment increased the concentration ninefold as compared with iontophoretic treatment alone. Combination treatment of ITP and MNs resulted in the highest delivery of sCT and therapeutic levels were achieved within 5 min of administration., (Copyright © 2012 Wiley Periodicals, Inc.)

The main objective of the present study was to investigate the plausibility of iontophoretic delivery of drugs to the nail matrix via proximal nail fold. The in vitro drug transport studies were performed in Franz diffusion cells across folded epidermis, which is used as a model for the proximal nail fold. The amount of drug transported into the receiver compartment following iontophoresis for 3 h at 0.5 mA/cm(2) was 150-fold higher than the control (0.008 ± 0.002 μg/cm(2)). The amount of drug present in the skin after iontophoresis (0.45 ± 0.12 μg/mg) was approximately fivefold higher as compared with that of the control (0.08 ± 0.01 μg/mg). Iontophoresis of terbinafine across the proximal nail fold was assessed using excised cadaver toe model as well. A custom-designed foam-pad-type patch system was used for iontophoresis in cadaver toes. The amount of the drug delivered into the nail matrix following iontophoresis for 3 h was significantly higher than the minimum inhibition concentration of terbinafine. However, on the contrary, passive delivery for about 24 h did not result in any detectable drug levels in the nail matrix. Iontophoresis across the proximal nail fold could be developed as a potential method to target drugs to nail matrix., (Copyright © 2012 Wiley Periodicals, Inc.)

Calcium alginate gel has some unique properties, such as the capability to keep the drugs, bioadhesiveness, safety, and low cost. The purpose of this study is to determine whether calcium alginate gel can be used as a matrix of electrodes for iontophoresis (IOP). We measured the concentration of lidocaine transported from calcium alginate gels with various concentrations of alginic acid using an in vitro experimental cell with square-wave alternating current (AC) application. Temperature and pH changes were also determined during AC-IOP. The results revealed that lidocaine was released from calcium alginate gels at concentrations nearly 1.71-fold larger at 5 V, 60 min after AC application than in the case of passive diffusion. Lidocaine transport depended on the alginic acid concentration in the gels. Although there were slight increases in temperature and pH, chemical and thermal burns were not severe enough to be a concern. In conclusion, the calcium alginate gel can be used as a possible matrix for IOP electrodes.

Aim: The feasibility of transdermal delivery of naloxone, an opioid antagonist, by anodal iontophoresis patches using Ag/AgCl electrodes was investigated., Methods: To examine the effect of current strength, species variation and drug concentration on skin permeability of naloxone, in vitro skin permeation studies were performed using rat dorsal skin and porcine ear skin as the membrane. To determine in vivo transdermal absorption rate of naloxone, the iontophoretic patch system was applied to the dorsal skin of conscious rat with a constant current supply for 24h., Results: The in vitro steady-state skin permeation flux of naloxone current-proportionally (0-360 μA/cm(2)) increased without significant differences between these two different skin types. The in vitro delivery rate through the porcine skin was found to be independent of the concentration of naloxone hydrochloride dehydrate in the donor patch over the range from 1 to 10% (w/v). In the in vivo pharmacokinetic study, plasma concentrations of naloxone steadily increased and sustained steady-state levels from 4h to 24h after the initiation of current application. In vivo steady-state transdermal absorption rates at 90 and 180 μA/cm(2) were 136 and 305 μg/h/cm(2), respectively., Conclusion: These results suggest that the transdermal delivery rates of naloxone by anodal iontophoresis are sufficient for the management of intoxication in opioid-overdosed patients., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: Monitoring of biomarkers, like urea, prostate-specific antigen (PSA), and osteopontin, is very important because they are related to kidney disease, prostate cancer, and ovarian cancer, respectively. It is well known that reverse iontophoresis can enhance transdermal extraction of small molecules, and even large molecules if reverse iontophoresis is used together with electroporation. Electroporation is the use of a high-voltage electrical pulse to create nanochannels within the stratum corneum, temporarily and reversibly. Reverse iontophoresis is the use of a small current to facilitate both charged and uncharged molecule transportation across the skin. The objectives of this in vitro study were to determine whether PSA and osteopontin are extractable transdermally and noninvasively and whether urea, PSA, and osteopontin can be extracted simultaneously by electroporation and reverse iontophoresis., Methods: All in vitro experiments were conducted using a diffusion cell assembled with the stratum corneum of porcine skin. Three different symmetrical biphasic direct currents (SBdc), five various electroporations, and a combination of the two techniques were applied to the diffusion cell via Ag/AgCl electrodes. The three different SBdc had the same current density of 0.3 mA/cm(2), but different phase durations of 0 (ie, no current, control group), 30, and 180 seconds. The five different electroporations had the same pulse width of 1 msec and number of pulses per second of 10, but different electric field strengths of 0 (ie, no voltage, control group), 74, 148, 296, and 592 V/cm. Before and after each extraction experiment, skin impedance was measured at 20 Hz., Results: It was found that urea could be extracted transdermally using reverse iontophoresis alone, and further enhancement of extraction could be achieved by combined use of electroporation and reverse iontophoresis. Conversely, PSA and osteopontin were found to be extracted transdermally only by use of reverse iontophoresis and electroporation with a high electrical field strength (> 296 V/cm). After application of reverse iontophoresis, electroporation, or a combination of the two techniques, a reduction in skin impedance was observed., Conclusion: Simultaneous transdermal extraction of urea, PSA, and osteopontin is possible only for the condition of applying reverse iontophoresis in conjunction with high electroporation.

A new type of electrochemical transdermal patch has been investigated using release/permeation experiments with excised nude mouse skin. The patch comprises a drug-containing hydrogel sandwiched between two electrodes that are arranged parallel to the skin surface. The objective was to determine the mechanism of working of enhanced flux for the drug fentanyl when low voltages are applied. The results indicate that a voltage-induced hydrolysis of the water present in the patch's hydrogel occurs. This causes a pH shift that results in deprotonization of the fentanyl and hence enhanced release/permeation. The enhanced flux is up to approximately 30 μg/(cm(2) h) over 20 h and requires only a low-voltage application over a duration of just 60 s. Because the enhancement mechanism occurs in the patch and not in the skin, the potential for substantially reduced skin irritation compared with iontophoresis is given., (Copyright © 2011 Wiley-Liss, Inc.)

Background: EZSCAN(®) (Impeto Medical, Paris, France), a noninvasive device that assesses sweat gland dysfunction using reverse iontophoresis, also detects early dysglycemia. Given the interrelationships among dysglycemia, vasculopathy, and neuropathy, EZSCAN may detect kidney disease in diabetes (DKD)., Methods: An EZSCAN score (0-100) was calculated using a proprietary algorithm based on the chronoamperometry analysis. We measured the score in 50 Chinese type 2 diabetes patients without DKD (urinary albumin-creatinine ratio [ACR] <2.5 mg/mmol in men or ACR <3.5 mg/mmol in women and estimated glomerular filtration rate [eGFR] >90 mL/min/1.73 m(2)) and 50 with DKD (ACR ≥25 mg/mmol and eGFR <60 mL/min/1.73 m(2)). We used spline analysis to determine the threshold value of the score in detecting DKD and its sensitivity and specificity., Results: EZSCAN scores were highly correlated with log values of eGFR (r=0.67, P<0.0001) and ACR (r=-0.66, P<0.0001). Using a cutoff value of 55, the score had 94% sensitivity, 78% specificity, and a likelihood ratio of 4.2 to detect DKD with a positive predictive value of 81% and a negative predictive value of 93%. On multivariable analysis, DKD was independently associated with EZSCAN score (β=-0.72, P=0.02), smoking status (1=never, 0=current/former) (β=-2.37, P=0.02), retinopathy (1=yes, 0=no) (β=3.019, P=0.01), triglycerides (β=2.56, P=0.013), and blood hemoglobin (β=-0.613, P=0.04). Patients without DKD but low EZSCAN score (n=10) had longer duration of disease (median [interquartile range], 13 [9-17] vs. 8 [4-16] years; P=0.017) and were more likely to have retinopathy (36.7% vs. 5.1%, P=0.02), lower eGFR (98 [95.00-103] vs. 106 [98.5-115], P=0.036), and treatment with renin-angiotensin system blockers (81.8% vs. 25.6%, P=0.002) than those with a normal score., Conclusion: EZSCAN may detect high-risk subjects for DKD in Chinese populations.

Microiontophoresis entails passage of current through a micropipette tip to deliver a solute at a designated site within an experimental preparation. Microiontophoresis can simulate synaptic transmission by delivering neurotransmitters and neuropeptides onto neurons reproducibly. Negligible volume (fluid) displacement avoids mechanical disturbance to the experimental preparation. Adapting these techniques to the microcirculation has enabled mechanisms of vasodilation and vasoconstriction to be studied at the microscopic level in vivo. A key advantage of such localized delivery is enabling vasomotor responses to be studied at defined sites within a microvascular network without evoking systemic or reflexive changes in blood pressure and tissue blood flow, thereby revealing intrinsic properties of microvessels. A limitation of microiontophoresis is that the precise concentration of agent delivered to the site of interest is difficult to ascertain. Nevertheless, its release from the micropipette tip is proportional to the intensity and duration of the ejection current, such that reproducible stimulus-response relationships can be readily determined under defined experimental conditions (described below). Additional factors affecting microiontophoretic delivery include solute concentration and its ionization in solution. The internal diameter of the micropipette tip should be ˜ 1 μm or less to minimize diffusional 'leak', which can be counteracted with a retaining current. Thus an outward (positive) current is used to eject a cation and a negative current used to retain it within the micropipette. Fabrication of micropipettes is facilitated with sophisticated electronic pullers. Micropipettes are pulled from glass capillary tubes containing a filament that 'wicks' solution into the tip of the micropipette when filled from the back end ("backfilled"). This is done by inserting a microcapillary tube connected to a syringe containing the solution of interest and ejecting the solution into the lumen of the micropipette. Micromanipulators enable desired placement of micropipettes within the experimental preparation. Micromanipulators mounted on a movable base can be positioned around the preparation according to the topography of microvascular networks (developed below). The present protocol demonstrates microiontophoresis of acetylcholine (ACh(+) Cl(-)) onto an arteriole of the mouse cremaster muscle preparation (See associated protocol: JoVE ID#2874) to produce endothelium-dependent vasodilation. Stimulus delivery is synchronized with digitized image acquisition using an electronic trigger. The use of Cx40(BAC)-GCaMP2 transgenic mice enables visualization of intracellular calcium responses underlying vasodilation in arteriolar endothelial cells in the living microcirculation.

The fluxes of charged and nonionic molecules across hairless mouse skin (HMS) were induced by direct current iontophoresis and used to characterize the transport pathways of the epidermal membrane. Experimental data were used to determine permeability coefficients from which the effective pore radii (Rp) of the transport pathways were calculated. Permeants used in these experiments were nonionic permeants (urea, mannitol, and raffinose), monovalent cationic permeants (sodium, tetraethylammonium, and tetraphenylphosphonium ions), and monovalent anionic permeants (chloride, salicylate, and taurocholate ions). The Rp estimates obtained by the anionic permeant pairs were 49, 22, and 20 Å for the chloride/salicylate (Cl:SA), chloride/taurocholate (Cl:TC), and salicylate/taurocholate (SA:TC) pairs, respectively; with the cationic permeant pairs, the Rp values obtained were 19, 30, and 24 Å for the sodium/tetraethylammonium (Na:TEA), sodium/tetraphenylphosphonium (Na:TPP), and the tetraethylammonium/tetraphenylphosphonium (TEA:TPP) pairs, respectively. Rp estimates for HMS obtained from nonionic permeant experiments ranged from 6.7 to 13.4 Å. When plotted versus their respective diffusion coefficients, all of the permeability coefficients for the cationic permeants were greater than those of the anionic permeants. Additionally, the magnitudes of permeability coefficients determined in the current study with HMS were of the same order of magnitude as those previously determined in our laboratory using human epidermal membrane under similar iontophoresis conditions., (Copyright © 2011 Wiley-Liss, Inc.)

Transdermal iontophoresis is an active drug delivery method that has the potential to transform treatment of conditions such as acute pain that require a succession of on-demand metered-dose drug deliveries. However, current monophasic iontophoresis methods fail to meet these requirements due to their inability to halt the passive diffusion of active agents when therapy is not required. We have developed a biphasic iontophoretic system to overcome these limitations. The viability of this system was assessed in an in vitro porcine skin preparation using FeCl(2) (127 Daltons), a charged molecule which can undergo both active and passive transdermal diffusion. The transport properties of the system were modeled using a Fourier Transform-derived optimum estimate transfer function. Using this model, experimental results showed good correlation to predicted values for both cumulative dose (R(2)=0.912, n=10), and density dose (R(2)=0.802, n=10). Results also showed the ability to effectively deliver the compound during active periods while minimizing delivery during inactive periods. While preliminary, our results suggest biphasic iontophoresis is a viable means of delivering on-demand drug therapy while minimizing unwanted off-demand delivery.

Background: Cardiovascular and kidney diseases are a global public health problem and impose a huge economic burden on health care services. Homocysteine, an amino acid, is associated with coronary heart disease, while urea is a harmful metabolic substance which can be used to reflect kidney function. Monitoring of these two substances is therefore very important. This in vitro study aimed to determine whether homocysteine is extractable transdermally and noninvasively, and whether homocysteine and urea can be extracted simultaneously by reverse iontophoresis., Methods: A diffusion cell incorporated with porcine skin was used for all experiments with the application of a direct current (dc) and four different symmetrical biphasic direct currents (SBdc) for 12 minutes via Ag/AgCl electrodes. The dc and the SBdc had a current density of 0.3 mA/cm(2)., Results: The SBdc has four different phase durations of 15 sec, 30 sec, 60 sec, and 180 sec. It was found that homocysteine can be transdermally extracted by reverse iontophoresis. Simultaneous extraction of homocysteine and urea by reverse iontophoresis is also possible., Conclusion: These results suggest that extraction of homocysteine and urea by SBdc are phase duration-dependent, and the optimum mode for simultaneous homocysteine and urea extraction is the SBdc with the phase duration of 60 sec.

Aim: We wished to develop a new iontophoretic device suitable for the treatment of local bone loss such as after fractures or in osteodystrophy., Methods: The new iontophoretic apparatus consists of two parts. The first part consists of two natural-based, chemically modified particles as potential medicines, while the other part is a 3-electrode electrophoretic device based on a new principle. This device 'knocks out' Ca²(+) and PO₄ ³⁻ ions from the particles with its impulse-like positive and negative charges transmitted through its electrodes placed on the skin. The current and the voltage of the electrodes can be adjusted separately in both leads. Subsequently, these 'knocked out' ions are channelled into the porotic bones with the help of the 3rd-reference-electrode., Results: In our preliminary in vitro studies, we used porcine tissues to test their calcium and phosphate content after iontophoresis; with or without using molecules. This preliminary analysis revealed that both calcium and phosphate ions became incorporated into the bone. Some in vivo data are also presented. Iontophoretic treatment increased speed of sound (SOS) as determined by ultrasonography in ovariectomized rats., Conclusion: Our results suggest that topical iontophoresis may be suitable to treat local osteoporosis or bone defects., (Copyright © 2010 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.)

Purpose: The main objective of this study was to assess the flux enhancement of insulin transdermally by utilizing a complex of chemical enhancers in combination with modulated iontophoresis., Methods: The experiments were performed on porcine epidermis model under three different circumstances, namely, (a) 1-hour modulated iontophoresis alone; (b) pretreatment with vehicle and chemical enhancer combinations and (c) combination of (a) and (b). The mechanism of action of the enhancers was studied using infra-red spectra by derivative and curve-fitting techniques and Confocal laser scanning microscopy. The efficacy of the optimized combination was tested in vivo in streptozocin-diabetic Wistar rats., Results: A blend of 1,8 cineole, oleic acid and sodium deoxycholate in propylene glycol : ethanol (7:3) resulted in 45% enhancement, when permeation was performed in combination with iontophoresis as compared to the latter alone. In-depth analysis of infra-red spectra revealed that each of the enhancers acted differentially on lipid-protein domains of the stratum corneum thereby supporting the observed synergism. Movement of fluorescently labeled insulin depicted highlighted follicular regions and paracellular accumulation of the probe after iontophoresis and chemical enhancer treatment respectively. Presence of the fluorescent peptide in these regions 4 hour after treatment with the combination reinforced the results of the permeation studies. Finally the combination of modulated iontophoresis with chemical enhancer blend resulted in lowering of blood glucose for 8 hour in vivo., Conclusions: The study proved the applicability of modulated iontophoresis with chemical pretreatment in delivering insulin transdermally.

Iontophoretic and electroporation transdermal delivery modes of ionic drugs have been utilized in a number of clinical and biomedical devices. However, applications of these methods have been found challenging for the delivery of many non polar and high molecular weight clinically important drugs. The main goal of the present study is to investigate whether transdermal transport of non polar macromolecular drugs such as insulin and terbinafine can be safely enhanced as a result of their polarization and activation by AC electrokinetic forces. An in vitro delivery system was developed to simulate a clinical application, where transdermal non invasive delivery of medication through a biological membrane is motivated by a combination of AC electrokinetic and AC iontophoresis protocols generated on a device located external to the membrane. The developed method resulted in an average transdermal delivery of 57% of insulin and 39% of terbinafine during several minutes long delivery cycle, which is at least an order of magnitude improvement over the results reported for these drugs in the literature for various passive and active transdermal delivery protocols. For the proposed drug delivery model quantification of the amounts of transported drugs and their relationship to experimental parameters, such as AC voltage amplitude and frequency, treatment time, and membrane thickness were investigated. Experimental results validated a computational model simulating the effects of major electrokinetic forces on drug particle in non uniform AC electric field. The presented transdermal approach overcomes many limitations of existing drug delivery technologies, providing efficient, regulated, localized, non invasive and safe delivery method for high molecular weight non polar macromolecules such as insulin., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)

This study aims to develop an amperometric glucose biosensor, based on carbon nanotubes material for reverse iontophoresis, fabricated by immobilizing a mixture of glucose oxidase (GOD) and multiwalled carbon nanotubes (MWCNT) epoxy-composite, on a planar screen-printed carbon electrode. MWCNT was employed to ensure proper incorporation into the epoxy mixture and faster electron transfer between the GOD and the transducer. Results showed this biosensor possesses a low detection potential (+500 mV), good sensitivity (4 microA/mM) and an excellent linear response range (r(2) = 0.999; 0-4 mM) of glucose detection at +500 mV (versus Ag/AgCl). The response time of the biosensor was about 25 s. In addition, the biosensor could be used in conjunction with reverse iontophoresis technique. In an actual evaluation model, an excellent linear relationship (r(2) = 0.986) was found between the glucose concentration of the actual model and the biosensor's current response. Thus, a glucose biosensor based on carbon nanotube composites and incorporated with reverse iontophoresis function was developed.