A Fully Integrated Closed-Loop System Based on Mesoporous Microneedles-Iontophoresis for Diabetes Treatment.

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.

Transdermal electroosmotic flow generated by a porous microneedle array patch.

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 / O2 battery) is also demonstrated as a possible totally organic iontophoresis patch.

Ultrasonically and Iontophoretically Enhanced Drug-Delivery System Based on Dissolving Microneedle Patches.

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.

Skin blood flow response to topically applied methyl nicotinate: Possible mechanisms.

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.

Development of Pyro-Drive Jet Injector With Controllable Jet Pressure.

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.

Wearable biosensors for healthcare monitoring.

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.

Enhanced Transdermal Drug Delivery by Sonophoresis and Simultaneous Application of Sonophoresis and Iontophoresis.

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.

Use of iontophoresis for the treatment of cancer.

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.

Longitudinal observations using simultaneous fMRI, multiple channel electrophysiology recording, and chemical microiontophoresis in the rat brain.

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.

Ocular drug delivery targeted by iontophoresis in the suprachoroidal space using a microneedle.

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.

The Application of SUDOSCAN for Screening Diabetic Peripheral Neuropathy in Chinese Population.

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.

Assessment of trans-scleral iontophoresis delivery of lutein to the human retina.

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/mm2 ) of treated samples was 1.3 times greater than controls (3.7 ± 1.0 ng/mm2 ; 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.

Integrated sudomotor axon reflex sweat stimulation for continuous sweat analyte analysis with individuals at rest.

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.

Valor de los parámetros de EZSCAN para el cribado de diabetes en la población china / Value of EZSCAN parameters for diabetes screening in Chinese

Objetivo: Estudiar los parámetros de EZSCAN como herramienta de cribado de la diabetes en la población china. Métodos: En el estudio participaron 6.270 sujetos. A todos ellos se les realizó la prueba EZSCAN, la prueba de fasting plasma glucose (FPG, «glucosa plasmática en ayunas»), el test de tolerancia oral de la glucosa y HbA1c. Resultados: 1. Se dividió a los sujetos en 4 grupos: el grupo normal, el grupo de riesgo bajo, formado por sujetos con anomalías metabólicas del azúcar, el grupo de riesgo medio y el grupo de alto riesgo. La diferencia en cuanto a incidencia de diabetes entre los 4 grupos fue estadísticamente significativa. Con el incremento de la puntuación EZSCAN, la prevalencia de diabetes se incrementó significativamente. Pero no se produjo diferencia estadísticamente significativa entre el grupo de bajo riesgo y el de riesgo medio. 2. Tras ajustar otras variables, se produjo una relación significativamente positiva entre la puntuación de riesgo EZSCAN y el riesgo de diabetes, mientras que no se produjo una diferencia estadísticamente significativa entre el grupo de bajo riesgo y el de riesgo medio. 3. El punto de corte de EZSCAN para la diabetes fue del 44,5%, con una sensibilidad del 73,2%, que fue superior a FPG y HbA1c. Conclusión:A medida que aumenta la puntuación de riesgo de diabetes EZSCAN, se incrementa el riesgo de la enfermedad. EZSCAN puede utilizarse como herramienta de cribado de la diabetes. Con un valor de punto de corte para el cribado de la diabetes del 44,5%, la sensibilidad es superior a la de los métodos tradicionales FPG y HbA1c (AU)

Objective: To study the parameters of EZSCAN as a screening tool for diabetes in Chinese. Methods: A total of 6,270 subjects participated in the study. All subjects underwent tests of EZSCAN, fasting plasma glucose (FPG), oral glucose tolerance test and HbA1c. Results: 1. All subjects were divided into 4 groups: the normal group, sugar metabolic abnormalities as low-risk group, middle-risk group and high-risk group. The difference of diabetes incidence among the 4 groups was statistically significant. With the increase of EZSCAN score, the prevalence of diabetes increased significantly. But there is no statistically difference between the low-risk group and the middle-risk group. 2. After adjustment for other variables, there is significantly positive relationship among EZSCAN risk score and the risk of diabetes. Meanwhile there is no statistically difference between the low-risk group and the middle-risk group. 3. The cut-off point of EZSCAN for diabetes was 44.5% with the sensitivity was 73.2% which was higher than of FPG and HbA1c. Conclusion: As EZSCAN-diabetes risk score increases, the risk of diabetes increases. EZSCAN can be used as a tool for screening for diabetes. At the best screening diabetes cut-off point value 44.5%, the sensitivity is higher than traditional method of FPG and HbA1c (AU)

Autonomous sweat extraction and analysis applied to cystic fibrosis and glucose monitoring using a fully integrated wearable platform.

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.

Transdermal reverse iontophoresis: A novel technique for therapeutic drug monitoring.

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.

Physical Medicine Devices; Reclassification of Iontophoresis Device Intended for Any Other Purposes. Final order.

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.

Iontophoretic device delivery for the localized treatment of pancreatic ductal adenocarcinoma.

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.

Design and functionality of a smart fentanyl iontophoretic transdermal system for the treatment of moderate-to-severe postoperative pain.

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.

Effect of potassium present in stratum corneum during non-invasive measurement of potassium in human subjects using reverse iontophoresis.

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.