Droplet-born air blowing: novel dissolving microneedle fabrication.

PubMed

Kim, Jung Dong; Kim, Miroo; Yang, Huisuk; Lee, Kwang; Jung, Hyungil

2013-09-28

The microneedle-mediated drug delivery system has been developed to provide painless self-administration of drugs in a patient-friendly manner. Current dissolving microneedle fabrication methods, however, require harsh conditions for biological drugs and also have problems standardizing the drug dose. Here, we suggested the droplet-born air blowing (DAB) method, which provides gentle (4-25 °C) and fast (≤10min) microneedle fabrication conditions without drug loss. The amount of drug in the microneedle can be controlled by the pressure and time of droplet dispenser and the air blowing shapes this droplet to the microneedle, providing a force sufficient to penetrate skin. Also, the introduction of a base structure of two layered DAB-microneedle could provide complete drug delivery without wasting of drug. The DAB-based insulin loaded microneedle shows similar bioavailability (96.6±2.4%) and down regulation of glucose level compared with subcutaneous injection. We anticipate that DAB described herein will be suitable to design dissolving microneedles for use in biological drug delivery to patients. Copyright © 2013 Elsevier B.V. All rights reserved.

Adenosine-loaded dissolving microneedle patches to improve skin wrinkles, dermal density, elasticity and hydration.

PubMed

Kang, G; Tu, T N T; Kim, S; Yang, H; Jang, M; Jo, D; Ryu, J; Baek, J; Jung, H

2018-04-01

Although dissolving microneedle patches have been widely studied in the cosmetics field, no comparisons have been drawn with the topical applications available for routine use. In this study, two wrinkle-improving products, adenosine-loaded dissolving microneedle patches and an adenosine cream, were evaluated for efficacy, with respect to skin wrinkling, dermal density, elasticity, and hydration, and safety in a clinical test on the crow's feet area. Clinical efficacy and safety tests were performed for 10 weeks on 22 female subjects with wrinkles around their eyes. The adenosine-loaded dissolving microneedle patch was applied once every 3 days, in the evening, for 8 weeks to the designated crow's feet area. The adenosine cream was applied two times per day, in the morning and evening, for 8 weeks to the other crow's feet area. Skin wrinkling, dermal density, elasticity, and hydration were measured by using PRIMOS ® premium, Dermascan ® C, Cutometer ® MPA580, and Corneometer ® CM 825, respectively. In addition, subjective skin irritation was evaluated by self-observation, and objective skin irritation was assessed through expert interviews. The adenosine-loaded dissolving microneedle patches had a similar or better efficacy than the adenosine cream. Both groups showed statistically significant efficacy for almost all parameters (P < 0.05). The dissolving microneedle patches had a long-lasting effect on the average wrinkle depth (P < 0.05), only showed efficacy in dermal density (P < 0.05), had an early improving effect on elasticity (P < 0.05), and demonstrated better hydration efficacy (P < 0.001). No adverse effects were observed in either group during the test period. In the clinical efficacy test of four skin-improvement parameters, adenosine-loaded dissolving microneedle patches showed the same or better effect than the adenosine cream, although the weekly adenosine dose was 140 times lower. The dissolving microneedle patches caused no adverse reactions. These adenosine-loaded dissolving microneedle patches are expected to be safe, effective, and novel cosmetics for skin improvement. © 2018 Society of Cosmetic Scientists and the Société Française de Cosmétologie.

Permeation of sumatriptan succinate across human skin using multiple types of self-dissolving microneedle arrays fabricated from sodium hyaluronate.

PubMed

Wu, Dan; Katsumi, Hidemasa; Quan, Ying-Shu; Kamiyama, Fumio; Kusamori, Kosuke; Sakane, Toshiyasu; Yamamoto, Akira

2016-09-01

Available formulations of sumatriptan succinate (SS) have low bioavailability or are associated with site reactions. We developed various types of self-dissolving microneedle arrays (MNs) fabricated from sodium hyaluronate as a new delivery system for SS and evaluated their skin permeation and irritation in terms of clinical application. In vitro permeation studies with human skin, physicochemical properties (needle length, thickness and density), and penetration enhancers (glycerin, sodium dodecyl sulfate and lauric acid diethanolamide) were investigated. SS-loaded high-density MNs of 800 µm in length were the optimal formulation and met clinical therapeutic requirements. Penetration enhancers did not significantly affect permeation of SS from MNs. Optical coherence tomography images demonstrated that SS-loaded high-density MNs (800 µm) uniformly created drug permeation pathways for the delivery of SS into the skin. SS-loaded high-density MNs induced moderate primary skin irritations in rats, but the skin recovered within 72 h of removal of the MNs. These findings suggest that high-density MNs of 800 µm in length are an effective and promising formulation for transdermal delivery of SS. To our knowledge, this is the first report of SS permeation across human skin using self-dissolving MNs.

Design of a Dissolving Microneedle Platform for Transdermal Delivery of a Fixed-Dose Combination of Cardiovascular Drugs.

PubMed

Quinn, Helen L; Bonham, Louise; Hughes, Carmel M; Donnelly, Ryan F

2015-10-01

Microneedles (MNs) are a minimally invasive drug delivery platform, designed to enhance transdermal drug delivery by breaching the stratum corneum. For the first time, this study describes the simultaneous delivery of a combination of three drugs using a dissolving polymeric MN system. In the present study, aspirin, lisinopril dihydrate, and atorvastatin calcium trihydrate were used as exemplar cardiovascular drugs and formulated into MN arrays using two biocompatible polymers, poly(vinylpyrrollidone) and poly(methylvinylether/maleic acid). Following fabrication, dissolution, mechanical testing, and determination of drug recovery from the MN arrays, in vitro drug delivery studies were undertaken, followed by HPLC analysis. All three drugs were successfully delivered in vitro across neonatal porcine skin, with similar permeation profiles achieved from both polymer formulations. An average of 126.3 ± 18.1 μg of atorvastatin calcium trihydrate was delivered, notably lower than the 687.9 ± 101.3 μg of lisinopril and 3924 ± 1011 μg of aspirin, because of the hydrophobic nature of the atorvastatin molecule and hence poor dissolution from the array. Polymer deposition into the skin may be an issue with repeat application of such a MN array, hence future work will consider more appropriate MN systems for continuous use, alongside tailoring delivery to less hydrophilic compounds. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

Design and physicochemical characterisation of novel dissolving polymeric microneedle arrays for transdermal delivery of high dose, low molecular weight drugs

PubMed Central

McCrudden, Maelíosa T.C.; Alkilani, Ahlam Zaid; McCrudden, Cian M.; McAlister, Emma; McCarthy, Helen O.; Woolfson, A. David; Donnelly, Ryan F.

2014-01-01

We describe formulation and evaluation of novel dissolving polymeric microneedle (MN) arrays for the facilitated delivery of low molecular weight, high dose drugs. Ibuprofen sodium was used as the model here and was successfully formulated at approximately 50% w/w in the dry state using the copolymer poly(methylvinylether/maleic acid). These MNs were robust and effectively penetrated skin in vitro, dissolving rapidly to deliver the incorporated drug. The delivery of 1.5 mg ibuprofen sodium, the theoretical mass of ibuprofen sodium contained within the dry MN alone, was vastly exceeded, indicating extensive delivery of the drug loaded into the baseplates. Indeed in in vitro transdermal delivery studies, approximately 33 mg (90%) of the drug initially loaded into the arrays was delivered over 24 h. Iontophoresis produced no meaningful increase in delivery. Biocompatibility studies and in vivo rat skin tolerance experiments raised no concerns. The blood plasma ibuprofen sodium concentrations achieved in rats (263 μg ml− 1 at the 24 h time point) were approximately 20 times greater than the human therapeutic plasma level. By simplistic extrapolation of average weights from rats to humans, a MN patch design of no greater than 10 cm2 could cautiously be estimated to deliver therapeutically-relevant concentrations of ibuprofen sodium in humans. This work, therefore, represents a significant progression in exploitation of MN for successful transdermal delivery of a much wider range of drugs. PMID:24556420

Predicting the optimal geometry of microneedles and their array for dermal vaccination using a computational model.

PubMed

Römgens, Anne M; Bader, Dan L; Bouwstra, Joke A; Oomens, Cees W J

2016-11-01

Microneedle arrays have been developed to deliver a range of biomolecules including vaccines into the skin. These microneedles have been designed with a wide range of geometries and arrangements within an array. However, little is known about the effect of the geometry on the potency of the induced immune response. The aim of this study was to develop a computational model to predict the optimal design of the microneedles and their arrangement within an array. The three-dimensional finite element model described the diffusion and kinetics in the skin following antigen delivery with a microneedle array. The results revealed an optimum distance between microneedles based on the number of activated antigen presenting cells, which was assumed to be related to the induced immune response. This optimum depends on the delivered dose. In addition, the microneedle length affects the number of cells that will be involved in either the epidermis or dermis. By contrast, the radius at the base of the microneedle and release rate only minimally influenced the number of cells that were activated. The model revealed the importance of various geometric parameters to enhance the induced immune response. The model can be developed further to determine the optimal design of an array by adjusting its various parameters to a specific situation.

Skin penetration of silicon dioxide microneedle arrays.

PubMed

Kim, Sangchae; Shetty, S; Price, D; Bhansali, S

2006-01-01

Out-of-plane hollow silicon dioxide microneedle arrays were fabricated and investigated to determine their efficacy for transdermal applications. The fabrication process of the SiO2 microneedles is described, and mechanical fracture forces were investigated on microneedles with different geometrical dimensions. Biomechanical characterization of the microneedles was performed to specifically test for reliable stratum corneum and skin insertion by changing the regulatory parameters such as needle width and cross-section.

Design, Optimization and Characterisation of Polymeric Microneedle Arrays Prepared by a Novel Laser-Based Micromoulding Technique

PubMed Central

Donnelly, Ryan F.; Majithiya, Rita; Singh, Thakur Raghu Raj; Morrow, Desmond I. J.; Garland, Martin J.; Demir, Yusuf K.; Migalska, Katarzyna; Ryan, Elizabeth; Gillen, David; Scott, Christopher J.; Woolfson, A. David

2010-01-01

Purpose Design and evaluation of a novel laser-based method for micromoulding of microneedle arrays from polymeric materials under ambient conditions. The aim of this study was to optimise polymeric composition and assess the performance of microneedle devices that possess different geometries. Methods A range of microneedle geometries was engineered into silicone micromoulds, and their physicochemical features were subsequently characterised. Results Microneedles micromoulded from 20% w/w aqueous blends of the mucoadhesive copolymer Gantrez® AN-139 were surprisingly found to possess superior physical strength than those produced from commonly used pharma polymers. Gantrez® AN-139 microneedles, 600 μm and 900 μm in height, penetrated neonatal porcine skin with low application forces (>0.03 N per microneedle). When theophylline was loaded into 600 μm microneedles, 83% of the incorporated drug was delivered across neonatal porcine skin over 24 h. Optical coherence tomography (OCT) showed that drug-free 600 μm Gantrez® AN-139 microneedles punctured the stratum corneum barrier of human skin in vivo and extended approximately 460 μm into the skin. However, the entirety of the microneedle lengths was not inserted. Conclusion In this study, we have shown that a novel laser engineering method can be used in micromoulding of polymeric microneedle arrays. We are currently carrying out an extensive OCT-informed study investigating the influence of microneedle array geometry on skin penetration depth, with a view to enhanced transdermal drug delivery from optimised laser-engineered Gantrez® AN-139 microneedles. PMID:20490627

Microneedles for drug and vaccine delivery

PubMed Central

Kim, Yeu-Chun; Park, Jung-Hwan; Prausnitz, Mark R.

2012-01-01

Microneedles were first conceptualized for drug delivery many decades ago, but only became the subject of significant research starting in the mid-1990’s when microfabrication technology enabled their manufacture as (i) solid microneedles for skin pretreatment to increase skin permeability, (ii) microneedles coated with drug that dissolves off in the skin, (iii) polymer microneedles that encapsulate drug and fully dissolve in the skin and (iv) hollow microneedles for drug infusion into the skin. As shown in more than 350 papers now published in the field, microneedles have been used to deliver a broad range of different low molecular weight drugs, biotherapeutics and vaccines, including published human studies with a number of small-molecule and protein drugs and vaccines. Influenza vaccination using a hollow microneedle is in widespread clinical use and a number of solid microneedle products are sold for cosmetic purposes. In addition to applications in the skin, microneedles have also been adapted for delivery of bioactives into the eye and into cells. Successful application of microneedles depends on device function that facilitates microneedle insertion and possible infusion into skin, skin recovery after microneedle removal, and drug stability during manufacturing, storage and delivery, and on patient outcomes, including lack of pain, skin irritation and skin infection, in addition to drug efficacy and safety. Building off a strong technology base and multiple demonstrations of successful drug delivery, microneedles are poised to advance further into clinical practice to enable better pharmaceutical therapies, vaccination and other applications. PMID:22575858

An update on coating/manufacturing techniques of microneedles.

PubMed

Tarbox, Tamara N; Watts, Alan B; Cui, Zhengrong; Williams, Robert O

2017-12-29

Recently, results have been published for the first successful phase I human clinical trial investigating the use of dissolving polymeric microneedles… Even so, further clinical development represents an important hurdle that remains in the translation of microneedle technology to approved products. Specifically, the potential for accumulation of polymer within the skin upon repeated application of dissolving and coated microneedles, combined with a lack of safety data in humans, predicates a need for further clinical investigation. Polymers are an important consideration for microneedle technology-from both manufacturing and drug delivery perspectives. The use of polymers enables a tunable delivery strategy, but the scalability of conventional manufacturing techniques could arguably benefit from further optimization. Micromolding has been suggested in the literature as a commercially viable means to mass production of both dissolving and swellable microneedles. However, the reliance on master molds, which are commonly manufactured using resource intensive microelectronics industry-derived processes, imparts notable material and design limitations. Further, the inherently multi-step filling and handling processes associated with micromolding are typically batch processes, which can be challenging to scale up. Similarly, conventional microneedle coating processes often follow step-wise batch processing. Recent developments in microneedle coating and manufacturing techniques are highlighted, including micromilling, atomized spraying, inkjet printing, drawing lithography, droplet-born air blowing, electro-drawing, continuous liquid interface production, 3D printing, and polyelectrolyte multilayer coating. This review provides an analysis of papers reporting on potentially scalable production techniques for the coating and manufacturing of microneedles.

Rapid fabrication of microneedles using magnetorheological drawing lithography.

PubMed

Chen, Zhipeng; Ren, Lei; Li, Jiyu; Yao, Lebin; Chen, Yan; Liu, Bin; Jiang, Lelun

2018-01-01

Microneedles are micron-sized needles that are widely applied in biomedical fields owing to their painless, minimally invasive, and convenient operation. However, most microneedle fabrication approaches are costly, time consuming, involve multiple steps, and require expensive equipment. In this study, we present a novel magnetorheological drawing lithography (MRDL) method to efficiently fabricate microneedle, bio-inspired microneedle, and molding-free microneedle array. With the assistance of an external magnetic field, the 3D structure of a microneedle can be directly drawn from a droplet of curable magnetorheological fluid. The formation process of a microneedle consists of two key stages, elasto-capillary self-thinning and magneto-capillary self-shrinking, which greatly affect the microneedle height and tip radius. Penetration and fracture tests demonstrated that the microneedle had sufficient strength and toughness for skin penetration. Microneedle arrays and a bio-inspired microneedle were also fabricated, which further demonstrated the versatility and flexibility of the MRDL method. Microneedles have been widely applied in biomedical fields owing to their painless, minimally invasive, and convenient operation. However, most microneedle fabrication approaches are costly, time consuming, involve multiple steps, and require expensive equipment. Furthermore, most researchers have focused on the biomedical applications of microneedles but have given little attention to the optimization of the fabrication process. This research presents a novel magnetorheological drawing lithography (MRDL) method to fabricate microneedle, bio-inspired microneedle, and molding-free microneedle array. In this proposed technique, a droplet of curable magnetorheological fluid (CMRF) is drawn directly from almost any substrate to produce a 3D microneedle under an external magnetic field. This method not only inherits the advantages of thermal drawing approach without the need for a mask and light irradiation but also eliminates the requirement for drawing temperature adjustment. The MRDL method is extremely simple and can even produce the complex and multiscale structure of bio-inspired microneedle. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Blood monitoring systems and methods thereof

NASA Technical Reports Server (NTRS)

Zander, Dennis (Inventor); Mir, Jose (Inventor)

2012-01-01

A blood monitoring system is capable of monitoring the blood of a subject in vivo. The blood monitoring system comprises: 1) an array of movable microneedle micromachined within associated wells; 2) array of motion actuators able to move each needle in and out of their associated wells; 3) array of microvalves associated with each microneedle able to control the flow of air around the microneedle; 4) an array of chemical sensors inserted into patient by movable microneedles; 5) an array of inductors able to measure chemical concentration in the vicinity of inserted chemical sensors; 6) conducting vias that provide timed actuating signal signals from a control system to each motion actuator; 7) conducting vias that transmit signal produced by array of chemical sensors to the control system for processing, although the blood monitoring system can comprise other numbers and types of elements in other configurations.

Improved immunogenicity of individual influenza vaccine components delivered with a novel dissolving microneedle patch stable at room temperature

PubMed Central

Vassilieva, Elena V.; Kalluri, Haripriya; McAllister, Devin; Taherbhai, Misha T.; Esser, E. Stein; Pewin, Winston P.; Pulit-Penaloza, Joanna A.; Prausnitz, Mark R.; Compans, Richard W.; Skountzou, Ioanna

2015-01-01

Prevention of seasonal influenza epidemics and pandemics relies on widespread vaccination coverage to induce protective immunity. In addition to a good antigenic match with the circulating viruses, the effectiveness of individual strains represented in the trivalent vaccines depends on their immunogenicity. In this study we evaluated the immunogenicity of H1N1, H3N2 and B seasonal influenza virus vaccine strains delivered individually with a novel dissolving microneedle patch and the stability of this formulation during storage at 25°C. Our data demonstrate that all strains retained their antigenic activity after incorporation in the dissolving patches as measured by SRID assay and immune responses to vaccination in BALB/c mice. After a single immunization all three antigens delivered with microneedle patches induced superior neutralizing antibody titers compared to intramuscular immunization. Cutaneous antigen delivery was especially beneficial for the less immunogenic B strain. Mice immunized with dissolving microneedle patches encapsulating influenza A/Brisbane/59/07 (H1N1) vaccine were fully protected against lethal challenge by homologous mouse-adapted influenza virus. All vaccine components retained activity during storage at room temperature for at least three months as measured in vitro by SRID assay and in vivo by mouse immunization studies. Our data demonstrate that dissolving microneedle patches are a promising advance for influenza cutaneous vaccination due to improved immune responses using less immunogenic influenza antigens and enhanced stability. PMID:25895053

Rapidly separating microneedles for transdermal drug delivery.

PubMed

Zhu, Dan Dan; Wang, Qi Lei; Liu, Xu Bo; Guo, Xin Dong

2016-09-01

The applications of polymer microneedles (MNs) into human skin emerged as an alternative of the conventional hypodermic needles. However, dissolving MNs require many minutes to be dissolved in the skin and typically have difficulty being fully inserted into the skin, which may lead to the low drug delivery efficiency. To address these issues, we introduce rapidly separating MNs that can rapidly deliver drugs into the skin in a minimally invasive way. For the rapidly separating MNs, drug loaded dissolving MNs are mounted on the top of solid MNs, which are made of biodegradable polylactic acid which eliminate the biohazardous waste. These MNs have sufficient mechanical strength to be inserted into the skin with the drug loaded tips fully embedded for subsequent dissolution. Compared with the traditional MNs, rapidly separating MNs achieve over 90% of drug delivery efficiency in 30s while the traditional MNs needs 2min to achieve the same efficiency. With the in vivo test in mice, the micro-holes caused by rapidly separating MNs can heal in 1h, indicating that the rapidly separating MNs are safe for future applications. These results indicate that the design of rapidly separating dissolvable MNs can offer a quick, high efficient, convenient, safe and potentially self-administered method of drug delivery. Polymer microneedles offer an attractive, painless and minimally invasive approach for transdermal drug delivery. However, dissolving microneedles require many minutes to be dissolved in the skin and typically have difficulty being fully inserted into the skin due to the skin deformation, which may lead to the low drug delivery efficiency. In this work we proposed rapidly separating microneedles which can deliver over 90% of drug into the skin in 30s. The in vitro and in vivo results indicate that the new design of these microneedles can offer a quick, high efficient, convenient and safe method for transdermal drug delivery. Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Novel strategy for immunomodulation: Dissolving microneedle array encapsulating thymopentin fabricated by modified two-step molding technology.

PubMed

Lin, Shiqi; Cai, Bingzhen; Quan, Guilan; Peng, Tingting; Yao, Gangtao; Zhu, Chune; Wu, Qiaoli; Ran, Hao; Pan, Xin; Wu, Chuanbin

2018-01-01

Thymopentin (TP5) is commonly used in the treatment for autoimmune diseases, with a short plasma half-life (30s) and a long treatment period (7 days to 6 months). It is usually administrated by syringe injection, resulting in compromised patient compliance. Dissolving microneedle array (DMNA) offers a superior approach for transdermal delivery of biological macromolecules, as it allows painless penetration through the stratum corneum and generates minimal biohazardous waste after dissolving in the skin. Despite recent advances in DMNA as a novel approach for transdermal drug delivery, problem of insufficient mechanical strength remains to be solved. In this study, TP5-loaded DMNA (TP5-DMNA) was uniquely developed using a modified two-step molding technology. The higher mechanical strength was furnished by employing bovine serum albumin (BSA) as a co-material to fabricate the needles. The obtained TP5-DMNA containing BSA displayed better skin penetration and higher drug loading efficiency than that without BSA. The in vivo pharmacodynamics study demonstrated that TP5-DMNA had comparative effect on immunomodulation to intravenous injection of TP5, in terms of ameliorating the CD4+/CD8+ ratio, SOD activity and MDA value to the basal level. Only mild irritation was observed at the site of administration. These results suggest that the novel TP5-DMNA utilizing BSA provides an alternative approach for convenient and safe transdermal delivery of TP5, which is a promising administration strategy for future clinical application. Copyright © 2017 Elsevier B.V. All rights reserved.

Enhanced Stability of Inactivated Influenza Vaccine Encapsulated in Dissolving Microneedle Patches

PubMed Central

Chu, Leonard Y.; Ye, Ling; Dong, Ke; Compans, Richard W.; Yang, Chinglai; Prausnitz, Mark R.

2015-01-01

Purpose This study tested the hypothesis that encapsulation of influenza vaccine in microneedle patches increases vaccine stability during storage at elevated temperature. Methods Whole inactivated influenza virus vaccine (A/Puerto Rico/8/34) was formulated into dissolving microneedle patches and vaccine stability was evaluated by in vitro and in vivo assays of antigenicity and immunogenicity after storage for up to 3 months at 4, 25, 37 and 45°C. Results While liquid vaccine completely lost potency as determined by hemagglutination (HA) activity within 1–2 weeks outside of refrigeration, vaccine in microneedle patches lost 40–50% HA activity during or shortly after fabrication, but then had no significant additional loss of activity over 3 months of storage, independent of temperature. This level of stability required reduced humidity by packaging with desiccant, but was not affected by presence of oxygen. This finding was consistent with additional stability assays, including antigenicity of the vaccine measured by ELISA, virus particle morphological structure captured by transmission electron microscopy and protective immune responses by immunization of mice in vivo. Conclusions These data show that inactivated influenza vaccine encapsulated in dissolving microneedle patches has enhanced stability during extended storage at elevated temperatures. PMID:26620313

Transdermal Delivery of siRNA through Microneedle Array

NASA Astrophysics Data System (ADS)

Deng, Yan; Chen, Jiao; Zhao, Yi; Yan, Xiaohui; Zhang, Li; Choy, Kwongwai; Hu, Jun; Sant, Himanshu J.; Gale, Bruce K.; Tang, Tao

2016-02-01

Successful development of siRNA therapies has significant potential for the treatment of skin conditions (alopecia, allergic skin diseases, hyperpigmentation, psoriasis, skin cancer, pachyonychia congenital) caused by aberrant gene expression. Although hypodermic needles can be used to effectively deliver siRNA through the stratum corneum, the major challenge is that this approach is painful and the effects are restricted to the injection site. Microneedle arrays may represent a better way to deliver siRNAs across the stratum corneum. In this study, we evaluated for the first time the ability of the solid silicon microneedle array for punching holes to deliver cholesterol-modified housekeeping gene (Gapdh) siRNA to the mouse ear skin. Treating the ear with microneedles showed permeation of siRNA in the skin and could reduce Gapdh gene expression up to 66% in the skin without accumulation in the major organs. The results showed that microneedle arrays could effectively deliver siRNA to relevant regions of the skin noninvasively.

Hollow silicon microneedle array based trans-epidermal antiemetic patch for efficient management of chemotherapy induced nausea and vomiting

NASA Astrophysics Data System (ADS)

Kharbikar, Bhushan N.; Kumar S., Harish; Kr., Sindhu; Srivastava, Rohit

2015-12-01

Chemotherapy Induced Nausea and Vomiting (CINV) is a serious health concern in the treatment of cancer patients. Conventional routes for administering anti-emetics (i.e. oral and parenteral) have several drawbacks such as painful injections, poor patient compliance, dependence on skilled personnel, non-affordability to majority of population (parenteral), lack of programmability and suboptimal bioavailability (oral). Hence, we have developed a trans-epidermal antiemetic drug delivery patch using out-of-plane hollow silicon microneedle array. Microneedles are pointed micron-scale structures that pierce the epidermal layer of skin to reach dermal blood vessels and can directly release the drug in their vicinity. They are painless by virtue of avoiding significant contact with dermal sensory nerve endings. This alternate approach gives same pharmacodynamic effects as par- enteral route at a sparse drug-dose requirement, hence negligible side-effects and improved patient compliance. Microneedle design attributes were derived by systematic study of human skin anatomy, natural micron-size structures like wasp-sting and cactus-spine and multi-physics simulations. We used deep reactive ion etching with Bosch process and optimized recipe of gases to fabricate high-aspect-ratio hollow silicon microneedle array. Finally, microneedle array and polydimethylsiloxane drug reservoir were assembled to make finished anti-emetic patch. We assessed microneedles mechanical stability, physico-chemical properties and performed in-vitro, ex- vivo and in-vivo studies. These studies established functional efficacy of the device in trans-epidermal delivery of anti-emetics, its programmability, ease of use and biosafety. Thus, out-of-plane hollow silicon microneedle array trans-epidermal antiemetic patch is a promising strategy for painless and effective management of CINV at low cost in mainstream healthcare.

Fabrication, Physicochemical Characterization, and Performance Evaluation of Biodegradable Polymeric Microneedle Patch System for Enhanced Transcutaneous Flux of High Molecular Weight Therapeutics.

PubMed

Shah, Viral; Choudhury, Bijaya Krushna

2017-11-01

A revolutionary paradigm shift is being observed currently, towards the use of therapeutic biologics for disease management. The present research was focused on designing an efficient dosage form for transdermal delivery of α-choriogonadotropin (high molecular weight biologic), through biodegradable polymeric microneedles. Polyvinylpyrrolidone-based biodegradable microneedle arrays loaded with high molecular weight polypeptide, α-choriogonadotropin, were fabricated for its systemic delivery via transdermal route. Varied process and formulation parameters were optimized for fabricating microneedle array, which in turn was expected to temporally rupture the stratum corneum layer of the skin, acting as a major barrier to drug delivery through transdermal route. The developed polymeric microneedles were optimized on the basis of quality attributes like mechanical strength, axial strength, insertion ratio, and insertion force analysis. The optimized polymeric microneedle arrays were characterized for in vitro drug release studies, ex vivo drug permeation studies, skin resealing studies, and in vivo pharmacokinetic studies. Results depicted that fabricated polymeric microneedle arrays with mechanical strength of above 5 N and good insertion ratio exhibited similar systemic bioavailability of α-choriogonadotropin in comparison to marketed subcutaneous injection formulation of α-choriogonadotropin. Thus, it was ultimately concluded that the designed drug delivery system can serve as an efficient tool for systemic delivery of therapeutic biologics, with an added benefit of overcoming the limitations of parenteral delivery, achieving better patient acceptability and compliance.

Finite element analysis of hollow out-of-plane HfO2 microneedles for transdermal drug delivery applications.

PubMed

Zhang, Yong-Hua; A Campbell, Stephen; Karthikeyan, Sreejith

2018-02-17

Transdermal drug delivery (TDD) based on microneedles is an excellent approach due to its advantages of both traditional transdermal patch and hypodermic syringes. In this paper, the fabrication method of hollow out-of-layer hafnium oxide (HfO 2 ) microneedles mainly based on deep reactive ion etching of silicon and atomic layer deposition of HfO 2  is described, and the finite element analysis of the microneedles based on ANSYS software is also presented. The fabrication process is simplified by using a single mask. The finite element analysis of a single microneedle shows that the flexibility of the microneedles can be easily adjusted for various applications. The finite element analysis of a 3 × 3 HfO 2 microneedle array applied on the skin well explains the "bed of nail" effect, i.e., the skin is not liable to be pierced when the density of microneedles in array increases. The presented research work here provides useful information for design optimization of HfO 2 microneedles used for TDD applications.

Design, modeling and simulation of MEMS-based silicon Microneedles

NASA Astrophysics Data System (ADS)

Amin, F.; Ahmed, S.

2013-06-01

The advancement in semiconductor process engineering and nano-scale fabrication technology has made it convenient to transport specific biological fluid into or out of human skin with minimum discomfort. Fluid transdermal delivery systems such as Microneedle arrays are one such emerging and exciting Micro-Electro Mechanical System (MEMS) application which could lead to a total painless fluid delivery into skin with controllability and desirable yield. In this study, we aimed to revisit the problem with modeling, design and simulations carried out for MEMS based silicon hollow out of plane microneedle arrays for biomedical applications particularly for transdermal drug delivery. An approximate 200 μm length of microneedle with 40 μm diameter of lumen has been successfully shown formed by isotropic and anisotropic etching techniques using MEMS Pro design tool. These microneedles are arranged in size of 2 × 4 matrix array with center to center spacing of 750 μm. Furthermore, comparisons for fluid flow characteristics through these microneedle channels have been modeled with and without the contribution of the gravitational forces using mathematical models derived from Bernoulli Equation. Physical Process simulations have also been performed on TCAD SILVACO to optimize the design of these microneedles aligned with the standard Si-Fabrication lines.

Arrays of hollow out-of-plane microneedles made by metal electrodeposition onto solvent cast conductive polymer structures

NASA Astrophysics Data System (ADS)

Mansoor, I.; Liu, Y.; Häfeli, U. O.; Stoeber, B.

2013-08-01

Transdermal drug delivery using microneedles is a technique to potentially replace hypodermic needles for injection of many vaccines and drugs. Fabrication of hollow metallic microneedles so far has been associated with time-consuming steps that restrict batch production of these devices. Here, we are presenting a novel method for making metallic microneedles with any desired height, spacing, and lumen size. In our process, we use solvent casting to coat a mold, which contains an array of pillars, with a conductive polymer composite layer. The conductive layer is then used as a seed layer in a metal electrodeposition process. To characterize the process, the conductivity of the polymer composite with respect to different filler concentrations was investigated. In addition, plasma etching of the polymer was characterized. The electroplating process was also studied further to control the thickness of the microneedle array plate. The strength of the microneedle devices was evaluated through a series of compression tests, while their performance for transdermal drug delivery was tested by injection of 2.28 µm fluorescent microspheres into animal skin. The fabricated metallic microneedles seem appropriate for subcutaneous delivery of drugs and microspheres.

Coated microneedle arrays for transcutaneous delivery of live virus vaccines

PubMed Central

Vrdoljak, Anto; McGrath, Marie G.; Carey, John B.; Draper, Simon J.; Hill, Adrian V.S.; O’Mahony, Conor; Crean, Abina M.; Moore, Anne C.

2016-01-01

Vaccines are sensitive biologics that require continuous refrigerated storage to maintain their viability. The vast majority of vaccines are also administered using needles and syringes. The need for cold chain storage and the significant logistics surrounding needle-and-syringe vaccination is constraining the success of immunization programs. Recombinant live viral vectors are a promising platform for the development of vaccines against a number of infectious diseases, however these viruses must retain infectivity to be effective. Microneedles offer an effective and painless method for delivery of vaccines directly into skin that in the future could provide solutions to current vaccination issues. Here we investigated methods of coating live recombinant adenovirus and modified vaccinia virus Ankara (MVA) vectors onto solid microneedle arrays. An effective spray-coating method, using conventional pharmaceutical processes, was developed, in tandem with suitable sugar-based formulations, which produces arrays with a unique coating of viable virus in a dry form around the shaft of each microneedle on the array. Administration of live virus-coated microneedle arrays successfully resulted in virus delivery, transcutaneous infection and induced an antibody or CD8+ T cell response in mice that was comparable to that obtained by needle-and-syringe intradermal immunization. To our knowledge, this is the first report of successful vaccination with recombinant live viral vectored vaccines coated on microneedle delivery devices. PMID:22245683

Coated microneedle arrays for transcutaneous delivery of live virus vaccines.

PubMed

Vrdoljak, Anto; McGrath, Marie G; Carey, John B; Draper, Simon J; Hill, Adrian V S; O'Mahony, Conor; Crean, Abina M; Moore, Anne C

2012-04-10

Vaccines are sensitive biologics that require continuous refrigerated storage to maintain their viability. The vast majority of vaccines are also administered using needles and syringes. The need for cold chain storage and the significant logistics surrounding needle-and-syringe vaccination is constraining the success of immunization programs. Recombinant live viral vectors are a promising platform for the development of vaccines against a number of infectious diseases, however these viruses must retain infectivity to be effective. Microneedles offer an effective and painless method for delivery of vaccines directly into skin that in the future could provide solutions to current vaccination issues. Here we investigated methods of coating live recombinant adenovirus and modified vaccinia virus Ankara (MVA) vectors onto solid microneedle arrays. An effective spray-coating method, using conventional pharmaceutical processes, was developed, in tandem with suitable sugar-based formulations, which produces arrays with a unique coating of viable virus in a dry form around the shaft of each microneedle on the array. Administration of live virus-coated microneedle arrays successfully resulted in virus delivery, transcutaneous infection and induced an antibody or CD8(+) T cell response in mice that was comparable to that obtained by needle-and-syringe intradermal immunization. To our knowledge, this is the first report of successful vaccination with recombinant live viral vectored vaccines coated on microneedle delivery devices. Copyright © 2011 Elsevier B.V. All rights reserved.

Single-Step Fabrication of Computationally Designed Microneedles by Continuous Liquid Interface Production

PubMed Central

Johnson, Ashley R.; Caudill, Cassie L.; Tumbleston, John R.; Bloomquist, Cameron J.; Moga, Katherine A.; Ermoshkin, Alexander; Shirvanyants, David; Mecham, Sue J.; Luft, J. Christopher; DeSimone, Joseph M.

2016-01-01

Microneedles, arrays of micron-sized needles that painlessly puncture the skin, enable transdermal delivery of medications that are difficult to deliver using more traditional routes. Many important design parameters, such as microneedle size, shape, spacing, and composition, are known to influence efficacy, but are notoriously difficult to alter due to the complex nature of microfabrication techniques. Herein, we utilize a novel additive manufacturing (“3D printing”) technique called Continuous Liquid Interface Production (CLIP) to rapidly prototype sharp microneedles with tuneable geometries (size, shape, aspect ratio, spacing). This technology allows for mold-independent, one-step manufacturing of microneedle arrays of virtually any design in less than 10 minutes per patch. Square pyramidal CLIP microneedles composed of trimethylolpropane triacrylate, polyacrylic acid and photopolymerizable derivatives of polyethylene glycol and polycaprolactone were fabricated to demonstrate the range of materials that can be utilized within this platform for encapsulating and controlling the release of therapeutics. These CLIP microneedles effectively pierced murine skin ex vivo and released the fluorescent drug surrogate rhodamine. PMID:27607247

Induction of CD8(+) T cell responses and protective efficacy following microneedle-mediated delivery of a live adenovirus-vectored malaria vaccine.

PubMed

Pearson, Frances E; O'Mahony, Conor; Moore, Anne C; Hill, Adrian V S

2015-06-22

There is an urgent need for improvements in vaccine delivery technologies. This is particularly pertinent for vaccination programmes within regions of limited resources, such as those required for adequate provision for disposal of used needles. Microneedles are micron-sized structures that penetrate the stratum corneum of the skin, creating temporary conduits for the needle-free delivery of drugs or vaccines. Here, we aimed to investigate immunity induced by the recombinant simian adenovirus-vectored vaccine ChAd63.ME-TRAP; currently undergoing clinical assessment as a candidate malaria vaccine, when delivered percutaneously by silicon microneedle arrays. In mice, we demonstrate that microneedle-mediated delivery of ChAd63.ME-TRAP induced similar numbers of transgene-specific CD8(+) T cells compared to intradermal (ID) administration with needle-and-syringe, following a single immunisation and after a ChAd63/MVA heterologous prime-boost schedule. When mice immunised with ChAd63/MVA were challenged with live Plasmodium berghei sporozoites, microneedle-mediated ChAd63.ME-TRAP priming demonstrated equivalent protective efficacy as did ID immunisation. Furthermore, responses following ChAd63/MVA immunisation correlated with a specific design parameter of the array used ('total array volume'). The level of transgene expression at the immunisation site and skin-draining lymph node (dLN) was also linked to total array volume. These findings have implications for defining silicon microneedle array design for use with live, vectored vaccines. Copyright © 2015 Elsevier Ltd. All rights reserved.

Rapidly dissolving polymeric microneedles for minimally invasive intraocular drug delivery.

PubMed

Thakur, Raghu Raj Singh; Tekko, Ismaiel A; Al-Shammari, Farhan; Ali, Ahlam A; McCarthy, Helen; Donnelly, Ryan F

2016-12-01

In this study, dissolving microneedles (MNs) were used to enhance ocular drug delivery of macromolecules. MNs were fabricated using polyvinylpyrrolidone (PVP) polymer of various molecular weights (MWs) containing three model molecules of increasing MW, namely fluorescein sodium and fluorescein isothiocyanate-dextrans (with MW of 70 k and 150 k Da). Arrays (3 × 3) of PVP MNs with conical shape measuring about 800 μm in height with a 300 μm base diameter, containing the model drugs, were fabricated and characterized for their fracture forces, insertion forces (in the sclera and cornea), depth of penetration (using OCT and confocal imaging), dissolution time and in vitro permeation. The average drug content of the MNs (only in MN shafts) ranged from 0.96 to 9.91 μg, and the average moisture content was below 11 %. High MW PVP produced MNs that can withstand higher forces with minimal reduction in needle height. PVP MNs showed rapid dissolution that ranged from 10 to 180 s, which was dependent upon PVP's MW. In vitro studies showed significant enhancement of macromolecule permeation when MNs were used, across both the corneal and scleral tissues, in comparison to topically applied aqueous solutions. Confocal images showed that the macromolecules formed depots within the tissues, which led to sustained permeation. However, use of MNs did not significantly benefit the permeation of small molecules; nevertheless, MN application has the potential for drug retention within the selected ocular tissues unlike topical application for small molecules. The material used in the fabrication of the MNs was found to be biocompatible with retinal cells (i.e. ARPE-19). Overall, this study reported the design and fabrication of minimally invasive rapidly dissolving polymeric MN arrays which were able to deliver high MW molecules to the eye via the intrastromal or intrascleral route. Thus, dissolving MNs have potential applications in enhancing ocular delivery of both small and macromolecules.

Transdermal Delivery of Drugs with Microneedles—Potential and Challenges

PubMed Central

Ita, Kevin

2015-01-01

Transdermal drug delivery offers a number of advantages including improved patient compliance, sustained release, avoidance of gastric irritation, as well as elimination of pre-systemic first-pass effect. However, only few medications can be delivered through the transdermal route in therapeutic amounts. Microneedles can be used to enhance transdermal drug delivery. In this review, different types of microneedles are described and their methods of fabrication highlighted. Microneedles can be fabricated in different forms: hollow, solid, and dissolving. There are also hydrogel-forming microneedles. A special attention is paid to hydrogel-forming microneedles. These are innovative microneedles which do not contain drugs but imbibe interstitial fluid to form continuous conduits between dermal microcirculation and an attached patch-type reservoir. Several microneedles approved by regulatory authorities for clinical use are also examined. The last part of this review discusses concerns and challenges regarding microneedle use. PMID:26131647

Silicon microneedle array for minimally invasive human health monitoring

NASA Astrophysics Data System (ADS)

Smith, Rosemary L.; Collins, Scott D.; Duy, Janice; Minogue, Timothy D.

2018-02-01

A silicon microneedle array with integrated microfluidic channels is presented, which is designed to extract dermal interstitial fluid (ISF) for biochemical analysis. ISF is a cell-free biofluid that is known to contain many of the same constituents as blood plasma, but the scope and dynamics of biomarker similarities are known for only a few components, most notably glucose. Dermal ISF is accessible just below the outer skin layer (epidermis), which can be reached and extracted with minimal sensation and tissue trauma by using a microneedle array. The microneedle arrays presented here are being developed to extract dermal ISF for off-chip profiling of nucleic acid constituents in order to identify potential biomarkers of disease. In order to assess sample volume requirements, preliminary RNA profiling was performed with suction blister ISF. The microneedles are batch fabricated using established silicon technology (low cost), are small in size, and can be integrated with sensors for on-chip analysis. This approach portends a more rapid, less expensive, self-administered assessment of human health than is currently achievable with blood sampling, especially in non-clinical and austere settings. Ultimately, a wearable device for monitoring a person's health in any setting is envisioned.

The Use of a Pressure-Indicating Sensor Film to Provide Feedback upon Hydrogel-Forming Microneedle Array Self-Application In Vivo.

PubMed

Vicente-Pérez, Eva M; Quinn, Helen L; McAlister, Emma; O'Neill, Shannon; Hanna, Lezley-Anne; Barry, Johanne G; Donnelly, Ryan F

2016-12-01

To evaluate the combination of a pressure-indicating sensor film with hydrogel-forming microneedle arrays, as a method of feedback to confirm MN insertion in vivo. Pilot in vitro insertion studies were conducted using a Texture Analyser to insert MN arrays, coupled with a pressure-indicating sensor film, at varying forces into excised neonatal porcine skin. In vivo studies involved twenty human volunteers, who self-applied two hydrogel-forming MN arrays, one with a pressure-indicating sensor film incorporated and one without. Optical coherence tomography was employed to measure the resulting penetration depth and colorimetric analysis to investigate the associated colour change of the pressure-indicating sensor film. Microneedle insertion was achieved in vitro at three different forces, demonstrating the colour change of the pressure-indicating sensor film upon application of increasing pressure. When self-applied in vivo, there was no significant difference in the microneedle penetration depth resulting from each type of array, with a mean depth of 237 μm recorded. When the pressure-indicating sensor film was present, a colour change occurred upon each application, providing evidence of insertion. For the first time, this study shows how the incorporation of a simple, low-cost pressure-indicating sensor film can indicate microneedle insertion in vitro and in vivo, providing visual feedback to assure the user of correct application. Such a strategy may enhance usability of a microneedle device and, hence, assist in the future translation of the technology to widespread clinical use.

Hydrogel-Forming Microneedle Arrays for Enhanced Transdermal Drug Delivery

PubMed Central

Donnelly, Ryan F; Singh, Thakur Raghu Raj; Garland, Martin J; Migalska, Katarzyna; Majithiya, Rita; McCrudden, Cian M; Kole, Prashant Laxman; Mahmood, Tuan Mazlelaa Tuan; McCarthy, Helen O; Woolfson, A David

2012-01-01

Unique microneedle arrays prepared from crosslinked polymers, which contain no drug themselves, are described. They rapidly take up skin interstitial fluid upon skin insertion to form continuous, unblockable, hydrogel conduits from attached patch-type drug reservoirs to the dermal microcirculation. Importantly, such microneedles, which can be fabricated in a wide range of patch sizes and microneedle geometries, can be easily sterilized, resist hole closure while in place, and are removed completely intact from the skin. Delivery of macromolecules is no longer limited to what can be loaded into the microneedles themselves and transdermal drug delivery is now controlled by the crosslink density of the hydrogel system rather than the stratum corneum, while electrically modulated delivery is also a unique feature. This technology has the potential to overcome the limitations of conventional microneedle designs and greatly increase the range of the type of drug that is deliverable transdermally, with ensuing benefits for industry, healthcare providers and, ultimately, patients. PMID:23606824

Effects of process parameters on the molding quality of the micro-needle array

NASA Astrophysics Data System (ADS)

Qiu, Z. J.; Ma, Z.; Gao, S.

2016-07-01

Micro-needle array, which is used in medical applications, is a kind of typical injection molded products with microstructures. Due to its tiny micro-features size and high aspect ratios, it is more likely to produce short shots defects, leading to poor molding quality. The injection molding process of the micro-needle array was studied in this paper to find the effects of the process parameters on the molding quality of the micro-needle array and to provide theoretical guidance for practical production of high-quality products. With the shrinkage ratio and warpage of micro needles as the evaluation indices of the molding quality, the orthogonal experiment was conducted and the analysis of variance was carried out. According to the results, the contribution rates were calculated to determine the influence of various process parameters on molding quality. The single parameter method was used to analyse the main process parameter. It was found that the contribution rate of the holding pressure on shrinkage ratio and warpage reached 83.55% and 94.71% respectively, far higher than that of the other parameters. The study revealed that the holding pressure is the main factor which affects the molding quality of micro-needle array so that it should be focused on in order to obtain plastic parts with high quality in the practical production.

Microneedle Array Design Determines the Induction of Protective Memory CD8+ T Cell Responses Induced by a Recombinant Live Malaria Vaccine in Mice

PubMed Central

Carey, John B.; Pearson, Frances E.; Vrdoljak, Anto; McGrath, Marie G.; Crean, Abina M.; Walsh, Patrick T.; Doody, Timothy; O'Mahony, Conor; Hill, Adrian V. S.; Moore, Anne C.

2011-01-01

Background Vaccine delivery into the skin has received renewed interest due to ease of access to the immune system and microvasculature, however the stratum corneum (SC), must be breached for successful vaccination. This has been achieved by removing the SC by abrasion or scarification or by delivering the vaccine intradermally (ID) with traditional needle-and-syringes or with long microneedle devices. Microneedle patch-based transdermal vaccine studies have predominantly focused on antibody induction by inactivated or subunit vaccines. Here, our principal aim is to determine if the design of a microneedle patch affects the CD8+ T cell responses to a malaria antigen induced by a live vaccine. Methodology and Findings Recombinant modified vaccinia virus Ankara (MVA) expressing a malaria antigen was percutaneously administered to mice using a range of silicon microneedle patches, termed ImmuPatch, that differed in microneedle height, density, patch area and total pore volume. We demonstrate that microneedle arrays that have small total pore volumes induce a significantly greater proportion of central memory T cells that vigorously expand to secondary immunization. Microneedle-mediated vaccine priming induced significantly greater T cell immunity post-boost and equivalent protection against malaria challenge compared to ID vaccination. Notably, unlike ID administration, ImmuPatch-mediated vaccination did not induce inflammatory responses at the site of immunization or in draining lymph nodes. Conclusions/Significance This study demonstrates that the design of microneedle patches significantly influences the magnitude and memory of vaccine-induced CD8+ T cell responses and can be optimised for the induction of desired immune responses. Furthermore, ImmuPatch-mediated delivery may be of benefit to reducing unwanted vaccine reactogenicity. In addition to the advantages of low cost and lack of pain, the development of optimised microneedle array designs for the induction of T cell responses by live vaccines aids the development of solutions to current obstacles of immunization programmes. PMID:21799855

Simple and cost-effective fabrication of solid biodegradable polymer microneedle arrays with adjustable aspect ratio for transdermal drug delivery using acupuncture microneedles

NASA Astrophysics Data System (ADS)

Cha, Kyoung Je; Kim, Taewan; Jea Park, Sung; Kim, Dong Sung

2014-11-01

Polymer microneedle arrays (MNAs) have received much attention for their use in transdermal drug delivery and microneedle therapy systems due to the advantages they offer, such as low cost, good mechanical properties, and a versatile choice of materials. Here, we present a simple and cost-effective method for the fabrication of a biodegradable polymer MNA in which the aspect ratio of each microneedle is adjustable using commercially available acupuncture microneedles. In our process, a master template with acupuncture microneedles, whose shape will be the final MNA, was carefully prepared by fixing them onto a plastic substrate with selectively drilled holes which, in turn, determine the aspect ratios of the microneedles. A polylactic acid (PLA; a biodegradable polymer) MNA was fabricated by a micromolding process with a polydimethylsiloxane (PDMS) mold containing the cavity of the microneedles, which was obtained by the PDMS replica molding against the master template. The mechanical force and degradation behavior of the replicated PLA MNA were characterized with the help of a compression test and an accelerated degradation test, respectively. Finally, the transdermal drug delivery performance of the PLA MNA was successfully simulated by two different methods of penetration and staining, using the skin of a pig cadaver. These results indicated that the proposed method can be effectively used for the fabrication of polymer MNAs which can be used in various microneedle applications.

Hydrogel-forming Microneedle Arrays Exhibit Antimicrobial Properties: Potential for Enhanced Patient Safety

PubMed Central

Donnelly, Ryan F.; Singh, Thakur Raghu Raj; Alkilani, Ahlam Zaid; McCrudden, Maelíosa T.C.; O’Mahony, Conor; Armstrong, Keith; McLoone, Nabla; Kole, Prashant; Woolfson, A. David

2014-01-01

We describe, for the first time, the microbial characterisation of hydrogel-forming polymeric microneedle arrays and the potential for passage of microorganisms into skin following microneedle penetration. Uniquely, we also present insights into the storage stability of these hydroscopic formulations, from physical and microbiological viewpoints, and examine clinical performance and safety in human volunteers. Experiments employing excised porcine skin and radiolabelled microorganisms showed that microorganisms can penetrate skin beyond the stratum corneum following microneedle puncture. Indeed, the numbers of microorganisms crossing the stratum corneum following microneedle puncture was greater than 105 cfu in each case. However, no microorganisms crossed the epidermal skin. When using a 21G hypodermic needle, more than 104 microorganisms penetrated into the viable tissue and 106 cfu of C. albicans and S. epidermidis completely crossed the epidermal skin in 24 h. The hydrogel-forming materials contained no microorganisms following de-moulding and exhibited no microbial growth during storage, while also maintaining their mechanical strength, apart from when stored at relative humidities of 86%. No microbial penetration through the swelling microneedles was detectable, while human volunteer studies confirmed that skin or systemic infection is highly unlikely when polymeric microneedles are used for transdermal drug delivery. Since no pharmacopoeial standards currently exist for microneedle-based products, the exact requirements for a proprietary product based on hydrogel-forming microneedles are at present unclear. However, we are currently working towards a comprehensive specification set for this microneedle system that may inform future developments in this regard. PMID:23644043

Skin Barrier Restoration and Moisturization Using Horse Oil-Loaded Dissolving Microneedle Patches.

PubMed

Lee, Chisong; Eom, Younghyon Andrew; Yang, Huisuk; Jang, Mingyu; Jung, Sang Uk; Park, Ye Oak; Lee, Si Eun; Jung, Hyungil

2018-01-01

Horse oil (HO) has skin barrier restoration and skin-moisturizing effects. Although cream formulations have been used widely and safely, their limited penetration through the stratum corneum is a major obstacle to maximizing the cosmetic efficacy of HO. Therefore, we aimed to encapsulate HO in a cosmetic dissolving microneedle (DMN) for efficient transdermal delivery. To overcome these limitations of skin permeation, HO-loaded DMN (HO-DMN) patches were developed and evaluated for their efficacy and safety using in vitro and clinical studies. Despite the lipophilic nature of HO, the HO-DMN patches had a sharp shape and uniform array, with an average length and tip diameter of 388.36 ± 16.73 and 38.54 ± 5.29 µm, respectively. The mechanical strength of the HO-DMN patches was sufficient (fracture force of 0.29 ± 0.01 N), and they could successfully penetrate pig skin. During the 4-week clinical evaluation, HO-DMN patches caused significant improvements in skin and dermal density, skin elasticity, and moisturization. Additionally, a brief safety assessment showed that the HO-DMN patches induced negligible adverse events. The HO-DMNs are efficient, safe, and convenient for wide use in cosmetic applications for skin barrier restoration and moisturization. © 2018 S. Karger AG, Basel.

Drawing lithography for microneedles: a review of fundamentals and biomedical applications.

PubMed

Lee, Kwang; Jung, Hyungil

2012-10-01

A microneedle is a three-dimensional (3D) micromechanical structure and has been in the spotlight recently as a drug delivery system (DDS). Because a microneedle delivers the target drug after penetrating the skin barrier, the therapeutic effects of microneedles proceed from its 3D structural geometry. Various types of microneedles have been fabricated using subtractive micromanufacturing methods which are based on the inherently planar two-dimensional (2D) geometries. However, traditional subtractive processes are limited for flexible structural microneedles and makes functional biomedical applications for efficient drug delivery difficult. The authors of the present study propose drawing lithography as a unique additive process for the fabrication of a microneedle directly from 2D planar substrates, thus overcoming a subtractive process shortcoming. The present article provides the first overview of the principal drawing lithography technology: fundamentals and biomedical applications. The continuous drawing technique for an ultrahigh-aspect ratio (UHAR) hollow microneedle, stepwise controlled drawing technique for a dissolving microneedle, and drawing technique with antidromic isolation for a hybrid electro-microneedle (HEM) are reviewed, and efficient biomedical applications by drawing lithography-mediated microneedles as an innovative drug and gene delivery system are described. Drawing lithography herein can provide a great breakthrough in the development of materials science and biotechnology. Copyright © 2012 Elsevier Ltd. All rights reserved.

Microneedles as the technique of drug delivery enhancement in diverse organs and tissues.

PubMed

Rzhevskiy, Alexey S; Singh, Thakur Raghu Raj; Donnelly, Ryan F; Anissimov, Yuri G

2018-01-28

Microneedles is the technique of drug delivery enhancement, which was primarily designed for facilitating percutaneous drug delivery. Started from the development of simple solid microneedles, providing microporation of stratum corneum and therefore enhancement of topical drug delivery, for two decades the technique has progressed in various modifications such as hollow, coated, dissolving and hydrogel forming microneedles. In their turn, the modifications have resulted in new mechanisms of drug delivery enhancement and followed by the expansion of applicability range in terms of targeted tissues and organs. Thus, in addition to percutaneous drug delivery, microneedles have been considered as an efficient technique facilitating ocular, oral mucosal, gastrointestinal, ungual and vaginal drug administration. It is anticipated that the technique of microneedle-assisted drug delivery will soon become relevant for majority of organs and tissues. Copyright © 2017 Elsevier B.V. All rights reserved.

Insertion Testing of Polyethylene Glycol Microneedle Array into Cultured Human Skin with Biaxial Tension

NASA Astrophysics Data System (ADS)

Takano, Naoki; Tachikawa, Hiroto; Miyano, Takaya; Nishiyabu, Kazuaki

Aiming at the practical use of polyethylene glycol (PEG) microneedles for transdermal drug delivery system (DDS), a testing apparatus for their insertion into cultured human skin has been developed. To simulate the variety of conditions of human skin, biaxial tension can be applied to the cultured human skin. An adopted testing scheme to apply and control the biaxial tension is similar to the deep-draw forming technique. An attention was also paid to the short-time setup of small, thin and wet cultured skin. One dimensional array with four needles was inserted and influence of tension was discussed. It was found that tension, deflection of skin during insertion and original curvature of skin are the important parameters for microneedles array design.

From the Cover: Microfabricated needles for transdermal delivery of macromolecules and nanoparticles: Fabrication methods and transport studies

NASA Astrophysics Data System (ADS)

McAllister, Devin V.; Wang, Ping M.; Davis, Shawn P.; Park, Jung-Hwan; Canatella, Paul J.; Allen, Mark G.; Prausnitz, Mark R.

2003-11-01

Arrays of micrometer-scale needles could be used to deliver drugs, proteins, and particles across skin in a minimally invasive manner. We therefore developed microfabrication techniques for silicon, metal, and biodegradable polymer microneedle arrays having solid and hollow bores with tapered and beveled tips and feature sizes from 1 to 1,000 μm. When solid microneedles were used, skin permeability was increased in vitro by orders of magnitude for macromolecules and particles up to 50 nm in radius. Intracellular delivery of molecules into viable cells was also achieved with high efficiency. Hollow microneedles permitted flow of microliter quantities into skin in vivo, including microinjection of insulin to reduce blood glucose levels in diabetic rats. transdermal drug delivery | skin | microelectromechanical systems | solid microneedle | hollow needle injection

Design, modelling and preliminary characterisation of microneedle-based electrodes for tissue electroporation in vivo

NASA Astrophysics Data System (ADS)

O'Mahony, Conor; Houlihan, Ruth; Grygoryev, Konstantin; Ning, Zhenfei; Williams, John; Moore, Tom

2016-10-01

We analysed the use of microneedle-based electrodes to enhance electroporation of mouse testis with DNA vectors for production of transgenic mice. Different microneedle formats were developed and tested, and we ultimately used electrodes based on arrays of 500 μm tall microneedles. In a series of experiments involving injection of a DNA vector expressing Green Fluorescent Protein (GFP) and electroporation using microneedle electrodes and a commercially available voltage supply, we compared the performance of flat and microneedle electrodes by measuring GFP expression at various timepoints after electroporation. Our main finding, supported by both experimental and simulated data, is that needles significantly enhanced electroporation of testis.

Application of composite dissolving microneedles with high drug loading ratio for rapid local anesthesia.

PubMed

Zhan, Haohui; Ma, Fengsen; Huang, Yingcong; Zhang, Jie; Jiang, Xiayun; Qian, Yongchang

2018-06-14

We report a type of dissolving microneedles (DMNs) which was made of composite matrix materials of hydroxypropyl methyl cellulose (HPMC) and poly(methylvinylether‑co‑maleic anhydride) (PMVE/MA copolymer, Gantrez S-97), and was successfully loaded with lidocaine hydrochloride. The weight of lidocaine hydrochloride loaded in the microneedles tip was 70% of the weight of the whole tip. The content was 3.43 ± 0.12 mg in weight, which was determined by high performance liquid chromatography (HPLC). The results for mechanical test showed that these microneedles were able to penetrate into the skin of the experimental animals, that was proved using organic staining, texture analyzer and histological examination. The fracture force of the microneedles was 5.442 ± 0.412 N, which was much higher than the one required for the skin penetration. The DMNs with lidocaine hydrochloride could be dissolved inside of the rat skin in 5 min. The onset time would be faster (in <5 min) when it was applied to the guinea pig model, in comparing with a commercially available anesthesia cream that had an onset time for 100 min. However, the efficacy of the DMNs for the local anesthesia only lasted for 16 min. It was shorter than that of the commercially available anesthesia cream with which the efficacy could last for about 130 min. After the DMNs was packaged under the vacuum and dark condition, it was stable for 3 months under the condition of a temperature of 40 ± 2 °C and a humidity of 75 ± 5%. The result of the experiment for the safety evaluation showed that the microneedles were non-irritating and non-allergenic to the skin. In conclusion, the DMNs with lidocaine hydrochloride could be safely administered to the skin with a quick onset time for the local anesthesia. Copyright © 2018. Published by Elsevier B.V.

Modeling of transdermal drug delivery with a microneedle array

NASA Astrophysics Data System (ADS)

Lv, Y.-G.; Liu, J.; Gao, Y.-H.; Xu, B.

2006-11-01

Transdermal drug delivery is generally limited by the extraordinary barrier properties of the stratum corneum, the outer 10-15 µm layer of skin. A conventional needle inserted across this barrier and into deeper tissues could effectively deliver drugs. However, it would lead to infection and cause pain, thereby reducing patient compliance. In order to administer a frequent injection of insulin and other therapeutic agents more efficiently, integrated arrays with very short microneedles were recently proposed as very good candidates for painless injection or extraction. A variety of microneedle designs have thus been made available by employing the fabrication tools of the microelectronics industry and using materials such as silicon, metals, polymers and glass with feature sizes ranging from sub-micron to nanometers. At the same time, experiments were also made to test the capability of the microneedles to inject drugs into tissues. However, due to the difficulty encountered in measurement, a detailed understanding of the spatial and transient drug delivery process still remains unclear up to now. To better grasp the mechanisms involved, quantitative theoretical models were developed in this paper to simultaneously characterize the flow and drug transport, and numerical solutions were performed to predict the kinetics of dispersed drugs injected into the skin from a microneedle array. Calculations indicated that increasing the initial injection velocity and accelerating the blood circulation in skin tissue with high porosity are helpful to enhance the transdermal drug delivery. This study provides the first quantitative simulation of fluid injection through a microneedle array and drug species transport inside the skin. The modeling strategy can also possibly be extended to deal with a wider range of clinical issues such as targeted nanoparticle delivery for therapeutics or molecular imaging.

Injection moulded microneedle sensor for real-time wireless pH monitoring.

PubMed

Mirza, Khalid B; Zuliani, Claudio; Hou, Benjamin; Ng, Fu Siong; Peters, Nicholas S; Toumazou, Christofer

2017-07-01

This paper describes the development of an array of individually addressable pH sensitive microneedles using injection moulding and their integration within a portable device for real-time wireless recording of pH distributions in biological samples. The fabricated microneedles are subjected to gold patterning followed by electrodeposition of iridium oxide to sensitize them to 0.07 units of pH change. Miniaturised electronics suitable for the sensors readout, analog-to-digital conversion and wireless transmission of the potentiometric data are embodied within the device, enabling it to measure real-time pH of soft biological samples such as muscles. In this paper, real-time recording of the cardiac pH distribution, during ischemia followed by reperfusion cycles in cardiac muscles of male Wistar rats has been demonstrated by using the microneedle array.

Integrated carbon fiber electrodes within hollow polymer microneedles for transdermal electrochemical sensing

PubMed Central

Miller, Philip R.; Gittard, Shaun D.; Edwards, Thayne L.; Lopez, DeAnna M.; Xiao, Xiaoyin; Wheeler, David R.; Monteiro-Riviere, Nancy A.; Brozik, Susan M.; Polsky, Ronen; Narayan, Roger J.

2011-01-01

In this study, carbon fiber electrodes were incorporated within a hollow microneedle array, which was fabricated using a digital micromirror device-based stereolithography instrument. Cell proliferation on the acrylate-based polymer used in microneedle fabrication was examined with human dermal fibroblasts and neonatal human epidermal keratinocytes. Studies involving full-thickness cadaveric porcine skin and trypan blue dye demonstrated that the hollow microneedles remained intact after puncturing the outermost layer of cadaveric porcine skin. The carbon fibers underwent chemical modification in order to enable detection of hydrogen peroxide and ascorbic acid; electrochemical measurements were demonstrated using integrated electrode-hollow microneedle devices. PMID:21522504

Fabrication of a Micro-Needle Array Electrode by Thermal Drawing for Bio-Signals Monitoring

PubMed Central

Ren, Lei; Jiang, Qing; Chen, Keyun; Chen, Zhipeng; Pan, Chengfeng; Jiang, Lelun

2016-01-01

A novel micro-needle array electrode (MAE) fabricated by thermal drawing and coated with Ti/Au film was proposed for bio-signals monitoring. A simple and effective setup was employed to form glassy-state poly (lactic-co-glycolic acid) (PLGA) into a micro-needle array (MA) by the thermal drawing method. The MA was composed of 6 × 6 micro-needles with an average height of about 500 μm. Electrode-skin interface impedance (EII) was recorded as the insertion force was applied on the MAE. The insertion process of the MAE was also simulated by the finite element method. Results showed that MAE could insert into skin with a relatively low compression force and maintain stable contact impedance between the MAE and skin. Bio-signals, including electromyography (EMG), electrocardiography (ECG), and electroencephalograph (EEG) were also collected. Test results showed that the MAE could record EMG, ECG, and EEG signals with good fidelity in shape and amplitude in comparison with the commercial Ag/AgCl electrodes, which proves that MAE is an alternative electrode for bio-signals monitoring. PMID:27322278

Fabrication of a Micro-Needle Array Electrode by Thermal Drawing for Bio-Signals Monitoring.

PubMed

Ren, Lei; Jiang, Qing; Chen, Keyun; Chen, Zhipeng; Pan, Chengfeng; Jiang, Lelun

2016-06-17

A novel micro-needle array electrode (MAE) fabricated by thermal drawing and coated with Ti/Au film was proposed for bio-signals monitoring. A simple and effective setup was employed to form glassy-state poly (lactic-co-glycolic acid) (PLGA) into a micro-needle array (MA) by the thermal drawing method. The MA was composed of 6 × 6 micro-needles with an average height of about 500 μm. Electrode-skin interface impedance (EII) was recorded as the insertion force was applied on the MAE. The insertion process of the MAE was also simulated by the finite element method. Results showed that MAE could insert into skin with a relatively low compression force and maintain stable contact impedance between the MAE and skin. Bio-signals, including electromyography (EMG), electrocardiography (ECG), and electroencephalograph (EEG) were also collected. Test results showed that the MAE could record EMG, ECG, and EEG signals with good fidelity in shape and amplitude in comparison with the commercial Ag/AgCl electrodes, which proves that MAE is an alternative electrode for bio-signals monitoring.

Hollow Microneedles for Intradermal Injection Fabricated by Sacrificial Micromolding and Selective Electrodeposition

PubMed Central

Norman, James J.; Choi, Seong-O; Tong, Nhien T.; Aiyar, Avishek R.; Patel, Samirkumar R.; Prausnitz, Mark R.; Allen, Mark G.

2012-01-01

Limitations with standard intradermal injections have created a clinical need for an alternative, low-cost injection device. In this study, we designed a hollow metal microneedle for reliable intradermal injection and developed a high-throughput micromolding process to produce metal microneedles with complex geometries. To fabricate the microneedles, we laser-ablated a 70 μm × 70 μm square cavity near the tip of poly(lactic acid-co-glyoclic acid) (PLGA) microneedles. The master structure was a template for multiple micromolded PLGA replicas. Each replica was sputtered with a gold seed layer with minimal gold deposited in the cavity due to masking effects. In this way, nickel was electrodeposited selectively outside of the cavity, after which the polymer replica was dissolved to produce a hollow metal microneedle. Force-displacement tests showed the microneedles, with 12 μm thick electrodeposition, could penetrate skin with an insertion force 9 times less than their axial failure force. We injected fluid with the microneedles into pig skin in vitro and hairless guinea pig skin in vivo. The injections targeted 90% of the material within the skin with minimal leakage onto the skin surface. We conclude that hollow microneedles made by this simple microfabrication method can achieve targeted intradermal injection. PMID:23053452

Effect of lipophilicity on the bioavailability of drugs after percutaneous administration by dissolving microneedles.

PubMed

Ito, Yukako; Yoshimura, Masahiro; Tanaka, Tsutomu; Takada, Kanji

2012-03-01

To elucidate drug lipophilicity effects on the bioavailability (BA) of drugs from skin after administration by dissolving microneedles, nine compounds with different lipophilicity indexes (log p value) were formulated into two-layered dissolving microneedles and administered percutaneously to rat skin: desmopressin (DDAVP), sumatriptan (ST), fluorescein (FL), granisetron (GRN), pindolol (PDL), pravastatin (PRV), rhodamine 123 (Rho), rifampicin (RFP), and salmeterol (SLM). Plasma drug concentrations were measured using liquid chromatography-tandem mass spectrometry and spectrofluorometry. In vivo dissolution and diffusion in both horizontal and vertical directions of FL and RH in the skin were studied using fluorescence microscopy. Respective BAs were 95.1 ± 7.9% (DDAVP), 84.2 ± 2.7% (ST), 82.3 ± 7.2% (FL), 82.7 ± 6.7% (GRN), 71.6 ± 3.8% (PDL), 63.6 ± 7.5% (PRV), 53.7 ± 8.3% (Rho), 46.2 ± 6.1% (RFP), and 38.4 ± 2.7% (SM). BA decreased as the lipophilicity index, log p value, of the drug increased from-1.95 to 1.73. The respective remaining percentages in skin tissue were 1.4 ± 0.7% (DDAVP), 0.9 ± 0.1% (ST), 1.0 ± 0.2% (FL), 3.4 ± 1.2% (GRN), 14.5 ± 3.7% (PDL), 23.4 ± 5.2% (PRV), 32.2 ± 6.0% (Rho), 40.7 ± 4.9% (RFP), and 40.6 ± 5.1% (SLM), dependent on log p. Fluorescence microscopy showed no FL or Rho in skin tissue within 4 and 24 h after administration, respectively. The BA of drugs delivered by dissolving microneedles depends on the drug solubility in the skin epidermis and dermis. Copyright © 2011 Wiley Periodicals, Inc.

A Transdermal Drug Delivery System Based on LIGA Technology and Soft Lithography

NASA Astrophysics Data System (ADS)

Matteucci, Marco; Perennes, Frederic; Marmiroli, Benedetta; Di Fabrizio, Enzo

2007-01-01

This report presents a transdermal drug delivery system based on LIGA fabricated microparts. It is a portable device combining a magnetically actuated micro gear pump with a microneedle array. The fluidic behaviour of the system is analyzed in order to predict its performance according to the dimension of the microparts and then compared to experimental data. The manufacturing process of both micropump and microneedle array are described.

Spatially controlled coating of continuous liquid Interface production microneedles for transdermal protein delivery.

PubMed

Caudill, Cassie L; Perry, Jillian L; Tian, Shaomin; Luft, J Christopher; DeSimone, Joseph M

2018-06-09

Microneedle patches, arrays of micron-scale projections that penetrate skin in a minimally invasive manner, are a promising tool for transdermally delivering therapeutic proteins. However, current microneedle fabrication techniques are limited in their ability to fabricate microneedles rapidly and with a high degree of control over microneedle design parameters. We have previously demonstrated the ability to fabricate microneedle patches with a range of compositions and geometries using the novel additive manufacturing technique Continuous Liquid Interface Production (CLIP). Here, we establish a method for dip coating CLIP microneedles with protein cargo in a spatially controlled manner. Microneedle coating mask devices were fabricated with CLIP and utilized to coat polyethylene glycol-based CLIP microneedles with model proteins bovine serum albumin, ovalbumin, and lysozyme. The design of the coating mask device was used to control spatial deposition and loading of coated protein cargo on the microneedles. CLIP microneedles rapidly released coated protein cargo both in solution and upon insertion into porcine skin. The model enzyme lysozyme was shown to retain its activity throughout the CLIP microneedle coating process, and permeation of bovine serum albumin across full thickness porcine skin was observed after application with coated CLIP microneedles. Protein-coated CLIP microneedles were applied to live mice and showed sustained retention of protein cargo in the skin over 72 h. These results demonstrate the utility of a versatile coating platform for preparation of precisely coated microneedles for transdermal therapeutic delivery. Copyright © 2018. Published by Elsevier B.V.

Langerin negative dendritic cells promote potent CD8+ T-cell priming by skin delivery of live adenovirus vaccine microneedle arrays

PubMed Central

Bachy, Veronique; Hervouet, Catherine; Becker, Pablo D.; Chorro, Laurent; Carlin, Leo M.; Herath, Shanthi; Papagatsias, Timos; Barbaroux, Jean-Baptiste; Oh, Sea-Jin; Benlahrech, Adel; Athanasopoulos, Takis; Dickson, George; Patterson, Steven; Kwon, Sung-Yun; Geissmann, Frederic; Klavinskis, Linda S.

2013-01-01

Stabilization of virus protein structure and nucleic acid integrity is challenging yet essential to preserve the transcriptional competence of live recombinant viral vaccine vectors in the absence of a cold chain. When coupled with needle-free skin delivery, such a platform would address an unmet need in global vaccine coverage against HIV and other global pathogens. Herein, we show that a simple dissolvable microneedle array (MA) delivery system preserves the immunogenicity of vaccines encoded by live recombinant human adenovirus type 5 (rAdHu5). Specifically, dried rAdHu5 MA immunization induced CD8+ T-cell expansion and multifunctional cytokine responses equipotent with conventional injectable routes of immunization. Intravital imaging demonstrated MA cargo distributed both in the epidermis and dermis, with acquisition by CD11c+ dendritic cells (DCs) in the dermis. The MA immunizing properties were attributable to CD11c+ MHCIIhi CD8αneg epithelial cell adhesion molecule (EpCAMneg) CD11b+ langerin (Lang; CD207)neg DCs, but neither Langerhans cells nor Lang+ DCs were required for CD8+ T-cell priming. This study demonstrates an important technical advance for viral vaccine vectors progressing to the clinic and provides insights into the mechanism of CD8+ T-cell priming by live rAdHu5 MAs. PMID:23386724

Langerin negative dendritic cells promote potent CD8+ T-cell priming by skin delivery of live adenovirus vaccine microneedle arrays.

PubMed

Bachy, Veronique; Hervouet, Catherine; Becker, Pablo D; Chorro, Laurent; Carlin, Leo M; Herath, Shanthi; Papagatsias, Timos; Barbaroux, Jean-Baptiste; Oh, Sea-Jin; Benlahrech, Adel; Athanasopoulos, Takis; Dickson, George; Patterson, Steven; Kwon, Sung-Yun; Geissmann, Frederic; Klavinskis, Linda S

2013-02-19

Stabilization of virus protein structure and nucleic acid integrity is challenging yet essential to preserve the transcriptional competence of live recombinant viral vaccine vectors in the absence of a cold chain. When coupled with needle-free skin delivery, such a platform would address an unmet need in global vaccine coverage against HIV and other global pathogens. Herein, we show that a simple dissolvable microneedle array (MA) delivery system preserves the immunogenicity of vaccines encoded by live recombinant human adenovirus type 5 (rAdHu5). Specifically, dried rAdHu5 MA immunization induced CD8(+) T-cell expansion and multifunctional cytokine responses equipotent with conventional injectable routes of immunization. Intravital imaging demonstrated MA cargo distributed both in the epidermis and dermis, with acquisition by CD11c(+) dendritic cells (DCs) in the dermis. The MA immunizing properties were attributable to CD11c(+) MHCII(hi) CD8α(neg) epithelial cell adhesion molecule (EpCAM(neg)) CD11b(+) langerin (Lang; CD207)(neg) DCs, but neither Langerhans cells nor Lang(+) DCs were required for CD8(+) T-cell priming. This study demonstrates an important technical advance for viral vaccine vectors progressing to the clinic and provides insights into the mechanism of CD8(+) T-cell priming by live rAdHu5 MAs.

A flexible microneedle array as low-voltage electroporation electrodes for in vivo DNA and siRNA delivery.

PubMed

Wei, Zewen; Zheng, Shuquan; Wang, Renxin; Bu, Xiangli; Ma, Huailei; Wu, Yidi; Zhu, Ling; Hu, Zhiyuan; Liang, Zicai; Li, Zhihong

2014-10-21

In vivo electroporation is an appealing method to deliver nucleic acid into living tissues, but the clinical application of such a method was limited due to severe tissue damage and poor coverage of the tissue surface. Here we present the validation of a novel flexible microneedle array electrode (MNAE) chip, in which the microneedle array and the flexible substrate are integrated together to simultaneously facilitate low-voltage electroporation and accomplish good coverage of the tissue surface. The efficient delivery of both DNA and siRNA was demonstrated on mice. Upon penetrating the high-resistance stratum corneum, the electroporation voltage was reduced to about 35 V, which was generally recognized safe for humans. Also, a pathological analysis of the microneedle-electroporated tissues was carried out to thoroughly assess the skin damage, which is an important consideration in pre-clinical studies of electroporation devices. This MNAE constitutes a novel way of in vivo delivery of siRNA and DNA to certain tissues or organs with satisfactory efficiency and good adaptation to the tissue surface profile as well as minimum tissue damage, thus avoiding the disadvantages of existing electroporation methods.

Continuous minimally-invasive alcohol monitoring using microneedle sensor arrays.

PubMed

Mohan, A M Vinu; Windmiller, Joshua Ray; Mishra, Rupesh K; Wang, Joseph

2017-05-15

The present work describes an attractive skin-worn microneedle sensing device for the minimally invasive electrochemical monitoring of subcutaneous alcohol. The device consists of an assembly of pyramidal microneedle structures integrated with Pt and Ag wires, each with a microcavity opening. The microneedle aperture was modified by electropolymerizing o-phenylene diamine onto the Pt wire microtransducer, followed by the immobilization of alcohol oxidase (AOx) in an intermediate chitosan layer, along with an outer Nafion layer. The resulting microneedle-based enzyme electrode displays an interference-free ethanol detection in artificial interstitial fluid without compromising its sensitivity, stability and response time. The skin penetration ability and the efficaciousness of the biosensor performance towards subcutaneous alcohol monitoring was substantiated by the ex vivo mice skin model analysis. Our results reveal that the new microneedle sensor holds considerable promise for continuous non-invasive alcohol monitoring in real-life situations. Copyright © 2017 Elsevier B.V. All rights reserved.

Continuous minimally-invasive alcohol monitoring using microneedle sensor arrays

PubMed Central

Vinu Mohan, A. M.; Windmiller, Joshua Ray; Mishra, Rupesh K.; Wang, Joseph

2017-01-01

The present work describes an attractive skin-worn microneedle sensing device for the minimally invasive electrochemical monitoring of subcutaneous alcohol. The device consists of an assembly of pyramidal microneedle structures integrated with Pt and Ag wires, each with a microcavity opening. The microneedle aperture was modified by electropolymerizing o-phenylene diamine onto the Pt wire microtransducer, followed by the immobilization of alcohol oxidase (AOx) in an intermediate chitosan layer, along with an outer Nafion layer. The resulting microneedle-based enzyme electrode displays an interference-free ethanol detection in artificial interstitial fluid without compromising its sensitivity, stability and response time. The skin penetration ability and the efficaciousness of the biosensor performance towards subcutaneous alcohol monitoring was substantiated by the ex vivo mice skin model analysis. Our results reveal that the new microneedle sensor holds considerable promise for continuous non-invasive alcohol monitoring in real-life situations. PMID:28088750

Two Photon Polymerization of Microneedles for Transdermal Drug Delivery

PubMed Central

Gittard, Shaun D.; Ovsianikov, Aleksandr; Chichkov, Boris N.; Doraiswamy, Anand; Narayan, Roger J.

2010-01-01

Importance of the field Microneedles are small-scale devices that are finding use for transdermal delivery of protein-based pharmacologic agents and nucleic acid-based pharmacologic agents; however, microneedles prepared using conventional microelectronics-based technologies have several shortcomings, which have limited translation of these devices into widespread clinical use. Areas covered in this review Two photon polymerization is a laser-based rapid prototyping technique that has been recently used for direct fabrication of hollow microneedles with a wide variety of geometries. In addition, an indirect rapid prototyping method that involves two photon polymerization and polydimethyl siloxane micromolding has been used for fabrication of solid microneedles with exceptional mechanical properties. What the reader will gain In this review, the use of two photon polymerization for fabricating in-plane and out-of-plane hollow microneedle arrays is described. The use of two photon polymerization-micromolding for fabrication of solid microneedles is also reviewed. In addition, fabrication of microneedles with antimicrobial properties is discussed; antimicrobial microneedles may reduce the risk of infection associated with formation of channels through the stratum corneum. Take home message It is anticipated that the use of two photon polymerization as well as two photon polymerization-micromolding for fabrication of microneedles and other microstructured drug delivery devices will increase over the coming years. PMID:20205601

Development of Novel Faster-Dissolving Microneedle Patches for Transcutaneous Vaccine Delivery

PubMed Central

Ono, Akihiko; Ito, Sayami; Sakagami, Shun; Saito, Mio; Quan, Ying-Shu; Kamiyama, Fumio; Hirobe, Sachiko; Okada, Naoki

2017-01-01

Microneedle (MN) patches are promising for transcutaneous vaccination because they enable vaccine antigens to physically penetrate the stratum corneum via low-invasive skin puncturing, and to be effectively delivered to antigen-presenting cells in the skin. In second-generation MN patches, the dissolving MNs release the loaded vaccine antigen into the skin. To shorten skin application time for clinical practice, this study aims to develop novel faster-dissolving MNs. We designed two types of MNs made from a single thickening agent, carboxymethylcellulose (CMC) or hyaluronan (HN). Both CMC-MN and HN-MN completely dissolved in rat skin after a 5-min application. In pre-clinical studies, both MNs could demonstrably increase antigen-specific IgG levels after vaccination and prolong antigen deposition compared with conventional injections, and deliver antigens into resected human dermal tissue. In clinical research, we demonstrated that both MNs could reliably and safely puncture human skin without any significant skin irritation from transepidermal water loss measurements and ICDRG (International Contact Dermatitis Research Group) evaluation results. PMID:28771172

Fabrication of Flexible Microneedle Array Electrodes for Wearable Bio-Signal Recording.

PubMed

Ren, Lei; Xu, Shujia; Gao, Jie; Lin, Zi; Chen, Zhipeng; Liu, Bin; Liang, Liang; Jiang, Lelun

2018-04-13

Laser-direct writing (LDW) and magneto-rheological drawing lithography (MRDL) have been proposed for the fabrication of a flexible microneedle array electrode (MAE) for wearable bio-signal monitoring. Conductive patterns were directly written onto the flexible polyethylene terephthalate (PET) substrate by LDW. The microneedle array was rapidly drawn and formed from the droplets of curable magnetorheological fluid with the assistance of an external magnetic field by MRDL. A flexible MAE can maintain a stable contact interface with curved human skin due to the flexibility of the PET substrate. Compared with Ag/AgCl electrodes and flexible dry electrodes (FDE), the electrode-skin interface impedance of flexible MAE was the minimum even after a 50-cycle bending test. Flexible MAE can record electromyography (EMG), electroencephalography (EEG) and static electrocardiography (ECG) signals with good fidelity. The main features of the dynamic ECG signal recorded by flexible MAE are the most distinguishable with the least moving artifacts. Flexible MAE is an attractive candidate electrode for wearable bio-signal monitoring.

Fabrication of Flexible Microneedle Array Electrodes for Wearable Bio-Signal Recording

PubMed Central

Ren, Lei; Xu, Shujia; Gao, Jie; Lin, Zi; Chen, Zhipeng; Liu, Bin; Liang, Liang; Jiang, Lelun

2018-01-01

Laser-direct writing (LDW) and magneto-rheological drawing lithography (MRDL) have been proposed for the fabrication of a flexible microneedle array electrode (MAE) for wearable bio-signal monitoring. Conductive patterns were directly written onto the flexible polyethylene terephthalate (PET) substrate by LDW. The microneedle array was rapidly drawn and formed from the droplets of curable magnetorheological fluid with the assistance of an external magnetic field by MRDL. A flexible MAE can maintain a stable contact interface with curved human skin due to the flexibility of the PET substrate. Compared with Ag/AgCl electrodes and flexible dry electrodes (FDE), the electrode–skin interface impedance of flexible MAE was the minimum even after a 50-cycle bending test. Flexible MAE can record electromyography (EMG), electroencephalography (EEG) and static electrocardiography (ECG) signals with good fidelity. The main features of the dynamic ECG signal recorded by flexible MAE are the most distinguishable with the least moving artifacts. Flexible MAE is an attractive candidate electrode for wearable bio-signal monitoring. PMID:29652835

Rapid fabrication method of a microneedle mold with controllable needle height and width.

PubMed

Lin, Yen-Heng; Lee, I-Chi; Hsu, Wei-Chieh; Hsu, Ching-Hong; Chang, Kai-Ping; Gao, Shao-Syuan

2016-10-01

The main issue of transdermal drug delivery is that macromolecular drugs cannot diffuse through the stratum corneum of skin. Many studies have pursued micro-sized needles encapsulated with drugs to overcome this problem, as these needles can pierce the stratum corneum and allow drugs to enter the circulatory system of the human body. However, most microneedle fabrication processes are time-consuming and require expensive equipment. In this study, we demonstrate a rapid method for fabricating a microneedle mold using drawing lithography and a UV-cured resin. The mold was filled with a water-soluble material, polyvinylpyrrolidone (PVP), which was then demolded to produce a water-soluble microneedle array. The results of an in vitro skin insertion test using PVP microneedles and pig ear skin demonstrated the feasibility of the microneedle mold. In addition, by controlling the viscosity of the UV-cured resin through various heat treatments, microneedles with different heights and aspect ratios were produced. Compared with other methods, this technology significantly simplifies and accelerates the mold fabrication process. In addition, the required equipment is relatively simple and inexpensive. Through this technology, we can rapidly fabricate microneedle molds with controllable dimensions for various applications.

A novel scalable manufacturing process for the production of hydrogel-forming microneedle arrays.

PubMed

Lutton, Rebecca E M; Larrañeta, Eneko; Kearney, Mary-Carmel; Boyd, Peter; Woolfson, A David; Donnelly, Ryan F

2015-10-15

A novel manufacturing process for fabricating microneedle arrays (MN) has been designed and evaluated. The prototype is able to successfully produce 14×14 MN arrays and is easily capable of scale-up, enabling the transition from laboratory to industry and subsequent commercialisation. The method requires the custom design of metal MN master templates to produce silicone MN moulds using an injection moulding process. The MN arrays produced using this novel method was compared with centrifugation, the traditional method of producing aqueous hydrogel-forming MN arrays. The results proved that there was negligible difference between either methods, with each producing MN arrays with comparable quality. Both types of MN arrays can be successfully inserted in a skin simulant. In both cases the insertion depth was approximately 60% of the needle length and the height reduction after insertion was in both cases approximately 3%. Copyright © 2015 Elsevier B.V. All rights reserved.

A novel scalable manufacturing process for the production of hydrogel-forming microneedle arrays

PubMed Central

Lutton, Rebecca E.M.; Larrañeta, Eneko; Kearney, Mary-Carmel; Boyd, Peter; Woolfson, A.David; Donnelly, Ryan F.

2015-01-01

A novel manufacturing process for fabricating microneedle arrays (MN) has been designed and evaluated. The prototype is able to successfully produce 14 × 14 MN arrays and is easily capable of scale-up, enabling the transition from laboratory to industry and subsequent commercialisation. The method requires the custom design of metal MN master templates to produce silicone MN moulds using an injection moulding process. The MN arrays produced using this novel method was compared with centrifugation, the traditional method of producing aqueous hydrogel-forming MN arrays. The results proved that there was negligible difference between either methods, with each producing MN arrays with comparable quality. Both types of MN arrays can be successfully inserted in a skin simulant. In both cases the insertion depth was approximately 60% of the needle length and the height reduction after insertion was in both cases approximately 3%. PMID:26302858

Measles vaccination using a microneedle patch☆

PubMed Central

Edens, Chris; Collins, Marcus L.; Ayers, Jessica; Rota, Paul A.; Prausnitz, Mark R.

2013-01-01

Measles vaccination programs would benefit from delivery methods that decrease cost, simplify logistics, and increase safety. Conventional subcutaneous injection is limited by the need for skilled healthcare professionals to reconstitute and administer injections, and by the need for safe needle handling and disposal to reduce the risk of disease transmission through needle re-use and needlestick injury. Microneedles are micron-scale, solid needles coated with a dry formulation of vaccine that dissolves in the skin within minutes after patch application. By avoiding the use of hypodermic needles, vaccination using a microneedle patch could be carried out by minimally trained personnel with reduced risk of blood-borne disease transmission. The goal of this study was to evaluate measles vaccination using a microneedle patch to address some of the limitations of subcutaneous injection. Viability of vaccine virus dried onto a microneedle patch was stabilized by incorporation of the sugar, trehalose, and loss of viral titer was less than 1 log10(TCID50) after storage for at least 30 days at room temperature. Microneedle patches were then used to immunize cotton rats with the Edmonston-Zagreb measles vaccine strain. Vaccination using microneedles at doses equaling the standard human dose or one-fifth the human dose generated neutralizing antibody levels equivalent to those of a subcutaneous immunization at the same dose. These results show that measles vaccine can be stabilized on microneedles and that vaccine efficiently reconstitutes in vivo to generate a neutralizing antibody response equivalent to that generated by subcutaneous injection. PMID:23044406

Microneedles from Fishscale-Nanocellulose Blends Using Low Temperature Mechanical Press Method.

PubMed

Olatunji, Ololade; Olsson, Richard T

2015-09-24

Fish scale biopolymer blended with nanocellulose crystals is used for production of microneedles applying mechanical press microfabrication and the effect of nanocellulose on microfabrication, water absorption, moisture stability and mechanical properties of the microneedles is reported. The results show that microneedles produced from the nanocellulose loaded fish scale biopolymer requires higher temperature for micromolding (80 ± 5 °C) than microneedles from only fish scale biopolymer, which were moldable at 50 ± 5 °C. The mechanical properties of the fish scale biopolymer-nanocellulose (FSBP-NC) films showed that the addition of nanocellulose (NC) resulted in lower elongation and higher tensile stress compared to fish scale biopolymer (FSBP) films. The nanocellulose also prevented dissolution of the needles and absorbed up to 300% and 234% its own weight in water (8% and 12% w/w NC/FSBP), whereas FSBP films dissolved completely within 1 min, Indicating that the FSBP-NC films can be used to produce microneedles with prolonged dissolution rate. FTIR spectrometry of the FSBP films was compared with the FSBP-NC films and the NC gels. The FTIR showed typical peaks for fish scale polymer and nanocellulose with evidence of interactions. SEM micrographs showed relatively good dispersion of NC in FSBP at both NC contents corresponding to 8% and 12% w/w NC/FSBP respectively.

Microneedles from Fishscale-Nanocellulose Blends Using Low Temperature Mechanical Press Method

PubMed Central

Olatunji, Ololade; Olsson, Richard T.

2015-01-01

Fish scale biopolymer blended with nanocellulose crystals is used for production of microneedles applying mechanical press microfabrication and the effect of nanocellulose on microfabrication, water absorption, moisture stability and mechanical properties of the microneedles is reported. The results show that microneedles produced from the nanocellulose loaded fish scale biopolymer requires higher temperature for micromolding (80 ± 5 °C) than microneedles from only fish scale biopolymer, which were moldable at 50 ± 5 °C. The mechanical properties of the fish scale biopolymer-nanocellulose (FSBP-NC) films showed that the addition of nanocellulose (NC) resulted in lower elongation and higher tensile stress compared to fish scale biopolymer (FSBP) films. The nanocellulose also prevented dissolution of the needles and absorbed up to 300% and 234% its own weight in water (8% and 12% w/w NC/FSBP), whereas FSBP films dissolved completely within 1 min, Indicating that the FSBP-NC films can be used to produce microneedles with prolonged dissolution rate. FTIR spectrometry of the FSBP films was compared with the FSBP-NC films and the NC gels. The FTIR showed typical peaks for fish scale polymer and nanocellulose with evidence of interactions. SEM micrographs showed relatively good dispersion of NC in FSBP at both NC contents corresponding to 8% and 12% w/w NC/FSBP respectively. PMID:26404358

Self-powered microneedle-based biosensors for pain-free high-accuracy measurement of glycaemia in interstitial fluid.

PubMed

Strambini, L M; Longo, A; Scarano, S; Prescimone, T; Palchetti, I; Minunni, M; Giannessi, D; Barillaro, G

2015-04-15

In this work a novel self-powered microneedle-based transdermal biosensor for pain-free high-accuracy real-time measurement of glycaemia in interstitial fluid (ISF) is reported. The proposed transdermal biosensor makes use of an array of silicon-dioxide hollow microneedles that are about one order of magnitude both smaller (borehole down to 4µm) and more densely-packed (up to 1×10(6)needles/cm(2)) than state-of-the-art microneedles used for biosensing so far. This allows self-powered (i.e. pump-free) uptake of ISF to be carried out with high efficacy and reliability in a few seconds (uptake rate up to 1µl/s) by exploiting capillarity in the microneedles. By coupling the microneedles operating under capillary-action with an enzymatic glucose biosensor integrated on the back-side of the needle-chip, glucose measurements are performed with high accuracy (±20% of the actual glucose level for 96% of measures) and reproducibility (coefficient of variation 8.56%) in real-time (30s) over the range 0-630mg/dl, thus significantly improving microneedle-based biosensor performance with respect to the state-of-the-art. Copyright © 2014 Elsevier B.V. All rights reserved.

Fabrication of a Ti porous microneedle array by metal injection molding for transdermal drug delivery.

PubMed

Li, Jiyu; Liu, Bin; Zhou, Yingying; Chen, Zhipeng; Jiang, Lelun; Yuan, Wei; Liang, Liang

2017-01-01

Microneedle arrays (MA) have been extensively investigated in recent decades for transdermal drug delivery due to their pain-free delivery, minimal skin trauma, and reduced risk of infection. However, porous MA received relatively less attention due to their complex fabrication process and ease of fracturing. Here, we present a titanium porous microneedle array (TPMA) fabricated by modified metal injection molding (MIM) technology. The sintering process is simple and suitable for mass production. TPMA was sintered at a sintering temperature of 1250°C for 2 h. The porosity of TPMA was approximately 30.1% and its average pore diameter was about 1.3 μm. The elements distributed on the surface of TPMA were only Ti and O, which may guarantee the biocompatibility of TPMA. TPMA could easily penetrate the skin of a human forearm without fracture. TPMA could diffuse dry Rhodamine B stored in micropores into rabbit skin. The cumulative permeated flux of calcein across TPMA with punctured skin was 27 times greater than that across intact skin. Thus, TPMA can continually and efficiently deliver a liquid drug through open micropores in skin.

Design, development, and evaluation of a novel microneedle array-based continuous glucose monitor.

PubMed

Jina, Arvind; Tierney, Michael J; Tamada, Janet A; McGill, Scott; Desai, Shashi; Chua, Beelee; Chang, Anna; Christiansen, Mark

2014-05-01

The development of accurate, minimally invasive continuous glucose monitoring (CGM) devices has been the subject of much work by several groups, as it is believed that a less invasive and more user-friendly device will result in greater adoption of CGM by persons with insulin-dependent diabetes. This article presents the results of preliminary clinical studies in subjects with diabetes of a novel prototype microneedle-based continuous glucose monitor. In this device, an array of tiny hollow microneedles is applied into the epidermis from where glucose in interstitial fluid (ISF) is transported via passive diffusion to an amperometric glucose sensor external to the body. Comparison of 1396 paired device glucose measurements and fingerstick blood glucose readings for up to 72-hour wear in 10 diabetic subjects shows the device to be accurate and well tolerated by the subjects. Overall mean absolute relative difference (MARD) is 15% with 98.4% of paired points in the A+B region of the Clarke error grid. The prototype device has demonstrated clinically accurate glucose readings over 72 hours, the first time a microneedle-based device has achieved such performance. © 2014 Diabetes Technology Society.

Two-photon polymerization for fabrication of biomedical devices

NASA Astrophysics Data System (ADS)

Ovsianikov, Aleksandr; Doraiswamy, Anand; Narayan, R.; Chichkov, B. N.

2007-01-01

Two-photon polymerization (2PP) is a novel technology which allows the fabrication of complex three-dimensional (3D) microstructures and nanostructures. The number of applications of this technology is rapidly increasing; it includes the fabrication of 3D photonic crystals [1-4], medical devices, and tissue scaffolds [5-6]. In this contribution, we discuss current applications of 2PP for microstructuring of biomedical devices used in drug delivery. While in general this sector is still dominated by oral administration of drugs, precise dosing, safety, and convenience are being addressed by transdermal drug delivery systems. Currently, main limitations arise from low permeability of the skin. As a result, only few types of pharmacological substances can be delivered in this manner [7]. Application of microneedle arrays, whose function is to help overcome the barrier presented by the epidermis layer of the skin, provides a very promising solution. Using 2PP we have fabricated arrays of hollow microneedles with different geometries. The effect of microneedle geometry on skin penetration is examined. Our results indicate that microneedles created using 2PP technique are suitable for in vivo use, and for integration with the next generation of MEMS- and NEMS-based drug delivery devices.

Skin vaccination with live virus vectored microneedle arrays induce long lived CD8(+) T cell memory.

PubMed

Becker, Pablo D; Hervouet, Catherine; Mason, Gavin M; Kwon, Sung-Yun; Klavinskis, Linda S

2015-09-08

A simple dissolvable microneedle array (MA) platform has emerged as a promising technology for vaccine delivery, due to needle-free injection with a formulation that preserves the immunogenicity of live viral vectored vaccines dried in the MA matrix. While recent studies have focused largely on design parameters optimized to induce primary CD8(+) T cell responses, the hallmark of a vaccine is synonymous with engendering long-lasting memory. Here, we address the capacity of dried MA vaccination to programme phenotypic markers indicative of effector/memory CD8(+) T cell subsets and also responsiveness to recall antigen benchmarked against conventional intradermal (ID) injection. We show that despite a slightly lower frequency of dividing T cell receptor transgenic CD8(+) T cells in secondary lymphoid tissue at an early time point, the absolute number of CD8(+) T cells expressing an effector memory (CD62L(-)CD127(+)) and central memory (CD62L(+)CD127(+)) phenotype during peak expansion were comparable after MA and ID vaccination with a recombinant human adenovirus type 5 vector (AdHu5) encoding HIV-1 gag. Similarly, both vaccination routes generated CD8(+) memory T cell subsets detected in draining LNs for at least two years post-vaccination capable of responding to secondary antigen. These data suggest that CD8(+) T cell effector/memory generation and long-term memory is largely unaffected by physical differences in vaccine delivery to the skin via dried MA or ID suspension. Copyright © 2015 Elsevier Ltd. All rights reserved.

Stabilization of Influenza Vaccine Enhances Protection by Microneedle Delivery in the Mouse Skin

PubMed Central

Yoo, Dae-Goon; Compans, Richard W.; Prausnitz, Mark R.; Kang, Sang-Moo

2009-01-01

Background Simple and effective vaccine administration is particularly important for annually recommended influenza vaccination. We hypothesized that vaccine delivery to the skin using a patch containing vaccine-coated microneedles could be an attractive approach to improve influenza vaccination compliance and efficacy. Methodology/Principal Findings Solid microneedle arrays coated with inactivated influenza vaccine were prepared for simple vaccine delivery to the skin. However, the stability of the influenza vaccine, as measured by hemagglutination activity, was found to be significantly damaged during microneedle coating. The addition of trehalose to the microneedle coating formulation retained hemagglutination activity, indicating stabilization of the coated influenza vaccine. For both intramuscular and microneedle skin immunization, delivery of un-stabilized vaccine yielded weaker protective immune responses including viral neutralizing antibodies, protective efficacies, and recall immune responses to influenza virus. Immunization using un-stabilized vaccine also shifted the pattern of antibody isotypes compared to the stabilized vaccine. Importantly, a single microneedle-based vaccination using stabilized influenza vaccine was found to be superior to intramuscular immunization in controlling virus replication as well as in inducing rapid recall immune responses post challenge. Conclusions/Significance The functional integrity of hemagglutinin is associated with inducing improved protective immunity against influenza. Simple microneedle influenza vaccination in the skin produced superior protection compared to conventional intramuscular immunization. This approach is likely to be applicable to other vaccines too. PMID:19779615

Human Growth Hormone Delivery with a Microneedle Transdermal System: Preclinical Formulation, Stability, Delivery and PK of Therapeutically Relevant Doses

PubMed Central

Ameri, Mahmoud; Kadkhodayan, Miryam; Nguyen, Joe; Bravo, Joseph A.; Su, Rebeca; Chan, Kenneth; Samiee, Ahmad; Daddona, Peter E.

2014-01-01

This study evaluated the feasibility of coating formulated recombinant human growth hormone (rhGH) on a titanium microneedle transdermal delivery system, Zosano Pharma (ZP)-hGH, and assessed preclinical patch delivery performance. Formulation rheology and surface activity were assessed by viscometry and contact angle measurement. rhGH liquid formulation was coated onto titanium microneedles by dip-coating and drying. The stability of coated rhGH was determined by size exclusion chromatography-high performance liquid chromatography (SEC-HPLC). Preclinical delivery and pharmacokinetic studies were conducted in female hairless guinea pigs (HGP) using rhGH coated microneedle patches at 0.5 and 1 mg doses and compared to Norditropin® a commercially approved rhGH subcutaneous injection. Studies demonstrated successful rhGH formulation development and coating on microneedle arrays. The ZP-hGH patches remained stable at 40 °C for six months with no significant change in % aggregates. Pharmacokinetic studies showed that the rhGH-coated microneedle patches, delivered with high efficiency and the doses delivered indicated linearity with average Tmax of 30 min. The absolute bioavailability of the microneedle rhGH patches was similar to subcutaneous Norditropin® injections. These results suggest that ZP-transdermal microneedle patch delivery of rhGH is feasible and may offer an effective and patient-friendly alternative to currently marketed rhGH injectables. PMID:24838219

Transcending epithelial and intracellular biological barriers; a prototype DNA delivery device.

PubMed

McCaffrey, Joanne; McCrudden, Cian M; Ali, Ahlam A; Massey, Ashley S; McBride, John W; McCrudden, Maelíosa T C; Vicente-Perez, Eva M; Coulter, Jonathan A; Robson, Tracy; Donnelly, Ryan F; McCarthy, Helen O

2016-03-28

Microneedle technology provides the opportunity for the delivery of DNA therapeutics by a non-invasive, patient acceptable route. To deliver DNA successfully requires consideration of both extra and intracellular biological barriers. In this study we present a novel two tier platform; i) a peptide delivery system, termed RALA, that is able to wrap the DNA into nanoparticles, protect the DNA from degradation, enter cells, disrupt endosomes and deliver the DNA to the nucleus of cells ii) a microneedle (MN) patch that will house the nanoparticles within the polymer matrix, breach the skin's stratum corneum barrier and dissolve upon contact with skin interstitial fluid thus releasing the nanoparticles into the skin. Our data demonstrates that the RALA is essential for preventing DNA degradation within the poly(vinylpyrrolidone) (PVP) polymer matrix. In fact the RALA/DNA nanoparticles (NPs) retained functionality when in the MN arrays after 28days and over a range of temperatures. Furthermore the physical strength and structure of the MNs was not compromised when loaded with the NPs. Finally we demonstrated the effectiveness of our MN-NP platform in vitro and in vivo, with systemic gene expression in highly vascularised regions. Taken together this 'smart-system' technology could be applied to a wide range of genetic therapies. Copyright © 2016. Published by Elsevier B.V.

Dissolving microneedles for transdermal drug delivery: Advances and challenges.

PubMed

Ita, Kevin

2017-09-01

Over the last number of years, a significant body of evidence has shown the benefit of using dissolving microneedles (DMNs) for transdermal drug delivery. These devices are prepared from a wide range of materials such as sugars and polymers. DMNs are mainly fabricated by micromolding, photopolymerization, drawing lithography and droplet-airborne blowing. In this review, we have focused on the advances made in the field in recent years using a representative set of studies. Although the list of studies is not exhaustive, they highlight the challenges encountered such as the need to increase mechanical strength as well as medication dose while ensuring fast release of the active ingredient. DMNs can be used to delivery low molecular drugs as well as peptides, proteins and other high molecular weight compounds. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Microneedle-mediated vaccine delivery: Harnessing cutaneous immunobiology to improve efficacy

PubMed Central

Al-Zahrani, S; Zaric, M; McCrudden, C; Scott, C; Kissenpfennig, A; Donnelly, Ryan F.

2014-01-01

Introduction We describe the use of microneedle arrays for delivery to targets within the skin itself. Breaching the skin’s stratum corneum barrier raises the possibility of administration of vaccines, gene vectors, antibodies and even nanoparticles, all of which have at least their initial effect on populations of skin cells. Areas Covered Intradermal vaccine delivery, in particular, holds enormous potential for improved therapeutic outcomes for patients, particularly those in the developing world. Various vaccine-delivery strategies have been employed and here we discuss each one in turn. We also describe the importance of cutaneous immunobiology on the effect produced by microneedle-mediated intradermal vaccination. Expert Opinion Microneedle-mediated vaccine holds enormous potential for patient benefit. In order for microneedle vaccine strategies to fulfil their potential, however, the proportion of an immune response that is due to local action of delivered vaccines on skin antigen presenting cells and what is due to a systemic effect from vaccine reaching the systemic circulation must be determined. Moreover, industry will need to invest significantly in new equipment and instrumentation in order to mass produce microneedle vaccines consistently. Finally, microneedles will need to demonstrate consistent dose delivery across patient groups and match this to reliable immune responses before they will replace tried- and-tested needle-and-syringe based-approaches. PMID:22475249

Fabrication of Composite Microneedle Array Electrode for Temperature and Bio-Signal Monitoring.

PubMed

Sun, Yiwei; Ren, Lei; Jiang, Lelun; Tang, Yong; Liu, Bin

2018-04-13

Body temperature and bio-signals are important health indicators that reflect the human health condition. However, monitoring these indexes is inconvenient and time-consuming, requires various instruments, and needs professional skill. In this study, a composite microneedle array electrode (CMAE) was designed and fabricated. It simultaneously detects body temperature and bio-signals. The CMAE consists of a 6 × 6 microneedles array with a height of 500 μm and a base diameter of 200 μm. Multiple insertion experiments indicate that the CMAE possesses excellent mechanical properties. The CMAE can pierce porcine skin 100 times without breaking or bending. A linear calibration relationship between temperature and voltage are experimentally obtained. Armpit temperature (35.8 °C) and forearm temperature (35.3 °C) are detected with the CMAE, and the measurements agree well with the data acquired with a clinical thermometer. Bio-signals including EII, ECG, and EMG are recorded and compared with those obtained by a commercial Ag/AgCl electrode. The CMAE continuously monitors bio-signals and is more convenient to apply because it does not require skin preparation and gel usage. The CMAE exhibits good potential for continuous and repetitive monitoring of body temperature and bio-signals.

Fabrication of a Ti porous microneedle array by metal injection molding for transdermal drug delivery

PubMed Central

Li, Jiyu; Liu, Bin; Zhou, Yingying; Chen, Zhipeng; Jiang, Lelun; Yuan, Wei; Liang, Liang

2017-01-01

Microneedle arrays (MA) have been extensively investigated in recent decades for transdermal drug delivery due to their pain-free delivery, minimal skin trauma, and reduced risk of infection. However, porous MA received relatively less attention due to their complex fabrication process and ease of fracturing. Here, we present a titanium porous microneedle array (TPMA) fabricated by modified metal injection molding (MIM) technology. The sintering process is simple and suitable for mass production. TPMA was sintered at a sintering temperature of 1250°C for 2 h. The porosity of TPMA was approximately 30.1% and its average pore diameter was about 1.3 μm. The elements distributed on the surface of TPMA were only Ti and O, which may guarantee the biocompatibility of TPMA. TPMA could easily penetrate the skin of a human forearm without fracture. TPMA could diffuse dry Rhodamine B stored in micropores into rabbit skin. The cumulative permeated flux of calcein across TPMA with punctured skin was 27 times greater than that across intact skin. Thus, TPMA can continually and efficiently deliver a liquid drug through open micropores in skin. PMID:28187179

Evaluation of a minimally invasive glucose biosensor for continuous tissue monitoring.

PubMed

Sharma, Sanjiv; Huang, Zhenyi; Rogers, Michelle; Boutelle, Martyn; Cass, Anthony E G

2016-11-01

We describe here a minimally invasive glucose biosensor based on a microneedle array electrode fabricated from an epoxy-based negative photoresist (SU8 50) and designed for continuous measurement in the dermal compartment with minimal pain. These minimally invasive, continuous monitoring sensor devices (MICoMS) were produced by casting the structures in SU8 50, crosslinking and then metallising them with platinum or silver to obtain the working and reference electrodes, respectively. The metallised microneedle array electrodes were subsequently functionalised by entrapping glucose oxidase in electropolymerised polyphenol (PP) film. Sensor performance in vitro showed that glucose concentrations down to 0.5 mM could be measured with a response times (T 90 ) of 15 s. The effect of sterilisation by Co60 irradiation was evaluated. In preparation for further clinical studies, these sensors were tested in vivo in a healthy volunteer for a period of 3-6 h. The sensor currents were compared against point measurements obtained with a commercial capillary blood glucometer. The epoxy MICoMS devices showed currents values that could be correlated with these. Graphical Abstract Microneedle arrays for continuous glucose monitoring in dermal interstitial fluid.

Fabrication of Composite Microneedle Array Electrode for Temperature and Bio-Signal Monitoring

PubMed Central

Sun, Yiwei; Ren, Lei; Jiang, Lelun; Tang, Yong; Liu, Bin

2018-01-01

Body temperature and bio-signals are important health indicators that reflect the human health condition. However, monitoring these indexes is inconvenient and time-consuming, requires various instruments, and needs professional skill. In this study, a composite microneedle array electrode (CMAE) was designed and fabricated. It simultaneously detects body temperature and bio-signals. The CMAE consists of a 6 × 6 microneedles array with a height of 500 μm and a base diameter of 200 μm. Multiple insertion experiments indicate that the CMAE possesses excellent mechanical properties. The CMAE can pierce porcine skin 100 times without breaking or bending. A linear calibration relationship between temperature and voltage are experimentally obtained. Armpit temperature (35.8 °C) and forearm temperature (35.3 °C) are detected with the CMAE, and the measurements agree well with the data acquired with a clinical thermometer. Bio-signals including EII, ECG, and EMG are recorded and compared with those obtained by a commercial Ag/AgCl electrode. The CMAE continuously monitors bio-signals and is more convenient to apply because it does not require skin preparation and gel usage. The CMAE exhibits good potential for continuous and repetitive monitoring of body temperature and bio-signals. PMID:29652837

Microneedle Device Prototype

DTIC Science & Technology

2014-05-01

Defense Threat Reduction Agency Research and Development Counter WMD Technologies Test Support Division 1680 Texas Street SE Kirtland AFB, NM...Device Prototype Final Report iv | List of Figures List of Figures Figure 3-1. Print screen of the STL file of a hollow microneedle design in Alibre...electrochemical characterization of gold electrode (n = 8) array with oxide dielectric defined working electrodes with 1 mM [Fe(CN)6] 3- in 0.1 M potassium

Micro Electromechanical Systems (MEMS) Based Microfluidic Devices for Biomedical Applications

PubMed Central

Ashraf, Muhammad Waseem; Tayyaba, Shahzadi; Afzulpurkar, Nitin

2011-01-01

Micro Electromechanical Systems (MEMS) based microfluidic devices have gained popularity in biomedicine field over the last few years. In this paper, a comprehensive overview of microfluidic devices such as micropumps and microneedles has been presented for biomedical applications. The aim of this paper is to present the major features and issues related to micropumps and microneedles, e.g., working principles, actuation methods, fabrication techniques, construction, performance parameters, failure analysis, testing, safety issues, applications, commercialization issues and future prospects. Based on the actuation mechanisms, the micropumps are classified into two main types, i.e., mechanical and non-mechanical micropumps. Microneedles can be categorized according to their structure, fabrication process, material, overall shape, tip shape, size, array density and application. The presented literature review on micropumps and microneedles will provide comprehensive information for researchers working on design and development of microfluidic devices for biomedical applications. PMID:21747700

Microneedle delivery of an M2e-TLR5 ligand fusion protein to skin confers broadly cross-protective influenza immunity.

PubMed

Wang, Bao-Zhong; Gill, Harvinder S; He, Cheng; Ou, Changbo; Wang, Li; Wang, Ying-Chun; Feng, Hao; Zhang, Han; Prausnitz, Mark R; Compans, Richard W

2014-03-28

Influenza vaccines with broad cross-protection are urgently needed to prevent an emerging influenza pandemic. A fusion protein of the Toll-like receptor (TLR) 5-agonist domains from flagellin and multiple repeats of the conserved extracellular domain of the influenza matrix protein 2 (M2e) was constructed, purified and evaluated as such a vaccine. A painless vaccination method suitable for possible self-administration using coated microneedle arrays was investigated for skin-targeted delivery of the fusion protein in a mouse model. The results demonstrate that microneedle immunization induced strong humoral as well as mucosal antibody responses and conferred complete protection against homo- and heterosubtypic lethal virus challenges. Protective efficacy with microneedles was found to be significantly better than that seen with conventional intramuscular injection, and comparable to that observed with intranasal immunization. Because of its advantages for administration, safety and storage, microneedle delivery of M2e-flagellin fusion protein is a promising approach for an easy-to-administer universal influenza vaccine. Copyright © 2014 Elsevier B.V. All rights reserved.

Rapid, low cost prototyping of transdermal devices for personal healthcare monitoring.

PubMed

Sharma, Sanjiv; Saeed, Anwer; Johnson, Christopher; Gadegaard, Nikolaj; Cass, Anthony Eg

2017-04-01

The next generation of devices for personal healthcare monitoring will comprise molecular sensors to monitor analytes of interest in the skin compartment. Transdermal devices based on microneedles offer an excellent opportunity to explore the dynamics of molecular markers in the interstitial fluid, however good acceptability of these next generation devices will require several technical problems associated with current commercially available wearable sensors to be overcome. These particularly include reliability, comfort and cost. An essential pre-requisite for transdermal molecular sensing devices is that they can be fabricated using scalable technologies which are cost effective. We present here a minimally invasive microneedle array as a continuous monitoring platform technology. Method for scalable fabrication of these structures is presented. The microneedle arrays were characterised mechanically and were shown to penetrate human skin under moderate thumb pressure. They were then functionalised and evaluated as glucose, lactate and theophylline biosensors. The results suggest that this technology can be employed in the measurement of metabolites, therapeutic drugs and biomarkers and could have an important role to play in the management of chronic diseases.

Development of three-dimension microelectrode array for bioelectric measurement using the liquidmetal-micromolding technique

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Ran, E-mail: liuran@tsinghua.edu.cn; Yang, Xueyao; Chen, Weixing

2013-11-04

A method of manufacturing three-dimension microneedle electrode arrays is presented in this paper using the micromolding technology with liquid metal at room temperature, based on the physical property of the Bi-In-Sn liquid metal alloy, being its melting point especially low. Observed under scanning electron microscopy, the needle body of the electrode chip manufactured using this method has a good consistency. Skin penetration test in-vitro indicates that the microneedle electrode can pierce the stratum corneum and cross the high-impedance layer to acquire electrical signals. Electrical impedance and polarization voltage experimental results show that the electrode chips have great electric characteristics andmore » meet the practical application demands.« less

Methylene Blue-Loaded Dissolving Microneedles: Potential Use in Photodynamic Antimicrobial Chemotherapy of Infected Wounds

PubMed Central

Caffarel-Salvador, Ester; Kearney, Mary-Carmel; Mairs, Rachel; Gallo, Luigi; Stewart, Sarah A.; Brady, Aaron J.; Donnelly, Ryan F.

2015-01-01

Photodynamic therapy involves delivery of a photosensitising drug that is activated by light of a specific wavelength, resulting in generation of highly reactive radicals. This activated species can cause destruction of targeted cells. Application of this process for treatment of microbial infections has been termed “photodynamic antimicrobial chemotherapy” (PACT). In the treatment of chronic wounds, the delivery of photosensitising agents is often impeded by the presence of a thick hyperkeratotic/necrotic tissue layer, reducing their therapeutic efficacy. Microneedles (MNs) are an emerging drug delivery technology that have been demonstrated to successfully penetrate the outer layers of the skin, whilst minimising damage to skin barrier function. Delivering photosensitising drugs using this platform has been demonstrated to have several advantages over conventional photodynamic therapy, such as, painless application, reduced erythema, enhanced cosmetic results and improved intradermal delivery. The aim of this study was to physically characterise dissolving MNs loaded with the photosensitising agent, methylene blue and assess their photodynamic antimicrobial activity. Dissolving MNs were fabricated from aqueous blends of Gantrez® AN-139 co-polymer containing varying loadings of methylene blue. A height reduction of 29.8% was observed for MNs prepared from blends containing 0.5% w/w methylene blue following application of a total force of 70.56 N/array. A previously validated insertion test was used to assess the effect of drug loading on MN insertion into a wound model. Staphylococcus aureus, Escherichia coli and Candida albicans biofilms were incubated with various methylene blue concentrations within the range delivered by MNs in vitro (0.1–2.5 mg/mL) and either irradiated at 635 nm using a Paterson Lamp or subjected to a dark period. Microbial susceptibility to PACT was determined by assessing the total viable count. Kill rates of >96%, were achieved for S. aureus and >99% for E. coli and C. albicans with the combination of PACT and methylene blue concentrations between 0.1 and 2.5 mg/mL. A reduction in the colony count was also observed when incorporating the photosensitiser without irradiation, this reduction was more notable in S. aureus and E. coli strains than in C. albicans. PMID:26426040

Vaccination with Human Papillomavirus Pseudovirus-Encapsidated Plasmids Targeted to Skin Using Microneedles

PubMed Central

Kines, Rhonda C.; Zarnitsyn, Vladimir; Johnson, Teresa R.; Pang, Yuk-Ying S.; Corbett, Kizzmekia S.; Nicewonger, John D.; Gangopadhyay, Anu; Chen, Man; Liu, Jie; Prausnitz, Mark R.; Schiller, John T.; Graham, Barney S.

2015-01-01

Human papilloma virus-like particles (HPV VLP) serve as the basis of the current licensed vaccines for HPV. We have previously shown that encapsidation of DNA expressing the model antigen M/M2 from respiratory syncytial virus (RSV) in HPV pseudovirions (PsV) is immunogenic when delivered intravaginally. Because the HPV capsids confer tropism for basal epithelium, they represent attractive carriers for vaccination targeted to the skin using microneedles. In this study we asked: 1) whether HPV16 VLP administered by microneedles could induce protective immune responses to HPV16 and 2) whether HPV16 PsV-encapsidated plasmids delivered by microneedles could elicit immune responses to both HPV and the antigen delivered by the transgene. Mice immunized with HPV16 VLP coated microneedles generated robust neutralizing antibody responses and were protected from HPV16 challenge. Microneedle arrays coated with HPV16-M/M2 or HPV16-F protein (genes of RSV) were then tested and dose-dependent HPV and F-specific antibody responses were detected post-immunization, and M/M2-specific T-cell responses were detected post RSV challenge, respectively. HPV16 PsV-F immunized mice were fully protected from challenge with HPV16 PsV and had reduced RSV viral load in lung and nose upon intranasal RSV challenge. In summary, HPV16 PsV-encapsidated DNA delivered by microneedles induced neutralizing antibody responses against HPV and primed for antibody and T-cell responses to RSV antigens encoded by the encapsidated plasmids. Although the immunogenicity of the DNA component was just above the dose response threshold, the HPV-specific immunity was robust. Taken together, these data suggest microneedle delivery of lyophilized HPV PsV could provide a practical, thermostable combined vaccine approach that could be developed for clinical evaluation. PMID:25785935

Vaccination with human papillomavirus pseudovirus-encapsidated plasmids targeted to skin using microneedles.

PubMed

Kines, Rhonda C; Zarnitsyn, Vladimir; Johnson, Teresa R; Pang, Yuk-Ying S; Corbett, Kizzmekia S; Nicewonger, John D; Gangopadhyay, Anu; Chen, Man; Liu, Jie; Prausnitz, Mark R; Schiller, John T; Graham, Barney S

2015-01-01

Human papilloma virus-like particles (HPV VLP) serve as the basis of the current licensed vaccines for HPV. We have previously shown that encapsidation of DNA expressing the model antigen M/M2 from respiratory syncytial virus (RSV) in HPV pseudovirions (PsV) is immunogenic when delivered intravaginally. Because the HPV capsids confer tropism for basal epithelium, they represent attractive carriers for vaccination targeted to the skin using microneedles. In this study we asked: 1) whether HPV16 VLP administered by microneedles could induce protective immune responses to HPV16 and 2) whether HPV16 PsV-encapsidated plasmids delivered by microneedles could elicit immune responses to both HPV and the antigen delivered by the transgene. Mice immunized with HPV16 VLP coated microneedles generated robust neutralizing antibody responses and were protected from HPV16 challenge. Microneedle arrays coated with HPV16-M/M2 or HPV16-F protein (genes of RSV) were then tested and dose-dependent HPV and F-specific antibody responses were detected post-immunization, and M/M2-specific T-cell responses were detected post RSV challenge, respectively. HPV16 PsV-F immunized mice were fully protected from challenge with HPV16 PsV and had reduced RSV viral load in lung and nose upon intranasal RSV challenge. In summary, HPV16 PsV-encapsidated DNA delivered by microneedles induced neutralizing antibody responses against HPV and primed for antibody and T-cell responses to RSV antigens encoded by the encapsidated plasmids. Although the immunogenicity of the DNA component was just above the dose response threshold, the HPV-specific immunity was robust. Taken together, these data suggest microneedle delivery of lyophilized HPV PsV could provide a practical, thermostable combined vaccine approach that could be developed for clinical evaluation.

Smallpox DNA Vaccine Delivered by Novel Skin Electroporation Device Protects Mice Against Intranasal Poxvirus Challenge

DTIC Science & Technology

2006-11-27

response being elicited by microneedle -mediated skin electroporation. 2006 Elsevier Ltd. All rights reserved. i o a p ( c o t t v H f r eywords...localized skin infection containing infectious virus (i.e., ock), the infection can spread to other sites on the body e.g., ocular autoinoculation) or to...plasmid DNA-coated microneedle arrays. Mice vaccinated with the 4pox DNA vaccine mounted robust antibody responses against the four immunogens-of-interest

A bio-inspired swellable microneedle adhesive for mechanical interlocking with tissue

NASA Astrophysics Data System (ADS)

Yang, Seung Yun; O'Cearbhaill, Eoin D.; Sisk, Geoffroy C.; Park, Kyeng Min; Cho, Woo Kyung; Villiger, Martin; Bouma, Brett E.; Pomahac, Bohdan; Karp, Jeffrey M.

2013-04-01

Achieving significant adhesion to soft tissues while minimizing tissue damage poses a considerable clinical challenge. Chemical-based adhesives require tissue-specific reactive chemistry, typically inducing a significant inflammatory response. Staples are fraught with limitations including high-localized tissue stress and increased risk of infection, and nerve and blood vessel damage. Here inspired by the endoparasite Pomphorhynchus laevis, which swells its proboscis to attach to its host’s intestinal wall, we have developed a biphasic microneedle array that mechanically interlocks with tissue through swellable microneedle tips, achieving ~3.5-fold increase in adhesion strength compared with staples in skin graft fixation, and removal force of ~4.5 N cm-2 from intestinal mucosal tissue. Comprising a poly(styrene)-block-poly(acrylic acid) swellable tip and non-swellable polystyrene core, conical microneedles penetrate tissue with minimal insertion force and depth, yet high adhesion strength in their swollen state. Uniquely, this design provides universal soft tissue adhesion with minimal damage, less traumatic removal, reduced risk of infection and delivery of bioactive therapeutics.

A Bio-Inspired Swellable Microneedle Adhesive for Mechanical Interlocking with Tissue

PubMed Central

Yang, Seung Yun; O'Cearbhaill, Eoin D.; Sisk, Geoffroy C.; Park, Kyeng Min; Cho, Woo Kyung; Villiger, Martin; Bouma, Brett E.; Pomahac, Bohdan; Karp, Jeffrey M.

2013-01-01

Achieving significant adhesion to soft tissues while minimizing tissue damage poses a considerable clinical challenge. Chemical-based adhesives require tissue-specific reactive chemistry, typically inducing a significant inflammatory response. Staples are fraught with limitations including high-localized tissue stress and increased risk of infection, and nerve and blood vessel damage. Here, inspired by the endoparasite Pomphorhynchus laevis which swells its proboscis to attach to its host’s intestinal wall, we have developed a biphasic microneedle array that mechanically interlocks with tissue through swellable microneedle tips, achieving ~ 3.5 fold increase in adhesion strength compared to staples in skin graft fixation, and removal force of ~ 4.5 N/cm2 from intestinal mucosal tissue. Comprising a poly(styrene)-block-poly(acrylic acid) swellable tip and non-swellable polystyrene core, conical microneedles penetrate tissue with minimal insertion force and depth, yet high adhesion strength in their swollen state. Uniquely, this design provides universal soft tissue adhesion with minimal damage, less traumatic removal, reduced risk of infection and delivery of bioactive therapeutics. PMID:23591869

Curved Microneedle Array-Based sEMG Electrode for Robust Long-Term Measurements and High Selectivity

PubMed Central

Kim, Minjae; Kim, Taewan; Kim, Dong Sung; Chung, Wan Kyun

2015-01-01

Surface electromyography is widely used in many fields to infer human intention. However, conventional electrodes are not appropriate for long-term measurements and are easily influenced by the environment, so the range of applications of sEMG is limited. In this paper, we propose a flexible band-integrated, curved microneedle array electrode for robust long-term measurements, high selectivity, and easy applicability. Signal quality, in terms of long-term usability and sensitivity to perspiration, was investigated. Its motion-discriminating performance was also evaluated. The results show that the proposed electrode is robust to perspiration and can maintain a high-quality measuring ability for over 8 h. The proposed electrode also has high selectivity for motion compared with a commercial wet electrode and dry electrode. PMID:26153773

Microneedles As a Delivery System for Gene Therapy

PubMed Central

Chen, Wei; Li, Hui; Shi, De; Liu, Zhenguo; Yuan, Weien

2016-01-01

Gene delivery systems can be divided to two major types: vector-based (either viral vector or non-viral vector) and physical delivery technologies. Many physical carriers, such as electroporation, gene gun, ultrasound start to be proved to have the potential to enable gene therapy. A relatively new physical delivery technology for gene delivery consists of microneedles (MNs), which has been studied in many fields and for many molecule types and indications. Microneedles can penetrate the stratum corneum, which is the main barrier for drug delivery through the skin with ease of administration and without significant pain. Many different kinds of MNs, such as metal MNs, coated MNs, dissolving MNs have turned out to be promising in gene delivery. In this review, we discussed the potential as well as the challenges of utilizing MNs to deliver nucleic acids for gene therapy. We also proposed that a combination of MNs and other gene delivery approaches may lead to a better delivery system for gene therapy. PMID:27303298

Iontophoretic and Microneedle Mediated Transdermal Delivery of Glycopyrrolate

PubMed Central

Gujjar, Meera; Banga, Ajay K.

2014-01-01

Purpose: The objective of this study was to investigate the use of iontophoresis, soluble microneedles and their combination for the transdermal delivery of glycopyrrolate. Methods: In vitro permeation was tested using full thickness porcine ear skin mounted onto Franz diffusion cells. Iontophoresis (0.5 mA/cm2) was done for 4 h using Ag/AgCl electrodes. For microneedles, three line array (27 needles/line) of maltose microneedles were used to microporate the skin prior to mounting. Pore uniformity was determined by taking fluorescent images of distribution of calcein into pores and processing the images using an image analysis tool, which measured the fluorescent intensity in and around each pore to provide a pore permeability index (PPI). The donor chamber contained 500 µL of a 1 mg/mL solution of glycopyrrolate, and the receptor chamber contained 5 mL of 50 mM NaCl in deionized water. Samples were collected at predetermined time points over a period of 24 h and analyzed by HPLC. Skin irritation testing was performed with a 3D cell culture kit of human skin. MTT assay determined cell viability; viability less than 50% was considered irritant. Results: A control experiment which investigated passive permeation of glycopyrrolate delivered an average cumulative amount of 24.92 ± 1.77 µg/cm2 at 24 h, while microneedle pretreatment increased permeability to 46.54 ± 6.9 µg/cm2. Both iontophoresis (158.53 ± 17.50 µg/cm2) and a combination of iontophoresis and microneedles (182.43 ± 20.06 µg/ cm2) significantly increased delivery compared to passive and microneedles alone. Glycopyrrolate solution was found to be nonirritant with cell viability of 70.4% ± 5.03%. Conclusion: Iontophoresis and a combination of iontophoresis with microneedle pretreatment can be effectively used to enhance the transdermal delivery of glycopyrrolate. Glycopyrrolate was found to be non-irritant to skin. PMID:25533309

Transcutaneous immunization via rapidly dissolvable microneedles protects against hand-foot-and-mouth disease caused by enterovirus 71.

PubMed

Zhu, Zhuangzhi; Ye, Xiaohua; Ku, Zhiqiang; Liu, Qingwei; Shen, Chaoyun; Luo, Huafei; Luan, Hansen; Zhang, Chenghao; Tian, Shaoqiong; Lim, CheeYen; Huang, Zhong; Wang, Hao

2016-12-10

Recent large outbreaks of hand-foot-and-mouth disease (HFMD) have seriously affected the health of young children. Enterovirus 71 (EV71) is the main causative agent of HFMD. Herein, for the first time, rapidly dissolvable microneedles (MNs) loaded with EV71 virus-like particles (VLPs) were evaluated whether they could induce robust immune responses that confer protection against EV71 infection. The characteristics of prepared MNs including hygroscopy, mechanical strength, insertion capacity, dissolution profile, skin irritation and storage stability were comprehensively assessed. EV71 VLPs remained morphologically stable during fabrication. The MNs made of sodium hyaluronate maintained their insertion ability for at least 3h even at a high relative humidity of 75%. With the aid of spring-operated applicator, EV71 MNs (approximately 500μm length) could be readily penetrated into the mouse skin in vivo, and then rapidly dissolved to release encapsulated antigen within 2min. Additionally, MNs induced slight erythema that disappeared within a few hours. More importantly, mouse immunization and virus challenge studies demonstrated that MNs immunization induced high level of antibody responses conferring full protection against lethal EV71 virus challenge that were comparable to conventional intramuscular injection, but with only 1/10th of the delivered antigen (dose sparing). Consequently, our rapidly dissolving MNs may present as an effective and promising transcutaneous immunization device for HFMD prophylaxis among children. Copyright © 2016 Elsevier B.V. All rights reserved.

Enhanced immunity in intradermal vaccination by novel hollow microneedles.

PubMed

Ogai, N; Nonaka, I; Toda, Y; Ono, T; Minegishi, S; Inou, A; Hachiya, M; Fukamizu, H

2018-04-29

The intradermal (ID) route for vaccination represents an effective alternative to subcutaneous (SC)/intramuscular administration to induce protective immunity. However, a critical issue associated with ID vaccination is the precise delivery of solution in the upper dermis, which ensures enhanced immunity. We fabricated a hollow microneedle unit made of poly-glycolic acid by injection molding and bonding, and created a dedicated prototype injector. To ensure ID delivery of solution, the injected site was macroscopically and microscopically examined. Serum immunoglobulin G antibody production was measured by enzyme immunoassay and compared in groups of rats following either ID delivery with microneedles or SC administration with a 27-G stainless needle of graded vaccine doses. The unit used a tandem array of six microneedles, each with a side delivery hole, and a conduit inside for solution. Microneedles installed in the injector punctured the skin with the aid of a spring. Injection of solution formed a wheal due to ID distribution. Histologically, a wedge-shaped skin defect in the upper skin corresponded to each puncture site. Antibody titers following vaccinations on days 1 and 8 were significantly higher with ID injection than with SC delivery on day 15 and every 7 days thereafter until day 36 with mumps vaccination, and until day 36 with varicella vaccination. The microneedle unit presented here delivered solution intradermally without any difficulty and evoked antibody responses against viruses even with the reduced vaccine volume. Our findings confirm promising results of ID delivery as an immunogenic option to enhance vaccination efficacy. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Simultaneous recordings of force and sliding movement between a myosin-coated glass microneedle and actin cables in vitro.

PubMed

Chaen, S; Oiwa, K; Shimmen, T; Iwamoto, H; Sugi, H

1989-03-01

To elucidate the molecular mechanism of muscle contraction resulting from the ATP-dependent actin-myosin interaction, we constructed an assay system with which both the force and the movement produced by the actin-myosin interaction in vitro can be simultaneously recorded and analyzed. The assay system consisted of the giant internodal cells of an alga, Nitellopsis obtusa, which contain well-organized arrays of actin filaments (actin cables) running along the cell long axis, and a glass microneedle (tip diameter, approximately 7 microns; elastic coefficient, approximately 40 pN/microns), which was coated with skeletal muscle myosin at the tip and extended from a micromanipulator at right angles with the actin cables. When the myosin-coated tip of the microneedle was brought into contact with the exposed surface of the actin cables, it exhibited ATP-dependent movement along the actin cables over a distance of 20-150 microns in 20-200 s (20-23 degrees C) and eventually stopped due to a balance between forces generated by the actin-myosin interaction (800-6000 pN) and by the bent microneedle. Since the load on the force-generating myosin molecules increased with the bending displacement of the microneedle (auxotonic condition), the relation between the load and the sliding velocity of the myosin heads past the actin cables was determined from the time course of the microneedle movement recorded with a video system. The shape of the force-velocity curve thus obtained was convex upwards, similar to that of the force-velocity curve of intact frog muscle fibers obtained under the auxotonic condition.

Microneedle delivery of trivalent influenza vaccine to the skin induces long-term cross-protection.

PubMed

Kim, Yeu-Chun; Lee, Su-Hwa; Choi, Won-Hyung; Choi, Hyo-Jick; Goo, Tae-Won; Lee, Ju-Hie; Quan, Fu-Shi

2016-12-01

A painless self-immunization method with effective and broad cross-protection is urgently needed to prevent infections against newly emerging influenza viruses. In this study, we investigated the cross-protection efficacy of trivalent influenza vaccine containing inactivated A/PR/8/34 (H1N1), A/Hong Kong/68 (H3N2) and B/Lee/40 after skin vaccination using microneedle patches coated with this vaccine. Microneedle vaccination of mice in the skin provided 100% protection against lethal challenges with heterologous pandemic strain influenza A/California/04/09, heterogeneous A/Philippines/2/82 and B/Victoria/287 viruses 8 months after boost immunization. Cross-reactive serum IgG antibody responses against heterologous influenza viruses A/California/04/09, A/Philippines/2/82 and B/Victoria/287 were induced at high levels. Hemagglutination inhibition titers were also maintained at high levels against these heterogeneous viruses. Microneedle vaccination induced substantial levels of cross-reactive IgG antibody responses in the lung and cellular immune responses, as well as cross-reactive antibody-secreting plasma cells in the spleen. Viral loads in the lung were significantly (p < 0.05) reduced. All mice survived after viral challenges. These results indicate that skin vaccination with trivalent vaccine using a microneedle array could provide protection against seasonal epidemic or new pandemic strain of influenza viruses.

Fabrication of Micro-Needle Electrodes for Bio-Signal Recording by a Magnetization-Induced Self-Assembly Method

PubMed Central

Chen, Keyun; Ren, Lei; Chen, Zhipeng; Pan, Chengfeng; Zhou, Wei; Jiang, Lelun

2016-01-01

Micro-needle electrodes (MEs) have attracted more and more attention for monitoring physiological electrical signals, including electrode-skin interface impedance (EII), electromyography (EMG) and electrocardiography (ECG) recording. A magnetization-induced self-assembling method (MSM) was developed to fabricate a microneedle array (MA). A MA coated with Ti/Au film was assembled as a ME. The fracture and insertion properties of ME were tested by experiments. The bio-signal recording performance of the ME was measured and compared with a typical commercial wet electrode (Ag/AgCl electrode). The results show that the MA self-assembled from the magnetic droplet array under the sum of gravitational surface tension and magnetic potential energies. The ME had good toughness and could easily pierce rabbit skin without being broken or buckling. When the compression force applied on the ME was larger than 2 N, ME could stably record EII, which was a lower value than that measured by Ag/AgCl electrodes. EMG signals collected by ME varied along with the contraction of biceps brachii muscle. ME could record static ECG signals with a larger amplitude and dynamic ECG signals with more distinguishable features in comparison with a Ag/AgCl electrode, therefore, ME is an alternative electrode for bio-signal monitoring in some specific situations. PMID:27657072

Long-lived tissue resident HIV-1 specific memory CD8+ T cells are generated by skin immunization with live virus vectored microneedle arrays.

PubMed

Zaric, Marija; Becker, Pablo Daniel; Hervouet, Catherine; Kalcheva, Petya; Ibarzo Yus, Barbara; Cocita, Clement; O'Neill, Lauren Alexandra; Kwon, Sung-Yun; Klavinskis, Linda Sylvia

2017-12-28

The generation of tissue resident memory (T RM ) cells at the body surfaces to provide a front line defence against invading pathogens represents an important goal in vaccine development for a wide variety of pathogens. It has been widely assumed that local vaccine delivery to the mucosae is necessary to achieve that aim. Here we characterise a novel micro-needle array (MA) delivery system fabricated to deliver a live recombinant human adenovirus type 5 vaccine vector (AdHu5) encoding HIV-1 gag. We demonstrate rapid dissolution kinetics of the microneedles in skin. Moreover, a consequence of MA vaccine cargo release was the generation of long-lived antigen-specific CD8 + T cells that accumulate in mucosal tissues, including the female genital and respiratory tract. The memory CD8 + T cell population maintained in the peripheral mucosal tissues was attributable to a MA delivered AdHu5 vaccine instructing CD8 + T cell expression of CXCR3 + , CD103 +, CD49a + , CD69 + , CD127 + homing, retention and survival markers. Furthermore, memory CD8 + T cells generated by MA immunization significantly expanded upon locally administered antigenic challenge and showed a predominant poly-functional profile producing high levels of IFNγ and Granzyme B. These data demonstrate that skin vaccine delivery using microneedle technology induces mobilization of long lived, poly-functional CD8 + T cells to peripheral tissues, phenotypically displaying hallmarks of residency and yields new insights into how to design and deliver effective vaccine candidates with properties to exert local immunosurveillance at the mucosal surfaces. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Simultaneous recordings of force and sliding movement between a myosin-coated glass microneedle and actin cables in vitro.

PubMed Central

Chaen, S; Oiwa, K; Shimmen, T; Iwamoto, H; Sugi, H

1989-01-01

To elucidate the molecular mechanism of muscle contraction resulting from the ATP-dependent actin-myosin interaction, we constructed an assay system with which both the force and the movement produced by the actin-myosin interaction in vitro can be simultaneously recorded and analyzed. The assay system consisted of the giant internodal cells of an alga, Nitellopsis obtusa, which contain well-organized arrays of actin filaments (actin cables) running along the cell long axis, and a glass microneedle (tip diameter, approximately 7 microns; elastic coefficient, approximately 40 pN/microns), which was coated with skeletal muscle myosin at the tip and extended from a micromanipulator at right angles with the actin cables. When the myosin-coated tip of the microneedle was brought into contact with the exposed surface of the actin cables, it exhibited ATP-dependent movement along the actin cables over a distance of 20-150 microns in 20-200 s (20-23 degrees C) and eventually stopped due to a balance between forces generated by the actin-myosin interaction (800-6000 pN) and by the bent microneedle. Since the load on the force-generating myosin molecules increased with the bending displacement of the microneedle (auxotonic condition), the relation between the load and the sliding velocity of the myosin heads past the actin cables was determined from the time course of the microneedle movement recorded with a video system. The shape of the force-velocity curve thus obtained was convex upwards, similar to that of the force-velocity curve of intact frog muscle fibers obtained under the auxotonic condition. Images PMID:2922395

Innovative polymeric system (IPS) for solvent-free lipophilic drug transdermal delivery via dissolving microneedles.

PubMed

Dangol, Manita; Yang, Huisuk; Li, Cheng Guo; Lahiji, Shayan Fakhraei; Kim, Suyong; Ma, Yonghao; Jung, Hyungil

2016-02-10

Lipophilic drugs are potential drug candidates during drug development. However, due to the need for hazardous organic solvents for their solubilization, these drugs often fail to reach the pharmaceutical market, and in doing so highlight the importance of solvent free systems. Although transdermal drug delivery systems (TDDSs) are considered prospective safe drug delivery routes, a system involving lipophilic drugs in solvent free or powder form has not yet been described. Here, we report, for the first time, a novel approach for the delivery of every kind of lipophilic drug in powder form based on an innovative polymeric system (IPS). The phase transition of powder form of lipophilic drugs due to interior chemical bonds between drugs and biodegradable polymers and formation of nano-sized colloidal structures allowed the fabrication of dissolving microneedles (DMNs) to generate a powerful TDDS. We showed that IPS based DMN with powder capsaicin enhances the therapeutic effect for treatment of the rheumatic arthritis in a DBA/1 mouse model compared to a solvent-based system, indicating the promising potential of this new solvent-free platform for lipophilic drug delivery. Copyright © 2016 Elsevier B.V. All rights reserved.

Dissolving polymeric microneedle arrays for electrically assisted transdermal drug delivery.

PubMed

Garland, Martin J; Caffarel-Salvador, Ester; Migalska, Katarzyna; Woolfson, A David; Donnelly, Ryan F

2012-04-10

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, no reports exist on the combination of ITP with in situ drug loaded polymeric MN delivery systems. Furthermore, although a number of studies have highlighted the importance of MN design for transdermal drug delivery enhancement, to date, there has been no systematic investigation of the influence of MN geometry on the performance of polymeric MN arrays which are designed to remain in contact with the skin during the period of drug delivery. As such, for the first time, this study reports on the effect of MN heigth and MN density upon the transdermal delivery of small hydrophilic compounds (theophylline, methylene blue, and fluorescein sodium) across neonatal porcine skin in vitro, with the optimised MN array design evaluated for its potential in the electrically faciliatated delivery of peptide (bovine insulin) and protein (fluorescein isothiocyanate-labelled bovine serum albumin (FTIC-BSA)) macromolecules. The results of the in vitro drug release investigations revealed that the extent of transdermal delivery was dependent upon the design of the MN array employed, whereby an increase in MN height and an increase in MN density led to an increase in the extent of transdermal drug delivery achieved 6h after MN application. Overall, the in vitro permeation studies revealed that the MN design containing 361 MNs/cm(2) of 600 μm height resulted in the greatest extent of transdermal drug delivery. As such, this design was evaluated for its potential in the MN mediated iontophoretic transdermal delivery. Whilst the combination of MN and ITP did not further enhance the extent of small molecular weight solute delivery, the extent of peptide/protein release was significantly enhanced when ITP was used in combination of the soluble PMVE/MA MN arrays. For example, the cumulative amount of insulin permeated across neonatal porcine skin at 6h was found to be approximately 150 μg (3.25%), 227 μg (4.85%) and 462 μg (9.87%) for ITP, MN, and MN/ITP delivery strategies, respectively. Similarly, the cumulative amount of FTIC-BSA delivered across neonatal porcine skin after a 6h period was found to be approximately 110 μg (4.53%) for MN alone and 326 μg (13.40%) for MN in combination with anodal ITP (p<0.001). As such, drug loaded soluble PMVE/MA MN arrays show promise for the electrically controlled transdermal delivery of biomacromolecules in a simple, one-step approach. Copyright © 2012 Elsevier B.V. All rights reserved.

Hydrogel-forming microneedle arrays: Potential for use in minimally-invasive lithium monitoring.

PubMed

Eltayib, Eyman; Brady, Aaron J; Caffarel-Salvador, Ester; Gonzalez-Vazquez, Patricia; Zaid Alkilani, Ahlam; McCarthy, Helen O; McElnay, James C; Donnelly, Ryan F

2016-05-01

We describe, for the first time, hydrogel-forming microneedle (s) (MN) arrays for minimally-invasive extraction and quantification of lithium in vitro and in vivo. MN arrays, prepared from aqueous blends of hydrolysed poly(methyl-vinylether-co-maleic anhydride) and crosslinked by poly(ethyleneglycol), imbibed interstitial fluid (ISF) upon skin insertion. Such MN were always removed intact. In vitro, mean detected lithium concentrations showed no significant difference following 30min MN application to excised neonatal porcine skin for lithium citrate concentrations of 0.9 and 2mmol/l. However, after 1h application, the mean lithium concentrations extracted were significantly different, being appropriately concentration-dependent. In vivo, rats were orally dosed with lithium citrate equivalent to 15mg/kg and 30mg/kg lithium carbonate, respectively. MN arrays were applied 1h after dosing and removed 1h later. The two groups, having received different doses, showed no significant difference between lithium concentrations in serum or MN. However, the higher dosed rats demonstrated a lithium concentration extracted from MN arrays equivalent to a mean increase of 22.5% compared to rats which received the lower dose. Hydrogel-forming MN clearly have potential as a minimally-invasive tool for lithium monitoring in outpatient settings. We will now focus on correlation between serum and MN lithium concentrations. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Low temperature fabrication of biodegradable sugar glass microneedles for transdermal drug delivery applications.

PubMed

Martin, C J; Allender, C J; Brain, K R; Morrissey, A; Birchall, J C

2012-02-28

Transdermal drug delivery is limited by the barrier properties of the outer skin layer. Microneedles (MNs) effectively circumvent the skin barrier to offer this route as a potential alternative to oral and parenteral delivery of therapeutics. Biodegradable microneedles offer particular advantages however processing commonly requires elevated temperatures that may adversely affect heat-labile molecules and macromolecules. In this study, solid amorphous sugar glasses containing low residual quantities of water were created by dehydration of trehalose and sucrose sugar combination solutions. Biodegradable sugar glass MNs were fabricated following optimisation of a simple and novel low temperature vacuum deposition micromoulding methodology. These had absolute morphological fidelity to silicon master structures and demonstrated sufficient structural rigidity to efficiently penetrate excised human breast skin. Sugar glass MNs incorporating a marker compound dissolved rapidly and completely in situ releasing dye into deeper skin layers. The biological activity of a model macromolecule was partially retained over extended storage following incorporation into sugar glass. This is the first demonstration that MNs created from amorphous sugar glasses can be used for incorporating and delivering molecules, and potentially biologically active macromolecules, via the transdermal route. Copyright © 2011 Elsevier B.V. All rights reserved.

Multifunctional particle-constituted microneedle arrays as cutaneous or mucosal vaccine adjuvant-delivery systems

PubMed Central

Wang, Xueting; Wang, Ning; Li, Ning; Zhen, Yuanyuan; Wang, Ting

2016-01-01

ABSTRACT To overcome drawbacks of current injection vaccines, such as causing needle phobia, needing health professionals for inoculation, and generating dangerous sharps wastes, researchers have designed novel vaccines that are combined with various microneedle arrays (MAs), in particular, with the multifunctional particle-constructed MAs (MPMAs). MPMAs prove able to enhance vaccine stability through incorporating vaccine ingredients in the carrier, and can be painlessly inoculated by minimally trained workers or by self-administration, leaving behind no metal needle pollution while eliciting robust systemic and mucosal immunity to antigens, thanks to delivering vaccines to cutaneous or mucosal compartments enriched in professional antigen-presenting cells (APCs). Especially, MPMAs can be easily integrated with functional molecules fulfilling targeting vaccine delivery or controlling immune response toward a Th1 or Th2 pathway to generate desired immunity against pathogens. Herein, we introduce the latest research and development of various MPMAs which are a novel but promising vaccine adjuvant delivery system (VADS). PMID:27159879

Enhanced Transdermal Delivery by Combined Application of Dissolving Microneedle Patch on Serum-Treated Skin.

PubMed

Kim, Suyong; Dangol, Manita; Kang, Geonwoo; Lahiji, Shayan F; Yang, Huisuk; Jang, Mingyu; Ma, Yonghao; Li, Chengguo; Lee, Sang Gon; Kim, Chang Hyun; Choi, Young Wook; Kim, So Jeong; Ryu, Ja Hyun; Baek, Ji Hwoon; Koh, Jaesuk; Jung, Hyungil

2017-06-05

Dissolving microneedle (DMN), a transdermal drug delivery system in which drugs are encapsulated in a biodegradable polymeric microstructure, is designed to dissolve after skin penetration and release the encapsulated drugs into the body. However, because of limited loading capacity of drugs within microsized structures, only a small dosage can be delivered, which is often insufficient for patients. We propose a novel DMN application that combines topical and DMN application simultaneously to improve skin permeation efficiency. Drugs in pretreated topical formulation and encapsulated drugs in DMN patch are delivered into the skin through microchannels created by DMN application, thus greatly increasing the delivered dose. We used 4-n-butylresorcinol to treat human hyperpigmentation and found that sequential application of serum formulation and DMNs was successful. In skin distribution experiments using Alexa Fluor 488 and 568 dyes as model drugs, we confirmed that the pretreated serum formulation was delivered into the skin through microchannels created by the DMNs. In vitro skin permeation and retention experiments confirmed that this novel combined application delivered more 4-n-butylresorcinol into the skin than traditional DMN-only and serum-only applications. Moreover, this combined application showed a higher efficacy in reducing patients' melanin index and hyperpigmented regions compared with the serum-only application. As combined application of DMNs on serum-treated skin can overcome both dose limitations and safety concerns, this novel approach can advance developments in transdermal drug delivery.

Children's views on microneedle use as an alternative to blood sampling for patient monitoring.

PubMed

Mooney, Karen; McElnay, James C; Donnelly, Ryan F

2014-10-01

To explore children's views on microneedle use for this population, particularly as an alternative approach to blood sampling, in monitoring applications, and so, examine the acceptability of this approach to children. Focus groups were conducted with children (aged 10-14 years) in a range of schools across Northern Ireland. Convenience sampling was employed, i.e. children involved in a university-directed community-outreach project (Pharmacists in Schools) were recruited. A total of 86 children participated in 13 focus groups across seven schools in Northern Ireland. A widespread disapproval for blood sampling was evident, with pain, blood and traditional needle visualisation particularly unpopular aspects. In general, microneedles had greater visual acceptability and caused less fear. A patch-based design enabled minimal patient awareness of the monitoring procedure, with personalised designs, e.g. cartoon themes, favoured. Children's concerns included possible allergy and potential inaccuracies with this novel approach; however, many had confidence in the judgement of healthcare professionals if deeming this technique appropriate. They considered paediatric patient education critical for acceptance of this new approach and called for an alternative name, without any reference to 'needles'. The findings presented here support the development of blood-free, minimally invasive techniques and provide an initial indication of microneedle acceptability in children, particularly for monitoring purposes. A proactive response to these unique insights should enable microneedle array design to better meet the needs of this end-user group. Further work in this area is recommended to ascertain the perspectives of a purposive sample of children with chronic conditions who require regular monitoring. © 2013 Royal Pharmaceutical Society.

Titanium-based, fenestrated, in-plane microneedles for passive ocular drug delivery.

PubMed

Khandan, Omid; Famili, Amin; Kahook, Malik Y; Rao, Masaru P

2012-01-01

Drug delivery to the eye remains a key challenge, due to limitations inherent to prevailing delivery techniques. For example, while topical delivery offers simplicity and safety, its efficacy is often limited by poor bioavailability, due to natural transport barriers and clearance mechanisms. Similarly, while intravitreal injections performed across the ocular tunic provide means for circumventing such limitations, non-negligible potential for retinal detachment and other complications adversely affects safety. Herein, we discuss our initial efforts to address these limitations through development of titanium-based microneedles (MNs) which seek to provide a safer, simpler, and more efficacious means of ocular drug delivery. Devices with in-plane geometry and through-thickness fenestrations that serve as drug reservoirs for passive delivery via diffusive transport from fast-dissolving coatings are demonstrated. Details regarding device design, fabrication, and mechanical testing are presented, as are results from preliminary coating characterization and insertion testing in ex vivo rabbit cornea.

Clinical study and stability assessment of a novel transcutaneous influenza vaccination using a dissolving microneedle patch.

PubMed

Hirobe, Sachiko; Azukizawa, Hiroaki; Hanafusa, Takaaki; Matsuo, Kazuhiko; Quan, Ying-Shu; Kamiyama, Fumio; Katayama, Ichiro; Okada, Naoki; Nakagawa, Shinsaku

2015-07-01

Transcutaneous immunization (TCI) is an attractive vaccination method compared with conventional injectable vaccines because it is easier to administer without pain. We developed a dissolving microneedle patch (MicroHyala, MH) made of hyaluronic acid and showed that transcutaneous vaccination using MH induced a strong immune response against various antigens in mice. In the present study, we investigated the clinical safety and efficacy of a novel transcutaneous influenza vaccine using MH (flu-MH), which contains trivalent influenza hemagglutinins (15 μg each). Subjects of the TCI group were treated transcutaneously with flu-MH, and were compared with subjects who received subcutaneous injections of a solution containing 15 μg of each influenza antigen (SCI group). No severe local or systemic adverse events were detected in either group and immune responses against A/H1N1 and A/H3N2 strains were induced equally in the TCI and SCI groups. Moreover, the efficacy of the vaccine against the B strain in the TCI group was stronger than that in the SCI group. Influenza vaccination using MH is promising for practical use as an easy and effective method to replace conventional injections systems. Copyright © 2015 Elsevier Ltd. All rights reserved.

Proteomic Characterization of Dermal Interstitial Fluid Extracted Using a Novel Microneedle-Assisted Technique.

PubMed

Tran, Bao Quoc; Miller, Philip R; Taylor, Robert M; Boyd, Gabrielle; Mach, Phillip M; Rosenzweig, C Nicole; Baca, Justin T; Polsky, Ronen; Glaros, Trevor

2018-01-05

As wearable fitness devices have gained commercial acceptance, interest in real-time monitoring of an individual's physiological status using noninvasive techniques has grown. Microneedles have been proposed as a minimally invasive technique for sampling the dermal interstitial fluid (ISF) for clinical monitoring and diagnosis, but little is known about its composition. In this study, a novel microneedle array was used to collect dermal ISF from three healthy human donors and compared with matching serum and plasma samples. Using a shotgun quantitative proteomic approach, 407 proteins were quantified with at least one unique peptide, and of those, 135 proteins were differently expressed at least 2-fold. Collectively, these proteins tended to originate from the cytoplasm, membrane bound vesicles, and extracellular vesicular exosomes. Proteomic analysis confirmed previously published work that indicates that ISF is highly similar to both plasma and serum. In this study, less than one percent of proteins were uniquely identified in ISF. Taken together, ISF could serve as a minimally invasive alternative for blood-derived fluids with potential for real-time monitoring applications.

Non-insulated smooth motion, micro-needles RF fractional treatment for wrinkle reduction and lifting of the lower face: International study.

PubMed

Gold, Michael; Taylor, Mark; Rothaus, Kenneth; Tanaka, Yohei

2016-10-01

Skin aging occurs through both intrinsic and extrinsic processes. Fractional radiofrequency (RF) with a microneedling array is the newest form of fractional therapy to be useful in treating aging skin. The current study utilized a noninsulated fractional RF microneedling system. This multicenter clinical trial saw 49 patients complete 3 monthly treatments with the new fractional RF microneedling treatments and be followed for 3 months following their last treatment. Pain during treatment was recorded as well as overall improvement using a GAIS scale. Adverse events were also noted. Forty-nine patients completed all of the treatments and follow-ups. Mild to moderate erythema were reported immediately after treatment which lasted up to 12 hours after the treatment. Pain, as measured on a 1-10 VAS, was noted to 4, on average. The average Fitzpatrick's wrinkle scale score at baseline was 5.04 ± 1.22, 1 month after 3 treatments 3.829 ± 1.69 and 3 months after 3 treatments 3.5 ± 1.66. These results are statistically highly significant (correlated T-test, P < 0.001). Improvement was shown in 100% of patients while 65% of patients had significant improvement (GAIS levels 3-5). Significant skin tightening and skin lifting were also observed. No unusual adverse events were noted throughout the course of the study. This multicenter study showed significant wrinkle reduction, skin tightening, and lifting of the mid and lower face with the noninsulated fractional RF microneedling system. Lasers Surg. Med. 48:727-733, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Impact insertion of transfer-molded microneedle for localized and minimally invasive ocular drug delivery.

PubMed

Song, Hyun Beom; Lee, Kang Ju; Seo, Il Ho; Lee, Ji Yong; Lee, Sang-Mok; Kim, Jin Hyoung; Kim, Jeong Hun; Ryu, WonHyoung

2015-07-10

It has been challenging for microneedles to deliver drugs effectively to thin tissues with little background support such as the cornea. Herein, we designed a microneedle pen system, a single microneedle with a spring-loaded microneedle applicator to provide impact insertion. To firmly attach solid microneedles with 140 μm in height at the end of macro-scale applicators, a transfer molding process was employed. The fabricated microneedle pens were then applied to mouse corneas. The microneedle pens successfully delivered rhodamine dye deep enough to reach the stromal layer of the cornea with small entry only about 1000 μm(2). When compared with syringes or 30 G needle tips, microneedle pens could achieve more localized and minimally invasive delivery without any chances of perforation. To investigate the efficacy of microneedle pens as a way of drug delivery, sunitinib malate proven to inhibit in vitro angiogenesis, was delivered to suture-induced angiogenesis model. When compared with delivery by a 30 G needle tip dipped with sunitinib malate, only delivery by microneedle pens could effectively inhibit corneal neovascularization in vivo. Microneedle pens could effectively deliver drugs to thin tissues without impairing merits of using microneedles: localized and minimally invasive delivery. Copyright © 2015 Elsevier B.V. All rights reserved.

Considerations in the use of microneedles: pain, convenience, anxiety and safety.

PubMed

Jeong, Hye-Rin; Lee, Han-Sol; Choi, In-Jeong; Park, Jung-Hwan

2017-01-01

Transdermal delivery using microneedles is gaining increasing attention from pharmaceutical and cosmetic companies as one of the promising drug delivery methods. Microneedle products have recently become available on the market, and some of them are under evaluation for efficacy and safety. To be available in the market for cosmetic and therapeutic use, several factors should be considered, including pain, anxiety, convenience and safety. These factors are summarized and reviewed in this article according to type of microneedle. Various kinds of materials have been used for manufacturing microneedles and developing drug formulations for microneedles. Safety information about materials used for microneedles is summarized in terms of type of microneedles. In addition to their biocompatibility, mechanical safety is also discussed. This review can provide guidelines for designing microneedle products for proper use.

Insertion Process of Ceramic Nanoporous Microneedles by Means of a Novel Mechanical Applicator Design.

PubMed

Hartmann, Xavier H M; van der Linde, Peter; Homburg, Erik F G A; van Breemen, Lambert C A; de Jong, Arthur M; Luttge, Regina

2015-11-18

Arrays of microneedles (MNAs) are integrated in an out-of-plane fashion with a base plate and can serve as patches for the release of drugs and vaccines. We used soft-lithography and micromolding to manufacture ceramic nanoporous (np)MNAs. Failure modes of ceramic npMNAs are as yet poorly understood and the question remained: is our npMNA platform technology ready for microneedle (MN) assembly into patches? We investigated npMNAs by microindentation, yielding average crack fracture forces above the required insertion force for a single MN to penetrate human skin. We further developed a thumb pressure-actuated applicator-assisted npMNA insertion method, which enables anchoring of MNs in the skin by an adhesive in one handling step. Using a set of simple artificial skin models, we found a puncture efficiency of this insertion method a factor three times higher than by applying thumb pressure on the npMNA base plate directly. In addition, this new method facilitated zero MN-breakage due to a well-defined force distribution exerted onto the MNs and the closely surrounding area prior to bringing the adhesive into contact with the skin. Owing to the fact that such parameter space exists, we can conclude that npMNAs by soft lithography are a platform technology for MN assembly into a patch.

A microfluidic distribution system for an array of hollow microneedles

NASA Astrophysics Data System (ADS)

Hoel, Antonin; Baron, Nolwenn; Cabodevila, Gonzalo; Jullien, Marie-Caroline

2008-06-01

We report a microfluidic device able to control the ejection of fluid through a matrix of out-of-plane microneedles. The device comprises a matrix of open dispensing units connected to needles and filled by a common filling system. A deformable membrane (e.g. in PDMS) is brought into contact with the dispensing units. Pressure exerted on the deformable membrane closes (and thus individualizes) each dispensing unit and provokes the ejection of the dispensing unit content through the outlets. Sufficient pressure over the deformable membrane ensures that all dispensing units deliver a fixed volume (their content) irrespective of the hydrodynamic pressure outside the dispensing unit outlet. The size of the ensemble matrix of dispensing units, the number of liquid reservoirs, as well as the material can vary depending on the considered application of the device or on the conditions of use. In the present paper, the liquid reservoirs are geometrically identical. The geometrical parameters of the device are optimized to avoid as much dead volume as possible, as it was to handle plasmid DNA solutions which are very expensive. The conception, the fabrication and the experimental results are described in this paper. Our prototype is conceived to inject in a uniform way 10 µl of drug through 100 microneedles distributed over 1 cm2.

Analysis of Mechanical Failure of Polymer Microneedles by Axial Force

PubMed Central

Park, Jung-Hwan; Prausnitz, Mark R.

2010-01-01

A polymeric microneedle has been developed for drug delivery applications. The ultimate goal of the polymeric microneedle is insertion into the specified region without failure for effective transdermal drug delivery. Mechanical failure of various geometries of microneedles by axial load was modeled using the Euler formula and the Johnson formula to predict the failure force of tapered-column microneedles. These formulas were compared with measured data to identify the mechanical behavior of microneedles by determining the critical factors including the actual length and end-fixed factor. The comparison of the two formulas with the data showed good agreement at the end-fixity (K) of 0.7. This value means that a microneedle column has one fixed end and one pinned end, and that part of the microneedle was overloaded by axial load. When the aspect ratio of length to equivalent diameter is 12:1 at 3 GPa of Young’s modulus, there is a transition from the Euler region to the Johnson region by the decreased length and increased base diameter of the microneedle. A polymer having less than 3 GPa of stiffness would follow the Euler formula. A 12:1 aspect ratio of length to equivalent diameter of the microneedle was the mechanical indicator determining the failure mode between elastic buckling and inelastic buckling at less than 3 GPa of Young’s modulus of polymer. Microneedles with below a 12:1 aspect ratio of length-to-equivalent diameter and more than 3 GPa of Young’s were recommended for reducing sudden failure by buckling and for successfully inserting the microneedle into the skin. PMID:21218133

Microneedle arrays for biosensing and drug delivery

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Joseph; Windmiller, Joshua Ray; Narayan, Roger

Methods, structures, and systems are disclosed for biosensing and drug delivery techniques. In one aspect, a^ device for detecting an analyte and/or releasing a biochemical into a biological fluid can include an array of hollowed needles, in which each needle includes a protruded needle structure including an exterior wall forming a hollow interior and an opening at a terminal end of the protruded needle structure that exposes the hollow interior, and a probe inside the exterior wall to interact with one or more chemical or biological substances that come in contact with the probe via the opening to produce amore » probe sensing signal, and an array of wires that are coupled to probes of the array of hollowed needles, respectively, each wire being electrically conductive to transmit the probe sensing signal produced by a respective probe.« less

Microneedle arrays for biosensing and drug delivery

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Joseph; Windmiller, Joshua Ray; Narayan, Roger

Methods, structures, and systems are disclosed for biosensing and drug delivery techniques. In one aspect, a device for detecting an analyte and/or releasing a biochemical into a biological fluid can include an array of hollowed needles, in which each needle includes a protruded needle structure including an exterior wall forming a hollow interior and an opening at a terminal end of the protruded needle structure that exposes the hollow interior, and a probe inside the exterior wall to interact with one or more chemical or biological substances that come in contact with the probe via the opening to produce amore » probe sensing signal, and an array of wires that are coupled to probes of the array of hollowed needles, respectively, each wire being electrically conductive to transmit the probe sensing signal produced by a respective probe.« less

Hydrogel-forming microneedles increase in volume during swelling in skin, but skin barrier function recovery is unaffected

PubMed Central

Donnelly, Ryan F.; Mooney, Karen; McCrudden, Maelíosa T.C.; Vicente-Pérez, Eva M.; Belaid, Luc; González-Vázquez, Patricia; McElnay, James C.; Woolfson, A. David

2014-01-01

We describe, for the first time, quantification of in-skin swelling and fluid uptake by hydrogel-forming microneedle arrays (MN) and skin barrier recovery in human volunteers. Such MN, prepared from aqueous blends of hydrolysed poly(methylvinylether/maleicanhydride) (15% w/w) and the crosslinker poly(ethyleneglycol) 10,000 daltons (7.5% w/w), were inserted into the skin of human volunteers (n = 15) to depths of approximately 300 μm by gentle hand pressure. The MN swelled in skin, taking up skin interstitial fluid, such that their mass had increased by approximately 30% after 6 hours in skin. Importantly, however, skin barrier function recovered within 24 hours post microneedle removal, regardless of how long the MN had been in skin or how much their volume had increased with swelling. Further research on closure of MN-induced micropores is required, since transepidermal water loss measurements suggested micropore closure, while optical coherence tomography indicated that MN-induced micropores had not closed over, even 24 hours after MN had been removed. There were no complaints of skin reactions, adverse events or strong views against MN use by any of the volunteers. Only some minor erythema was noted after patch removal, although this always resolved within 48 hours and no adverse events were present on follow-up. PMID:24633895

In-vivo dynamic characterization of microneedle skin penetration using optical coherence tomography

NASA Astrophysics Data System (ADS)

Enfield, Joey; O'Connell, Marie-Louise; Lawlor, Kate; Jonathan, Enock; O'Mahony, Conor; Leahy, Martin

2010-07-01

The use of microneedles as a method of circumventing the barrier properties of the stratum corneum is receiving much attention. Although skin disruption technologies and subsequent transdermal diffusion rates are being extensively studied, no accurate data on depth and closure kinetics of microneedle-induced skin pores are available, primarily due to the cumbersome techniques currently required for skin analysis. We report on the first use of optical coherence tomography technology to image microneedle penetration in real time and in vivo. We show that optical coherence tomography (OCT) can be used to painlessly measure stratum corneum and epidermis thickness, as well as microneedle penetration depth after microneedle insertion. Since OCT is a real-time, in-vivo, nondestructive technique, we also analyze skin healing characteristics and present quantitative data on micropore closure rate. Two locations (the volar forearm and dorsal aspect of the fingertip) have been assessed as suitable candidates for microneedle administration. The results illustrate the applicability of OCT analysis as a tool for microneedle-related skin characterization.

Spatially discrete thermal drawing of biodegradable microneedles for vascular drug delivery.

PubMed

Choi, Chang Kuk; Lee, Kang Ju; Youn, Young Nam; Jang, Eui Hwa; Kim, Woong; Min, Byung-Kwon; Ryu, WonHyoung

2013-02-01

Spatially discrete thermal drawing is introduced as a novel method for the fabrication of biodegradable microneedles with ultra-sharp tip ends. This method provides the enhanced control of microneedle shapes by spatially controlling the temperature of drawn polymer as well as drawing steps and speeds. Particular focus is given on the formation of sharp tip ends of microneedles at the end of thermal drawing. Previous works relied on the fracture of polymer neck by fast drawing that often causes uncontrolled shapes of microneedle tips. Instead, this approach utilizes the surface energy of heated polymer to form ultra-sharp tip ends. We have investigated the effect of such temperature control, drawing speed, and drawing steps in thermal drawing process on the final shape of microneedles using biodegradable polymers. XRD analysis was performed to analyze the effect of thermal cycle on the biodegradable polymer. Load-displacement measurement also showed the dependency of mechanical strengths of microneedles on the microneedle shapes. Ex vivo vascular tissue insertion and drug delivery demonstrated microneedle insertion to tunica media layer of canine aorta and drug distribution in the tissue layer. Copyright © 2012 Elsevier B.V. All rights reserved.

Permeation of antigen protein-conjugated nanoparticles and live bacteria through microneedle-treated mouse skin

PubMed Central

Kumar, Amit; Li, Xinran; Sandoval, Michael A; Rodriguez, B Leticia; Sloat, Brian R; Cui, Zhengrong

2011-01-01

Background: The present study was designed to evaluate the extent to which pretreatment with microneedles can enhance skin permeation of nanoparticles in vitro and in vivo. Permeation of live bacteria, which are physically nanoparticles or microparticles, through mouse skin pretreated with microneedles was also studied to evaluate the potential risk of microbial infection. Methods and results: It was found that pretreatment of mouse skin with microneedles allowed permeation of solid lipid nanoparticles, size 230 nm, with ovalbumin conjugated on their surface. Transcutaneous immunization in a mouse skin area pretreated with microneedles with ovalbumin nanoparticles induced a stronger antiovalbumin antibody response than using ovalbumin alone. The dose of ovalbumin antigen determined whether microneedle-mediated transcutaneous immunization with ovalbumin nanoparticles induced a stronger immune response than subcutaneous injection of the same ovalbumin nanoparticles. Microneedle treatment permitted skin permeation of live Escherichia coli, but the extent of the permeation was not greater than that enabled by hypodermic injection. Conclusion: Transcutaneous immunization on a microneedle-treated skin area with antigens carried by nanoparticles can potentially induce a strong immune response, and the risk of bacterial infection associated with microneedle treatment is no greater than that with a hypodermic injection. PMID:21753877

Local transdermal delivery of phenylephrine to the anal sphincter muscle using microneedles

PubMed Central

Baek, Changyoon; Han, MeeRee; Min, Junghong; Prausnitz, Mark R.; Park, Jung-Hwan; Park, Jungho

2014-01-01

We propose pretreatment using microneedles to increase perianal skin permeability for locally targeted delivery of phenylephrine (PE), a drug that increases resting anal sphincter pressure to treat fecal incontinence. Microneedle patches were fabricated by micromolding poly-lactic-acid. Pre-treatment of human cadaver skin with microneedles increased PE delivery across the skin by up to 10-fold in vitro. In vivo delivery was assessed in rats receiving treatment with or without use of microneedles and with or without PE. Resting anal sphincter pressure was then measured over time using water-perfused anorectal manometry. For rats pretreated with microneedles, topical application of 30% PE gel rapidly increased the mean resting anal sphincter pressure from 7 ± 2 cm H2O to a peak value of 43 ± 17 cm H2O after 1 h, which was significantly greater than rats receiving PE gel without microneedle pretreatment. Additional safety studies showed that topically applied green fluorescent protein–expressing E. coli penetrated skin pierced with 23- and 26-gauge hypodermic needles, but E. coli was not detected in skin pretreated with microneedles, which suggests that microneedle-treated skin may not be especially susceptible to infection. In conclusion, this study demonstrates local transdermal delivery of PE to the anal sphincter muscle using microneedles, which may provide a novel treatment for fecal incontinence. PMID:21586307

OCT analysis of microneedle and Er:YAG surface ablation for enhanced transdermal delivery of hyperosmotic agents for optical skin clearing

NASA Astrophysics Data System (ADS)

Stumpp, Oliver F.; Welch, A. J.; Gill, Harvinder S.; Prausnitz, Mark R.

2004-07-01

The purpose of this study is to investigate the feasibility of using microneedles in comparison to Er:YAG skin surface laser ablation as a means to modify the epidermis of in-vitro hamster skin to facilitate delivery of topically applied hyper-osmotics such as glycerol into the skin to achieve optical skin clearing. This allows to temporarily reduce scattering of light in otherwise turbid tissues with potential applications pertaining to non-invasive optical imaging techniques such as optical coherence tomography (OCT) or therapeutic applications like laser blood vessel coagulation to treat port wine stains in skin. A portable, battery powered Er:YAG laser (Lasette) manufactured by Cell Robotics Inc. was used to produce holes in the stratum corneum and epidermis using individual 400 μs pulses causing localized ablation. Following each laser pulse the tissue was mechanically translated by 1 mm before another pulse was delivered. As an alternative method to the use of an expensive laser source requiring some kind of light scanning mechanism to treat larger skin areas efficiently, microneedles were investigated. They do not require an energy supply, are also pain-free and can be manufactured into arrays allowing treatment of larger skin areas. A single application forms micron scale holes in the stratum corneum through which topically applied skin clearing agents such as glycerol can penetrate into the tissue. In this feasibility study individual microneedles were used to manually induce holes in the skin each spaced approximately 1 mm apart from the other. Upon such epidermal modification by either technique, glycerol was then applied to the tissue surface and amplitude OCT measurements monitored changes of the optical properties of the tissue over time. Due to the geometry of the microneedle used in this study the cross sectional area of each hole in the epidermis was about 68% smaller than the comparable ablation site caused by an individual laser pulse. Results indicate enhanced skin clearing rates due to the induced holes in the stratum corneum in both cases by a factor of 5 to 8. Due to the larger area of laser ablation in comparison to the holes caused by microneedles, overall skin clearing rates are higher with the laser. However, localized data analysis near holes produced by either technique yields comparable results which show an increase in the clearing rate of up to 10 to 13 times over intact skin without any holes.

Micropore closure kinetics are delayed following microneedle insertion in elderly subjects.

PubMed

Kelchen, Megan N; Siefers, Kyle J; Converse, Courtney C; Farley, Matthew J; Holdren, Grant O; Brogden, Nicole K

2016-03-10

Transdermal delivery is an advantageous method of drug administration, particularly for an elderly population. Microneedles (MNs) allow transdermal delivery of otherwise skin-impermeable drugs by creating transient micropores that bypass the barrier function of the skin. The response of aging skin to MNs has not been explored, and we report for the first time that micropore closure is delayed in elderly subjects in a manner that is dependent upon MN length, number, and occlusion of the micropores. Twelve control subjects (25.6±2.8years) and 16 elderly subjects (77.3±6.8years) completed the study. Subjects were treated with MNs of 500μm or 750μm length, in arrays containing 10 or 50 MNs. Impedance measurements made at baseline, post-MN insertion, and at predetermined time points demonstrated that restoration of the skin barrier is significantly slower in elderly subjects under both occluded and non-occluded conditions. This was confirmed via calculation of the total permeable area created by the micropores (which would approximate the area available for drug delivery), as well as calculation of the micropore half-life. This pilot study demonstrates that longer timeframes are required to restore the barrier function of aged skin following MN insertion, suggesting that drug delivery windows could be longer following one treatment with a MN array. Copyright © 2016 Elsevier B.V. All rights reserved.

Vaccine delivery to the oral cavity using coated microneedles induces systemic and mucosal immunity

PubMed Central

Ma, Yunzhe; Tao, Wenqian; Krebs, Shelly J.; Sutton, William F.; Haigwood, Nancy L.; Gill, Harvinder S.

2014-01-01

Purpose The objective of this study is to evaluate the feasibility of using coated microneedles to deliver vaccines into the oral cavity to induce systemic and mucosal immune responses. Method Microneedles were coated with sulforhodamine, ovalbumin and two HIV antigens. Coated microneedles were inserted into the inner lower lip and dorsal surface of the tongue of rabbits. Histology was used to confirm microneedle insertion, and systemic and mucosal immune responses were characterized by measuring antigen-specific immunoglobulin G (IgG) in serum and immunoglobulin A (IgA) in saliva, respectively. Results Histological evaluation of tissues shows that coated microneedles can penetrate the lip and tongue to deliver coatings. Using ovalbumin as a model antigen it was found that the lip and the tongue are equally immunogenic sites for vaccination. Importantly, both sites also induced a significant (p < 0.05) secretory IgA in saliva compared to pre-immune saliva. Microneedle-based oral cavity vaccination was also compared to the intramuscular route using two HIV antigens, a virus-like particle and a DNA vaccine. Microneedle-based delivery to the oral cavity and the intramuscular route exhibited similar (p > 0.05) yet significant (p < 0.05) levels of antigen-specific IgG in serum. However, only the microneedle-based oral cavity vaccination group stimulated a significantly higher (p < 0.05) antigen-specific IgA response in saliva, but not intramuscular injection. Conclusion In conclusion, this study provides a novel method using microneedles to induce systemic IgG and secretory IgA in saliva, and could offer a versatile technique for oral mucosal vaccination. PMID:24623480

Infusion pressure and pain during microneedle injection into skin of human subjects.

PubMed

Gupta, Jyoti; Park, Sohyun S; Bondy, Brian; Felner, Eric I; Prausnitz, Mark R

2011-10-01

Infusion into skin using hollow microneedles offers an attractive alternative to hypodermic needle injections. However, the fluid mechanics and pain associated with injection into skin using a microneedle have not been studied in detail before. Here, we report on the effect of microneedle insertion depth into skin, partial needle retraction, fluid infusion flow rate and the co-administration of hyaluronidase on infusion pressure during microneedle-based saline infusion, as well as on associated pain in human subjects. Infusion of up to a few hundred microliters of fluid required pressures of a few hundred mmHg, caused little to no pain, and showed weak dependence on infusion parameters. Infusion of larger volumes up to 1 mL required pressures up to a few thousand mmHg, but still usually caused little pain. In general, injection of larger volumes of fluid required larger pressures and application of larger pressures caused more pain, although other experimental parameters also played a significant role. Among the intradermal microneedle groups, microneedle length had little effect; microneedle retraction lowered infusion pressure but increased pain; lower flow rate reduced infusion pressure and kept pain low; and use of hyaluronidase also lowered infusion pressure and kept pain low. We conclude that microneedles offer a simple method to infuse fluid into the skin that can be carried out with little to no pain. Copyright © 2011 Elsevier Ltd. All rights reserved.

Self-Assembly DNA Polyplex Vaccine inside Dissolving Microneedles for High-Potency Intradermal Vaccination.

PubMed

Liao, Jing-Fong; Lee, Jin-Ching; Lin, Chun-Kuang; Wei, Kuo-Chen; Chen, Pin-Yuan; Yang, Hung-Wei

2017-01-01

The strong immunogenicity induction is the powerful weapon to prevent the virus infections. This study demonstrated that one-step synthesis of DNA polyplex vaccine in microneedle (MN) patches can induce high immunogenicity through intradermal vaccination and increase the vaccine stability for storage outside the cold chain. More negative charged DNA vaccine was entrapped into the needle region of MNs followed by DNA polyplex formation with branched polyethylenimine (bPEI) pre-coated in the cavities of polydimethylsiloxane (PDMS) molds that can deliver more DNA vaccine to immune-cell rich epidermis with high transfection efficiency. Our data in this study support the safety and immunogenicity of the MN-based vaccine; the MN patch delivery system induced an immune response 3.5-fold as strong as seen with conventional intramuscular administration; the DNA polyplex formulation provided excellent vaccine stability at high temperature (could be stored at 45ºC for at least 4 months); the DNA vaccine is expected to be manufactured at low cost and not generate sharps waste. We think this study is significant to public health because there is a pressing need for an effective vaccination in developing countries.

Zein Microneedles for Localized Delivery of Chemotherapeutic Agents to Treat Breast Cancer: Drug Loading, Release Behavior, and Skin Permeation Studies.

PubMed

Bhatnagar, Shubhmita; Kumari, Pooja; Pattarabhiran, Srijanaki Paravastu; Venuganti, Venkata Vamsi Krishna

2018-05-01

Localized delivery of chemotherapeutic agents to treat breast cancer could limit their adverse drug reactions. The aim of this study was to investigate the influence of physico-chemical properties of chemotherapeutic agents in their loading, release behavior, and skin permeation using microneedles. Zein microneedles were fabricated using the micromolding technique containing 36 microneedles in a 1-cm 2 area. These microneedles were loaded with two anti-breast cancer drugs, tamoxifen and gemcitabine, having different water solubilities. Entrapment or surface coating of chemotherapeutic agents in zein microneedles was optimized to achieve greater loading efficiency. The greatest loading achieved was 607 ± 21 and 1459 ± 74 μg for tamoxifen and gemcitabine using the entrapment approach, respectively. Skin permeation studies in excised porcine skin showed that the coating on microneedles approach results in greater skin deposition for tamoxifen; while the poke-and-patch approach would provide greater skin permeation for gemcitabine. Taken together, it can be concluded that different loading strategies and skin penetration approaches have to be studied for delivery of small molecules using polymeric microneedles.

Blood-mimicking delivery in polygonal structure of inner quadrupletip microneedle with valveless micro-pump

NASA Astrophysics Data System (ADS)

Ibrahim, M. D.; Yunos, Y. S.; Rigit, A. R. H.; Mohtadzar, N. A. A.; Watanabe, N.; Sunami, Y.; Rahman, M. R. A.; Wong, L. K.; Mohtar, M. Z.

2017-04-01

This paper presents a titanium quadrupletip micro-needle integrated with a micro-pump with different inner designs, length and diameter of the micro-channels to measure and maximize the velocity flow in the micro-needle as blood delivered into human body. Titanium is used as the material of the micro-needle which are also the common material in manufacturing of micro-needle. The advancement of micro-needle technologies is improved in penetrating human outermost skin, stratum corneum and further to human blood vessels. The micro-needles with channel inner design of circular, square, hexagon, and dodecagon with quadruple tip designs are drawn with inner diameter parameter of 150μm and 100μm with two different channel length which are 10mm and 25mm. The characteristics of blood delivery in geometrically changed inner designs affect the output velocity in microneedle when the micropump is operating. The results showed that, when it is pumped at 0.04m/s, the blood velocity improved by 5.6% than when the pump is increased by 30% of its capacity. This is due to the backflow generated in the micropump.

Hollow agarose microneedle with silver coating for intradermal surface-enhanced Raman measurements: a skin-mimicking phantom study

NASA Astrophysics Data System (ADS)

Yuen, Clement; Liu, Quan

2015-06-01

Human intradermal components contain important clinical information beneficial to the field of immunology and disease diagnosis. Although microneedles have shown great potential to act as probes to break the human skin barrier for the minimally invasive measurement of intradermal components, metal microneedles that include stainless steel could cause the following problems: (1) sharp waste production, and (2) contamination due to reuse of microneedles especially in developing regions. In this study, we fabricate agarose microneedles coated with a layer of silver (Ag) and demonstrate their use as a probe for the realization of intradermal surface-enhanced Raman scattering measurements in a set of skin-mimicking phantoms. The Ag-coated agarose microneedle quantifies a range of glucose concentrations from 5 to 150 mM inside the skin phantoms with a root-mean-square error of 5.1 mM within 10 s. The needle is found enlarged by 53.9% after another 6 min inside the phantom. The shape-changing capability of this agarose microneedle ensures that the reuse of these microneedles is impossible, thus avoiding sharp waste production and preventing needle contamination, which shows the great potential for safe and effective needle-based measurements.

Fiberoptic microneedles: novel optical diffusers for interstitial delivery of therapeutic light.

PubMed

Kosoglu, Mehmet A; Hood, Robert L; Rossmeisl, John H; Grant, David C; Xu, Yong; Robertson, John L; Rylander, Marissa Nichole; Rylander, Christopher G

2011-11-01

Photothermal therapies have limited efficacy and application due to the poor penetration depth of light inside tissue. In earlier work, we described the development of novel fiberoptic microneedles to provide a means to mechanically penetrate dermal tissue and deliver light directly into a localized target area.This paper presents an alternate fiberoptic microneedle design with the capability of delivering more diffuse, but therapeutically useful photothermal energy. Laser lipolysis is envisioned as a future clinical application for this design. A novel fiberoptic microneedle was developed using hydrofluoric acid etching of optical fiber to permit diffuse optical delivery. Microneedles etched for 10, 30, and 50 minutes, and an optical fiber control were compared with three techniques. First, red light delivery from the microneedles was evaluated by imaging the reflectance of the light from a white paper.Second, spatial temperature distribution of the paper in response to near-IR light (1,064 nm, 1 W CW) was recorded using infrared thermography. Third, ex vivo adipose tissue response during 1,064 nm, (5 W CW)irradiation was recorded with bright field microscopy. Acid etching exposed a 3 mm length of the fiber core, allowing circumferential delivery of light along this length. Increasing etching time decreased microneedle diameter, resulting in increased uniformity of red and 1,064 nm light delivery along the microneedle axis. For equivalent total energy delivery, thinner microneedles reduced carbonization in the adipose tissue experiments. We developed novel microscale optical diffusers that provided a more homogeneous light distribution from their surfaces, and compared performance to a flat-cleaved fiber, a device currently utilized in clinical practice. These fiberoptic microneedles can potentially enhance clinical laser procedures by providing direct delivery of diffuse light to target chromophores, while minimizing undesirable photothermal damage in adjacent, non-target tissue. Copyright © 2011 Wiley Periodicals, Inc.

Diclofenac enables unprecedented week-long microneedle-enhanced delivery of a skin impermeable medication in humans

PubMed Central

Brogden, Nicole K.; Banks, Stan L.; Crofford, Leslie J.; Stinchcomb, Audra L.

2013-01-01

Microneedles applied to the skin create micropores, allowing transdermal drug delivery of skin-impermeable compounds. The first human study with this technique demonstrated delivery of naltrexone (an opioid antagonist) for two to three days. Rapid micropore closure, however, blunts the delivery window. Application of diclofenac (an anti-inflammatory) allows seven days of naltrexone delivery in animals. Purpose the purpose of the current work was to demonstrate delivery of naltrexone for seven days following one microneedle treatment in humans. Methods Human subjects were treated with microneedles, diclofenac (or placebo), and naltrexone. Impedance measurements were used as a surrogate marker to measure micropore formation, and plasma naltrexone concentrations were measured for seven days post-microneedle application. Results Impedance dropped significantly from baseline to post-microneedle treatment, confirming micropore formation. Naltrexone was detected for seven days in Group 1 (diclofenac + naltrexone, n = 6), vs. 72 hours in Group 2 (placebo + naltrexone, n = 2). At study completion, a significant difference in impedance was observed between intact and microneedle-treated skin in Group 1 (confirming the presence of micropores). Conclusion This is the first study demonstrating week-long drug delivery after one microneedle application, which would increase patient compliance and allow delivery of therapies for chronic diseases. PMID:23761054

Photoacoustic microscopy imaging for microneedle drug delivery

NASA Astrophysics Data System (ADS)

Moothanchery, Mohesh; Seeni, Razina Z.; Xu, Chenjie; Pramanik, Manojit

2018-02-01

The recent development of novel transdermal drug delivery systems (TDDS) using microneedle technology allows micron-sized conduits to be formed within the outermost skin layers attracting keen interest in skin as an interface for localized and systemic delivery of therapeutics. In light of this, researchers are using microneedles as tools to deliver nanoparticle formulations to targeted sites for effective therapy. However, in such studies the use of traditional histological methods are employed for characterization and do not allow for the in vivo visualization of drug delivery mechanism. Hence, this study presents a novel imaging technology to characterize microneedle based nanoparticle delivery systems using optical resolution-photoacoustic microscopy (OR-PAM). In this study in vivo transdermal delivery of gold nanoparticles using microneedles in mice ear and the spatial distribution of the nanoparticles in the tissue was successfully illustrated. Characterization of parameters that are relevant in drug delivery studies such as penetration depth, efficiency of delivered gold nanoparticles were monitored using the system. Photoacoustic microscopy proves an ideal tool for the characterization studies of microneedle properties and the studies shows microneedles as an ideal tool for precise and controlled drug delivery.

Intrastromal Delivery of Bevacizumab Using Microneedles to Treat Corneal Neovascularization

PubMed Central

Kim, Yoo C.; Grossniklaus, Hans E.; Edelhauser, Henry F.; Prausnitz, Mark R.

2014-01-01

Purpose. This study tested the hypothesis that highly targeted intrastromal delivery of bevacizumab using coated microneedles allows dramatic dose sparing compared with subconjunctival and topical delivery for treatment of corneal neovascularization. Methods. Stainless steel microneedles 400 μm in length were coated with bevacizumab. A silk suture was placed in the cornea approximately 1 mm from the limbus to induce corneal neovascularization in the eyes of New Zealand white rabbits that were divided into different groups: untreated, microneedle delivery, topical eye drop, and subconjunctival injection of bevacizumab. All drug treatments were initiated 4 days after suture placement and area of neovascularization was measured daily by digital photography for 18 days. Results. Eyes treated once with 4.4 μg bevacizumab using microneedles reduced neovascularization compared with untreated eyes by 44% (day 18). Eyes treated once with 2500 μg bevacizumab using subconjunctival injection gave similar results to microneedle-treated eyes. Eyes treated once with 4.4 μg subconjunctival bevacizumab showed no significant effect compared with untreated eyes. Eyes treated with 52,500 μg bevacizumab by eye drops three times per day for 14 days reduced the neovascularization area compared with untreated eyes by 6% (day 18), which was significantly less effective than the single microneedle treatment. Visual exam and histological analysis showed no observable effect of microneedle treatment on corneal transparency or microanatomical structure. Conclusions. This study shows that microneedles can target drug delivery to corneal stroma in a minimally invasive way and demonstrates effective suppression of corneal neovascularization after suture-induced injury using a much lower dose compared with conventional methods. PMID:25212779

Glass microneedles for force measurements: a finite-element analysis model

PubMed Central

Ayittey, Peter N.; Walker, John S.; Rice, Jeremy J.; de Tombe, Pieter P.

2010-01-01

Changes in developed force (0.1–3.0 μN) observed during contraction of single myofibrils in response to rapidly changing calcium concentrations can be measured using glass microneedles. These microneedles are calibrated for stiffness and deflect on response to developed myofibril force. The precision and accuracy of kinetic measurements are highly dependent on the structural and mechanical characteristics of the microneedles, which are generally assumed to have a linear force–deflection relationship. We present a finite-element analysis (FEA) model used to simulate the effects of measurable geometry on stiffness as a function of applied force and validate our model with actual measured needle properties. In addition, we developed a simple heuristic constitutive equation that best describes the stiffness of our range of microneedles used and define limits of geometry parameters within which our predictions hold true. Our model also maps a relation between the geometry parameters and natural frequencies in air, enabling optimum parametric combinations for microneedle fabrication that would reflect more reliable force measurement in fluids and physiological environments. We propose a use for this model to aid in the design of microneedles to improve calibration time, reproducibility, and precision for measuring myofibrillar, cellular, and supramolecular kinetic forces. PMID:19104827

Assessment of solid microneedle rollers to enhance transmembrane delivery of doxycycline and inhibition of MMP activity.

PubMed

Omolu, Abbie; Bailly, Maryse; Day, Richard M

2017-11-01

Many chronic wounds exhibit high matrix metalloproteinase (MMP) activity that impedes the normal wound healing process. Intradermal delivery (IDD) of sub-antimicrobial concentrations of doxycycline, as an MMP inhibitor, could target early stages of chronic wound development and inhibit further wound progression. To deliver doxycycline intradermally, the skin barrier must be disrupted. Microneedle rollers offer a minimally invasive technique to penetrate the skin by creating multiple microchannels that act as temporary conduits for drugs to diffuse through. In this study, an innovative and facile approach for delivery of doxycycline across Strat-M TM membrane was investigated using microneedle rollers. The quantity and rate of doxycycline diffusing through the micropores directly correlated with increasing microneedle lengths (250, 500 and 750 μm). Treatment of Strat-M TM with microneedle rollers resulted in a reduction in fibroblast-mediated collagen gel contraction and MMP activity compared with untreated Strat-M TM . Our results show that treatment of an epidermal mimetic with microneedle rollers provides sufficient permeabilization for doxycycline diffusion and inhibition of MMP activity. We conclude that microneedle rollers are a promising, clinically ready tool suitable for delivery of doxycycline intradermally to treat chronic wounds.

Microneedles for intradermal and transdermal delivery

PubMed Central

Tuan-Mahmood, Tuan-Mazlelaa; McCrudden, Maeliosa T.C.; Torrisi, Barbara M.; McAlister, Emma; Garland, Martin J; Singh, Thakur Raghu Raj; Donnelly, Ryan F

2014-01-01

The formidable barrier properties of the uppermost layer of the skin, the stratum corneum impose significant limitations for successful systemic delivery of a broad range of therapeutic molecules, particularly macromolecules and genetic material. Microneedle delivery has been proposed as a strategy to breach the SC barrier function in order to facilitate effective transport of molecules across the skin. This strategy involves the use of micron sized needles fabricated from different materials and using different geometries to create transient aqueous conduits across the skin. Microneedles in isolation, or in combination with other enhancing strategies, have been shown to dramatically enhance the skin permeability of numerous therapeutic molecules including biopharmaceuticals either in vitro, ex vivo or in vivo. Progress in the areas of microneedle design, development and manufacture have proven promising in terms of the potential use of this emerging delivery method in clinical applications such as insulin delivery, transcutaneous immunisations and cutaneous gene delivery. This review article focuses on recent and potential future developments in microneedle technologies. This will include the detailing of progress made in microneedle design, an exploration of the challenges faced in this field and potential forward strategies to embrace the exploitation of microneedle methodologies, while considering the inherent safety aspects of such therapeutic tools. PMID:23680534

Formulation and coating of microneedles with inactivated influenza virus to improve vaccine stability and immunogenicity

PubMed Central

Kim, Yeu-Chun; Quan, Fu-Shi; Compans, Richard W.; Kang, Sang-Moo; Prausnitz, Mark R.

2009-01-01

Microneedle patches coated with solid-state influenza vaccine have been developed to improve vaccine efficacy and patient coverage. However, dip coating microneedles with influenza vaccine can reduce antigen activity. In this study, we sought to determine the experimental factors and mechanistic pathways by which inactivated influenza vaccine can lose activity, as well as develop and assess improved microneedle coating formulations that protect the antigen from activity loss. After coating microneedles using a standard vaccine formulation, antigenicity was reduced to just 2%, as measured by hemagglutination activity. The presence of carboxymethylcellulose, which was added to increase viscosity of the coating formulation, was shown to contribute to vaccine activity loss. After screening a panel of candidate stabilizers, the addition of trehalose to the coating formulation was shown to protect the antigen and retain 48–82% antigen activity for all three major strains of seasonal influenza: H1N1, H3N2 and B. Influenza vaccine coated in this way also exhibited thermal stability, such that activity loss was independent of temperature over the range of 4 – 37°C for 24 h. Dynamic light scattering measurements showed that antigen activity loss was associated with virus particle aggregation, and that stabilization using trehalose largely blocked this aggregation. Finally, microneedles using an optimized vaccine coating formulation were applied to the skin to vaccinate mice. Microneedle vaccination induced robust systemic and functional antibodies and provided complete protection against lethal challenge infection similar to conventional intramuscular injection. Overall, these results show that antigen activity loss during microneedle coating can be largely prevented through optimized formulation and that stabilized microneedle patches can be used for effective vaccination. PMID:19840825

Biocompatible polymer microneedle for topical/dermal delivery of tranexamic acid.

PubMed

A Machekposhti, S; Soltani, M; Najafizadeh, P; Ebrahimi, S A; Chen, P

2017-09-10

Recently-introduced biocompatible polymeric microneedles offer an efficient method for drug delivery. Tranexamic acid is a novel drug for treating melasma that is administered both locally and orally and inhibits excessive melanin via melanocyte. The tranexamic acid biocompatible polymer microneedle used in this study was fabricated from PVP and methacrylic acid, using the lithography method. The required mechanical strength to pierce skin was attained by optimizing the ratio of PVP to methacrylic acid. Acute dermal toxicity was done, and drug diffusion in skin layers was simulated by calculating the diffusion coefficient of tranexamic acid in interstitial fluid (plasma). The biocompatible polymer microneedle was fabricated at 60°C. Needles could sustain 0.6N that is enough to pierce stratum corneum. 34% of the released drug was locally effective and the rest permeated through the skin. The pyramidal polymer microneedle in this study was fully released in skin in approx. 7h. This polymer microneedle has no dermal toxicity. Copyright © 2017 Elsevier B.V. All rights reserved.

Randomized trial of electrodynamic microneedle combined with 5% minoxidil topical solution for the treatment of Chinese male Androgenetic alopecia.

PubMed

Bao, Linlin; Gong, Lin; Guo, Menger; Liu, Taoming; Shi, Anyu; Zong, Haifeng; Xu, Xuegang; Chen, Hongduo; Gao, Xinghua; Li, Yuanhong

2017-10-13

In treating androgenetic alopecia, 5% minoxidil is a commonly used topical drug. By using electrodynamic microneedle at the same time may increase absorption of minoxidil and further stimulate hair growth. A 24-week, randomized, evaluator blinded, comparative study was performed to evaluate the efficacy of treating Chinese male androgenetic alopecia using microneedle combined with 5% minoxidil topical solution. Randomized subjects received topical 5% minoxidil (group 1, n = 20), local electrodynamic microneedle treatments (group 2, n = 20), or local electrodynamic microneedle treatments plus topical 5% minoxidil (group 3, n = 20). A total of 12 microneedle treatments were performed every 2 weeks with 2ml 5% minoxidil delivery in group 3 during each microneedle treatment. Patient receiving topical 5% minoxidil applied 1 ml of the solution twice daily over the course of the study. A total of 60 Chinese male subjects with Norwood-Hamilton type III-VI androgenetic alopecia were treated. The mean improvement in total hair density from baseline to 24 weeks was 18.8/cm 2 in group 1, 23.4/cm 2 in group 2, and 38.3/cm 2 in group 3. The hair growth in the 3 groups was significantly different (P = 0.002), but there were no significant differences in toxicity found between the 3 groups. Treatment with microneedle plus topical 5% minoxidil was associated with the best hair growth.

In vivo investigation of temporal effects and drug delivery induced by transdermal microneedles with optical coherence tomography

PubMed Central

Tsai, Meng-Tsan; Lee, I-Chi; Lee, Zhung-Fu; Liu, Hao-Li; Wang, Chun-Chieh; Choia, Yo-Chun; Chou, Hsin-Yi; Lee, Jiann-Der

2016-01-01

Transdermal drug-delivery systems (TDDS) have been a growing field in drug delivery because of their advantages over parenteral and oral administration. Recent studies illustrate that microneedles (MNs) can effectively penetrate through the stratum corneum barrier to facilitate drug delivery. However, the temporal effects on skin and drug diffusion are difficult to investigate in vivo. In this study, we used optical coherence tomography (OCT) to observe the process by which MNs dissolve and to investigate the temporal effects on mouse skin induced by MNs, including the morphological and vascular changes. Moreover, the recovery process of the skin was observed with OCT. Additionally, we proposed a method to observe drug delivery by estimation of cross-correlation relationship between sequential 2D OCT images obtained at the same location, reflecting the variation in the backscattered intensity due to the diffusion of the rhodamine molecules encapsulated in MNs. Our observations supported the hypothesis that the temporal effects on skin due to MNs, the dissolution of MNs, and the drug diffusion process can be quantitatively evaluated with OCT. The results showed that OCT can be a potential tool for in vivo monitoring of effects and outcomes when MNs are used as a TDDS. PMID:27231627

Biomedical applications of microneedles in therapeutics: recent advancements and implications in drug delivery.

PubMed

Rejinold, N Sanoj; Shin, Ju-Hyung; Seok, Hae Yong; Kim, Yeu-Chun

2016-01-01

The skin, as the largest organ, is a better option for drug delivery in many diseases. However, most transdermal delivery is difficult due to the low permeability of therapeutics across the various skin layers. There have been many innovations in transdermal drug delivery to enhance the therapeutic efficacy of the drugs administered. Microneedles (MN), micron sized needles, are of great interest to scientists as a new therapeutic vehicle through transdermal routes, especially for vaccines, drugs, small molecules, etc. This review covers new insights into different types of MNs such as solid, hollow, coated and dissolving MNs (SMNs, HMNs, CMNs, and DMNs) for selected biomedical applications in detail. Specific focus has been given to CMNs and DMNs for vaccine and drug delivery applications with recent developments in new MNs covered. This review explores the feasibility of innovative MNs used as a drug delivery carrier. Because most of the SMNs and HMNs have many limitations, it is difficult to achieve therapeutic efficacy. Therefore, many scientists are investigating functional modifications of MNs through covalent and non-covalent methods, especially for CMNs and DMNs. The biomedical applications of MNs are growing and new exciting improvements could be achieved, thus resulting in better micro/nano technologies in the near future.

Microneedles: quick and easy delivery methods of vaccines

PubMed Central

2017-01-01

Vaccination is the most efficient method for infectious disease prevention. Parenteral injections such as intramuscular, intradermal, and subcutaneous injections have several advantages in vaccine delivery, but there are many drawbacks. Thus, the development of a new vaccine delivery system has long been required. Recently, microneedles have been attracting attention as new vaccination tools. Microneedle is a highly effective transdermal vaccine delivery method due to its mechanism of action, painlessness, and ease of use. Here, we summarized the characteristics of microneedles and the possibilities as a new vaccine delivery route. PMID:28775980

Microneedles 2012.

PubMed

Broderick, Kate E

2012-08-01

The second international conference on Microneedles was held on 13-15 May 2012 in Cork, Republic of Ireland, following on from a successful first meeting at the Georgia Institute of Technology (GA, USA) in May 2010. The meeting showcased the latest international developments in microneedle technology and applications. The gathering provided a platform to facilitate interdisciplinary communications and new collaborations for delegates from academic, industrial and clinical backgrounds. The meeting opened with a half-day short course on microneedle technology and applications, followed by invited lectures and poster presentations over 2 days, divided into sessions such as 'Design and technology--solid and hollow microneedles', 'Vaccine delivery' and 'Drug delivery'. This conference report summarizes the keynote and invited speaker lectures from leaders in the field such as Mark Prausnitz (Georgia Institute of Technology) and Mark Kendall (University of Queensland, Australia).

Intrascleral Drug Delivery to the Eye Using Hollow Microneedles

PubMed Central

Jiang, Jason; Moore, Jason S.; Edelhauser, Henry F.; Prausnitz, Mark R.

2010-01-01

Purpose This study tested the hypothesis that hollow microneedles can infuse solutions containing soluble molecules, nanoparticles, and microparticles into sclera in a minimally invasive manner. Methods Individual hollow microneedles were inserted into, but not across, human cadaver sclera and aqueous solutions containing sulforhodamine or fluorescently-tagged nanoparticles or microparticles were infused into sclera at constant pressure. The infused volume of fluid was measured and imaged histologically as a function of scleral thickness, infusion pressure, needle retraction depth and the presence of spreading enzymes (hyaluronidase and collagenase). Results Individual hollow microneedles were able to insert into sclera. Fluid infusion was extremely slow after microneedle insertion into the sclera without retraction, but partial retraction of the microneedle over a distance of 200–300 μm enabled infusion of 10–35 μl of fluid into the tissue. Scleral thickness and infusion pressure had insignificant effects on fluid delivery. Nanoparticle suspensions were also delivered into sclera, but microparticles were delivered only in the presence of hyaluronidase and collagenase spreading enzymes, which suggested the role of scleral glycosaminoglycans and collagen fibers as rate-limiting barriers. Conclusion This study shows that hollow microneedles can infuse solutions into the sclera for minimally invasive delivery of soluble molecules, nanoparticles and microparticles. PMID:18979189

Suprachoroidal Drug Delivery to the Back of the Eye Using Hollow Microneedles

PubMed Central

Patel, Samirkumar R.; Lin, Angela S. P.; Edelhauser, Henry F.

2011-01-01

Purpose In this work, we tested the hypothesis that microneedles provide a minimally invasive method to inject particles into the suprachoroidal space for drug delivery to the back of the eye. Methods A single, hollow microneedle was inserted into the sclera, and infused nanoparticle and microparticle suspensions into the suprachoroidal space. Experiments were performed on whole rabbit, pig, and human eyes ex vivo. Particle delivery was imaged using brightfield and fluorescence microscopy as well as microcomputed tomography. Results Microneedles were shown to deliver sulforhodamine B as well as nanoparticle and microparticle suspensions into the suprachoroidal space of rabbit, pig, and human eyes. Volumes up to 35 μL were administered consistently. Optimization of the delivery device parameters showed that microneedle length, pressure, and particle size played an important role in determining successful delivery into the suprachoroidal space. Needle lengths of 800–1,000 μm and applied pressures of 250–300 kPa provided most reliable delivery. Conclusions Microneedles were shown for the first time to deliver nanoparticle and microparticle suspensions into the suprachoroidal space of rabbit, pig and human eyes. This shows that microneedles may provide a minimally invasive method for controlled drug delivery to the back of the eye. PMID:20857178

Delivery of Methotrexate and Characterization of Skin Treated by Fabricated PLGA Microneedles and Fractional Ablative Laser.

PubMed

Nguyen, Hiep X; Banga, Ajay K

2018-02-21

This study investigated in vitro transdermal delivery of methotrexate through dermatomed porcine ear and cadaver human skin treated with poly (D,L-lactide-co-glycolide) acid microneedles or fractional ablative laser. PLGA microneedles were fabricated and characterized using scanning electron microscopy and mechanical assessment techniques. The integrity of treated skin was evaluated by rheometer, transepidermal water loss, and skin electrical resistance measurements. Successful skin microporation was demonstrated by dye binding, histology, pore uniformity, confocal laser microscopy, and DermaScan studies. In vitro permeation experiment was performed on Franz diffusion cells to determine drug delivery into and across the skin. Both physical treatments resulted in a considerable decrease in skin resistance and an increase in transepidermal water loss value. The laser-created microchannels were significantly larger than those formed by microneedles (p < 0.05). An effective force of 41.04 ± 18.33 N was required to achieve 100% penetration efficiency of the microneedles. For both porcine ear and human skin, laser ablation provided a significantly higher methotrexate permeability into the receptor chamber and skin layers compared to microneedle poration and untreated skin (p < 0.05). Both fractional ablative laser and polymeric microneedles markedly enhanced in vitro transdermal delivery of methotrexate into and across skin. Graphical Abstract ᅟ.

In vivo histological evaluation of non-insulated microneedle radiofrequency applicator with novel fractionated pulse mode.

PubMed

Harth, Yoram; Frank, Ido

2013-12-01

Microneedle radiofrequency is a novel method that allows non-thermal penetration of the epidermis followed by RF coagulation in selected depth of the dermis surrounded by zone of non-coagulative volumetric heating. The first generation of Microneedle RF applicators used insulated needles. These treatments were limited by a few factors, including low volume of dermal heating, lack of effect in the papillary dermis and pinpoint bleeding during the treatment. The system tested in this study (EndyMed PRO, Intensif applicator, EndyMed Medical, Cesarea, Israel) utilizes special extra sharp tapered non-insulated microneedles and a special pulse mode, allowing full coagulation during treatment and higher effective volume of dermal heat. After Ethics Committee approval, one female pig (Type Large white X Landrace, 34 Kg) was chosen for the study. The animal was anesthetized using Ketamine, Xylazin and Isofluran. The EndyMed PRO, Intensif applicator (was used for treatment with different needle depth penetration (1 mm-3.5 mm) and in multiple energy settings. Six mm punch biopsies were harvested for histological analysis at the following time points: immediately after the treatment, 4 days after the treatment and 14 days after the treatment. H&E and Masson-Trichrome stains were processed. Visual inspection of the treated skin, immediately after the treatment, revealed arrays of pinpoint erythematous papules surrounded by undamaged epidermal tissue. Treatment field showed no sign of bleeding. Mild to moderate Erythema and Edema developed a few minutes after the treatment, varying according to the total energy delivered. The histologies taken 4-day after therapy showed in all energy settings, dry micro crusts over the treatment zones, with full healing of epidermis. In the 14-day specimens there was a replacement of the crusts/debris by a normal looking stratum corneum with complete healing of epidermis and dermis. The current in vivo study confirms that the EndyMed PRO Intensif applicator effective and predictable tool to create cylindrical micro zones of coagulation in the papillary and reticular dermis with minimal damage to the epidermis. The histologies taken 4 days and 14 days after treatment show rapid epidermal renewal with predictable volume of coagulation in dermis related to the length of the needle and the power used. Coagulation of capillaries during treatment allows a dry treatment field. The predictability of the effect and minimal downtime may offer a significant advantage over treatments with ablative fractional lasers of insulated RF microneedles.

Lidocaine-loaded fish scale-nanocellulose biopolymer composite microneedles.

PubMed

Medhi, Pangkhi; Olatunji, Ololade; Nayak, Atul; Uppuluri, Chandra Teja; Olsson, Richard T; Nalluri, Buchi N; Das, Diganta B

2017-07-01

Microneedle (MN) technology has emerged as an effective drug delivery system, and it has tremendous potential as a patient friendly substitute for conventional methods for transdermal drug delivery (TDD). In this paper, we report on the preparation of lidocaine-loaded biodegradable microneedles, which are manufactured from fish scale-derived collagen. Lidocaine, a common tissue numbing anaesthetic, is loaded in these microneedles with an aim of delivering the drug with controlled skin permeation. Evaluation of lidocaine permeation in porcine skin has been successfully performed using Franz diffusion cell (FDC) which has shown that the drug permeation rate increases from 2.5 to 7.5% w/w after 36 h and pseudo steady state profile is observed from 5.0 to 10.0% w/w lidocaine-loaded microneedle. Swelling experiments have suggested that the microneedles have negligible swellability which implies that the patch would stick to the tissue when inserted. The experiments on MN dissolution have depicted that the lidocaine loaded in the patch is lower than the theoretical loading, which is expected as there can be losses of the drug during initial process manufacture.

Design considerations of a hollow microneedle-optofluidic biosensing platform incorporating enzyme-linked assays

NASA Astrophysics Data System (ADS)

Ranamukhaarachchi, Sahan A.; Padeste, Celestino; Häfeli, Urs O.; Stoeber, Boris; Cadarso, Victor J.

2018-02-01

A hollow metallic microneedle is integrated with microfluidics and photonic components to form a microneedle-optofluidic biosensor suitable for therapeutic drug monitoring (TDM) in biological fluids, like interstitial fluid, that can be collected in a painless and minimally-invasive manner. The microneedle inner lumen surface is bio-functionalized to trap and bind target analytes on-site in a sample volume as small as 0.6 nl, and houses an enzyme-linked assay on its 0.06 mm2 wall. The optofluidic components are designed to rapidly quantify target analytes present in the sample and collected in the microneedle using a simple and sensitive absorbance scheme. This contribution describes how the biosensor components were optimized to detect in vitro streptavidin-horseradish peroxidase (Sav-HRP) as a model analyte over a large detection range (0-7.21 µM) and a very low limit of detection (60.2 nM). This biosensor utilizes the lowest analyte volume reported for TDM with microneedle technology, and presents significant avenues to improve current TDM methods for patients, by potentially eliminating blood draws for several drug candidates.

3D printed microneedles for insulin skin delivery.

PubMed

Pere, Cristiane Patricia Pissinato; Economidou, Sophia N; Lall, Gurprit; Ziraud, Clémentine; Boateng, Joshua S; Alexander, Bruce D; Lamprou, Dimitrios A; Douroumis, Dennis

2018-06-15

In this study, polymeric microneedle patches were fabricated by stereolithography, a 3D printing technique, for the transdermal delivery of insulin. A biocompatible resin was photopolymerized to build pyramid and cone microneedle designs followed by inkjet print coating of insulin formulations. Trehalose, mannitol and xylitol were used as drug carriers with the aim to preserve insulin integrity and stability but also to facilitate rapid release rates. Circular dichroism and Raman analysis demonstrated that all carriers maintained the native form of insulin, with xylitol presenting the best performance. Franz cell release studies were used for in vitro determination of insulin release rates in porcine skin. Insulin was released rapidly within 30 min irrespectively of the microneedle design. 3D printing was proved an effective technology for the fabrication of biocompatible and scalable microneedle patches. Copyright © 2018 Elsevier B.V. All rights reserved.

Inkjet Printing of Amphotericin B onto Biodegradable Microneedles Using Piezoelectric Inkjet Printing

NASA Astrophysics Data System (ADS)

Boehm, Ryan D.; Miller, Philip R.; Schell, Wiley A.; Perfect, John R.; Narayan, Roger J.

2013-04-01

The delivery of amphotericin B, a pharmacologic agent with activity against a broad spectrum of fungi as well as against parasitic protozoa, has been complicated by the fact that amphotericin B exhibits poor solubility in aqueous solutions at physiologic pH levels. In this study, piezoelectric inkjet printing was used to modify the surfaces of Gantrez 169 BF microneedles (Ashland, Covington, KY). These amphotericin B-loaded microneedles demonstrated activity against Candida parapsilosis in a radial diffusion assay. The results of this study suggest that a combination of visible light dynamic mask microstereolithography, micromolding, and piezoelectric inkjet printing may be used to prepare amphotericin B-loaded microneedles with antifungal properties. It is envisioned that microneedles containing amphotericin B may be used for transdermal delivery of pharmacologic agents for the treatment of cutaneous fungal infections as well as cutaneous leishmaniasis.

Microneedle-based vaccines

PubMed Central

Prausnitz, Mark R.; Mikszta, John A.; Cormier, Michel; Andrianov, Alexander K.

2010-01-01

The threat of pandemic influenza and other public health needs motivates development of better vaccine delivery systems. To address this need, microneedles have been developed as micron-scale needles fabricated using low-cost manufacturing methods that administer vaccine into the skin using a simple device that may be suitable for self-administration. Delivery using solid or hollow microneedles can be accomplished by (i) piercing the skin and then applying a vaccine formulation or patch onto the permeabilized skin, (ii) coating or encapsulating vaccine onto or within microneedles for rapid, or delayed, dissolution and release in the skin and (iii) injection into the skin using a modified syringe or pump. Extensive clinical experience with smallpox, TB and other vaccines has shown that vaccine delivery into the skin using conventional intradermal injection is generally safe and effective and often elicits the same immune responses at lower doses compared to intramuscular injection. Animal experiments using microneedles have shown similar benefits. Microneedles have been used to deliver whole, inactivated virus; trivalent split antigen vaccines; and DNA plasmid encoding the influenza hemagglutinin to rodents and found strong antibody responses. In addition, ChimeriVax™-JE against yellow fever was administered to non-human primates and generated protective levels of neutralizing antibodies more than seven times greater than subcutaneous delivery; DNA plasmid encoding hepatitis B surface antigen was administered to mice and generated antibody and T cell responses at least as strong as hypodermic injections; recombinant Protective Antigen of Baccilus anthracis was administered to rabbits and provided complete protection from lethal aerosol anthrax spore challenge at a lower dose than intramuscular injection; and DNA plasmid encoding four vaccinia virus genes administered to mice in combination with electroporation generated neutralizing antibodies that apparently included both Th1 and Th2 responses. Dose sparing with microneedles was specifically studied in mice with the model vaccine ovalbumin. At low dose (1 µg), specific antibody titers from microneedles were one order of magnitude greater than subcutaneous injection and two orders of magnitude greater than intramuscular injection. At higher doses, antibody responses increased for all delivery methods. At the highest levels (20–80 µg), the route of administration had no significant effect on the immune response. Concerning safety, no infections or other serious adverse events have been observed in well over 1000 microneedle insertions in human and animal subjects. Bleeding generally does not occur for short microneedles (<1 mm). Highly localized, mild and transient erythema is often observed. Microneedle pain has been reported as non-existent to mild, and always much less than a hypodermic needle control. Overall, these studies suggest that microneedles may provide a safe and effective method to deliver vaccines with possible added attributes of requiring lower vaccines doses, permitting low-cost manufacturing, and enabling simple distribution and administration. PMID:19768415

A sustained release formulation of novel quininib-hyaluronan microneedles inhibits angiogenesis and retinal vascular permeability in vivo.

PubMed

Galvin, Orla; Srivastava, Akshay; Carroll, Oliver; Kulkarni, Rajiv; Dykes, Steve; Vickers, Steven; Dickinson, Keith; Reynolds, Alison L; Kilty, Claire; Redmond, Gareth; Jones, Rob; Cheetham, Sharon; Pandit, Abhay; Kennedy, Breandán N

2016-07-10

Pathologic neovascularisation and ocular permeability are hallmarks of proliferative diabetic retinopathy and age-related macular degeneration. Current pharmacologic interventions targeting VEGF are effective in only 30-60% of patients and require multiple intraocular injections associated with iatrogenic infection. Thus, our goal is to develop novel small molecule drugs that are VEGF-independent are amenable to sustained ocular-release, and which reduce retinal angiogenesis and retinal vascular permeability. Here, the anti-angiogenic drug quininib was formulated into hyaluronan (HA) microneedles whose safety and efficacy was evaluated in vivo. Quininib-HA microneedles were formulated via desolvation from quininib-HA solution and subsequent cross-linking with 4-arm-PEG-amine prior to freeze-drying. Scanning electron microscopy revealed hollow needle-shaped particle ultrastructure, with a zeta potential of -35.5mV determined by electrophoretic light scattering. The incorporation efficiency and pharmacokinetic profile of quininib released in vitro from the microneedles was quantified by HPLC. Quininib incorporation into these microneedles was 90%. In vitro, 20% quininib was released over 4months; or in the presence of increasing concentrations of hyaluronidase, 60% incorporated quininib was released over 4months. Zebrafish hyaloid vasculature assays demonstrated quininib released from these microneedles significantly (p<0.0001) inhibited ocular developmental angiogenesis compared to control. Sustained amelioration of retinal vascular permeability (RVP) was demonstrated using a bespoke cysteinyl leukotriene induced rodent model. Quininib-HA microparticles significantly inhibited RVP in Brown Norway rats one month after administration compared to neat quininib control (p=0.0071). In summary, quininib-HA microneedles allow for sustained release of quininib; are safe in vivo and quininib released from these microneedles effectively inhibits angiogenesis and RVP in vivo. Copyright © 2016 Elsevier B.V. All rights reserved.

Assessing the Potential Cost-Effectiveness of Microneedle Patches in Childhood Measles Vaccination Programs: The Case for Further Research and Development.

PubMed

Adhikari, Bishwa B; Goodson, James L; Chu, Susan Y; Rota, Paul A; Meltzer, Martin I

2016-12-01

Currently available measles vaccines are administered by subcutaneous injections and require reconstitution with a diluent and a cold chain, which is resource intensive and challenging to maintain. To overcome these challenges and potentially increase vaccination coverage, microneedle patches are being developed to deliver the measles vaccine. This study compares the cost-effectiveness of using microneedle patches with traditional vaccine delivery by syringe-and-needle (subcutaneous vaccination) in children's measles vaccination programs. We built a simple spreadsheet model to compute the vaccination costs for using microneedle patch and syringe-and-needle technologies. We assumed that microneedle vaccines will be, compared with current vaccines, more heat stable and require less expensive cool chains when used in the field. We used historical data on the incidence of measles among communities with low measles vaccination rates. The cost of microneedle vaccination was estimated at US$0.95 (range US$0.71-US$1.18) for the first dose, compared with US$1.65 (range US$1.24-US$2.06) for the first dose delivered by subcutaneous vaccination. At 95 % vaccination coverage, microneedle patch vaccination was estimated to cost US$1.66 per measles case averted (range US$1.24-US$2.07) compared with an estimated cost of US$2.64 per case averted (range US$1.98-US$3.30) using subcutaneous vaccination. Use of microneedle patches may reduce costs; however, the cost-effectiveness of patches would depend on the vaccine recipients' acceptability and vaccine effectiveness of the patches relative to the existing conventional vaccine-delivery method. This study emphasizes the need to continue research and development of this vaccine-delivery method that could boost measles elimination efforts through improved access to vaccines and increased vaccination coverage.

Transdermal Delivery of Functional Collagen Via Polyvinylpyrrolidone Microneedles

PubMed Central

Sun, Wenchao; Inayathullah, Mohammed; Manoukian, Martin A. C.; Malkovskiy, Andrey V.; Manickam, Sathish; Marinkovich, M. Peter; Lane, Alfred T.; Tayebi, Lobat; Seifalian, Alexander M.; Rajadas, Jayakumar

2017-01-01

Collagen makes up a large proportion of the human body, particularly the skin. As the body ages, collagen content decreases, resulting in wrinkled skin and decreased wound healing capabilities. This paper presents a method of delivering type I collagen into porcine and human skin utilizing a polyvinylpyrrolidone microneedle delivery system. The microneedle patches were made with concentrations of 1, 2, 4, and 8% type I collagen (w/w). Microneedle structures and the distribution of collagen were characterized using scanning electron microscopy and confocal microscopy. Patches were then applied on the porcine and human skin, and their effectiveness was examined using fluorescence microscopy. The results illustrate that this microneedle delivery system is effective in delivering collagen I into the epidermis and dermis of porcine and human skin. Since the technique presented in this paper is quick, safe, effective and easy, it can be considered as a new collagen delivery method for cosmetic and therapeutic applications. PMID:26066056

Effect of microneedles on transdermal permeation enhancement of amlodipine.

PubMed

Nalluri, Buchi N; Uppuluri, Chandrateja; Devineni, Jyothirmayee; Nayak, Atul; Nair, Karthik J; Whiteside, Benjamin R; Das, Diganta B

2017-06-01

The present study aimed to investigate the effect of microneedle (MN) geometry parameters like length, density, shape and type on transdermal permeation enhancement of amlodipine (AMLO). Two types of MN devices viz. AdminPatch® arrays (ADM) (0.6, 1.2 and 1.5 mm lengths) and laboratory-fabricated polymeric MNs (PM) of 0.6 mm length were employed. In the case of PMs, arrays were applied thrice at different places within a 1.77-cm 2 skin area (PM-3) to maintain the MN density closer to 0.6 mm ADM. Scaling analyses were done using dimensionless parameters like concentration of AMLO (C t /C s ), thickness (h/L) and surface area of the skin (Sa/L 2 ). Microinjection moulding technique was employed to fabricate PM. Histological studies revealed that the PM, owing to their geometry/design, formed wider and deeper microconduits when compared to ADM of similar length. Approximately 6.84- and 6.11-fold increase in the cumulative amount (48 h) of AMLO permeated was observed with 1.5 mm ADM and PM-3 treatments respectively, when compared to passive permeation amounts. Good correlations (R 2  > 0.89) were observed between different dimensionless parameters with scaling analyses. The enhancement in AMLO permeation was found to be in the order of 1.5 mm ADM ≥ PM-3 > 1.2 mm ADM > 0.6 mm ADM ≥PM-1 > passive. The study suggests that MN application enhances the AMLO transdermal permeation and the geometrical parameters of MNs play an important role in the degree of such enhancement.

Non-ablative fractional laser in conjunction with microneedle arrays for improved cutaneous vaccination

NASA Astrophysics Data System (ADS)

Wang, Ji; Li, Bo; Wu, Mei X.

2015-03-01

Skin is more potent than the muscle for vaccination, but it is not a common site for immunization to date owing, in part, to a relatively high rate of pains and skin irritation and difficulty of administration. Here, we show effective and lesion free cutaneous vaccination by a combination of a biodegradable microneedle array (MNs) and an FDA-approved nonablative fractional laser (NAFL). Delivering a vaccine into many micropores, instead of a single "big" pore in the skin, effectively segregated vaccine-induced inflammation into many microzones and resulted in quick resolution of the inflammation, provided that distances between any two micropores were far enough. When the inoculation site was treated by NAFL prior to insertion of the MNs comprised of PR8 model influenza vaccine, the mice displayed vigorous antigen-uptake, giving rise to strong, Th1-biased immunity. The mice were protected from a challenge of homologous influenza virus at a high dose as well as heterologous H1N1 and H3N2 viruses. The adjuvant effect of NAFL was ascribed primarily to activation of the dsDNA sensing pathway by dsDNA released from laser-damaged skin cells. Thus, mice deficient in the dsDNA sensing pathway, but not toll like receptor (TLR) or inflammasome pathways, showed poor response to NAFL. Importantly, both mice and swine exhibited strong, protective immunity, but no overt skin reactions with this approach, in sharp contrast to intradermal injections that caused severe, overt skin reactions. The effective lesion-free transcutaneous vaccination merits further clinical studies.

Paediatricians' opinions of microneedle-mediated monitoring: a key stage in the translation of microneedle technology from laboratory into clinical practice.

PubMed

Mooney, Karen; McElnay, James C; Donnelly, Ryan F

2015-08-01

Microneedle (MN) arrays could offer an alternative method to traditional drug delivery and blood sampling methods. However, acceptance among key end-users is critical for new technologies to succeed. MNs have been advocated for use in children and so, paediatricians are key potential end-users. However, the opinions of paediatricians on MN use have been previously unexplored. The aim of this study was to investigate the views of UK paediatricians on the use of MN technology within neonatal and paediatric care. An online survey was developed and distributed among UK paediatricians to gain their opinions of MN technology and its use in the neonatal and paediatric care settings, particularly for MN-mediated monitoring. A total of 145 responses were obtained, with a completion response rate of 13.7 %. Respondents believed an alternative monitoring technique to blood sampling in children was required. Furthermore, 83 % of paediatricians believed there was a particular need in premature neonates. Overall, this potential end-user group approved of the MN technology and a MN-mediated monitoring approach. Minimal pain and the perceived ease of use were important elements in gaining favour. Concerns included the need for confirmation of correct application and the potential for skin irritation. The findings of this study provide an initial indication of MN acceptability among a key potential end-user group. Furthermore, the concerns identified present a challenge to those working within the MN field to provide solutions to further improve this technology. The work strengthens the rationale behind MN technology and facilitates the translation of MN technology from lab bench into the clinical setting.

A systematic approach to fabricate high aspect ratio silicon micro-needles for transdermal drug delivery

NASA Astrophysics Data System (ADS)

Ng, H. B.; Shearwood, C.

2007-12-01

The successful development of micro-needles can help transport drugs and vaccines both effectively and painlessly across the skin. However, not all micro-needles are strong enough to withstand the insertion forces and viscoelasticity of the skin. The work here focuses on the micro-fabrication of high aspect ratio needles with careful control of needle-profile using dry etching technologies. Silicon micro-needles, 150μm in length with base-diameters ranging from 90 to 240μm have been investigated in this study. A novel, multiple-sacrificial approach has been demonstrated as suited to the fabrication of long micro-needle bodies with positive profiles. The parameters that control the isotropic etching are adjusted to control the ratio of the needle-base diameter to needle length. By careful control of geometry, the needle profile can be engineered to give a suitable tip size for penetration, as well as a broad needle base to facilitate the creation of either single or multiple-through holes. This approach allows the mechanical properties of the otherwise brittle needles to be optimized. Finite element analysis indicates that the micro-needles will fracture prematurely due to buckling, with forces ranging from 10 to 30mN.

A boosting skin vaccination with dissolving microneedle patch encapsulating M2e vaccine broadens the protective efficacy of conventional influenza vaccines.

PubMed

Zhu, Wandi; Pewin, Winston; Wang, Chao; Luo, Yuan; Gonzalez, Gilbert X; Mohan, Teena; Prausnitz, Mark R; Wang, Bao-Zhong

2017-09-10

The biodegradable microneedle patch (MNP) is a novel technology for vaccine delivery that could improve the immunogenicity of vaccines. To broaden the protective efficiency of conventional influenza vaccines, a new 4M2e-tFliC fusion protein construct containing M2e sequences from different subtypes was generated. Purified fusion protein was encapsulate into MNPs with a biocompatible polymer for use as a boosting vaccine. The results demonstrated that mice receiving a conventional inactivated vaccine followed by a skin-applied dissolving 4M2e-tFliC MNP boost could better maintain the humoral antibody response than that by the conventional vaccine-prime alone. Compared with an intramuscular injection boost, mice receiving the MNP boost showed significantly enhanced cellular immune responses, hemagglutination-inhibition (HAI) titers, and neutralization titers. Increased frequency of antigen-specific plasma cells and long-lived bone marrow plasma cells was detected in the MNP boosted group as well, indicating that skin vaccination with 4M2e-tFliC facilitated a long-term antibody-mediated immunity. The 4M2e-tFliC MNP-boosted group also possessed enhanced protection against high lethal dose challenges against homologous A/PR/8/34 and A/Aichi/2/68 viruses and protection for a majority of immunized mice against a heterologous A/California/07/2009 H1N1 virus. High levels of M2e specific immune responses were observed in the 4M2e-tFliC MNP-boosted group as well. These results demonstrate that a skin-applied 4M2e-tFliC MNP boosting immunization to seasonal vaccine recipients may be a rapid approach for increasing the protective efficacy of seasonal vaccines in response to a significant drift seen in circulating viruses. The results also provide a new perspective for future exploration of universal influenza vaccines. Copyright © 2017 Elsevier B.V. All rights reserved.

Treatment of acne vulgaris with fractional radiofrequency microneedling.

PubMed

Kim, Sang Tae; Lee, Kang Hoon; Sim, Hyung Jun; Suh, Kee Suck; Jang, Min Soo

2014-07-01

Fractional radiofrequency microneedling is a novel radiofrequency technique that uses insulated microneedles to deliver energy to the deep dermis at the point of penetration without destruction of the epidermis. It has been used for the treatment of various dermatological conditions including wrinkles, atrophic scars and hypertrophic scars. There have been few studies evaluating the efficacy of fractional radiofrequency microneedling in the treatment of acne, and none measuring objective parameters like the number of inflammatory and non-inflammatory acne lesions or sebum excretion levels. The safety and efficacy of fractional radiofrequency microneedling in the treatment of acne vulgaris was investigated. In a prospective clinical trial, 25 patients with moderate to severe acne were treated with fractional radiofrequency microneedling. The procedure was carried out three times at 1-month intervals. Acne lesion count, subjective satisfaction score, sebum excretion level and adverse effects were assessed at baseline and at 4, 8 and 12 weeks after the first treatment as well as 4, 8 and 12 weeks after the last treatment. Number of acne lesions (inflammatory and non-inflammatory) decreased. Sebum excretion and subjective satisfaction were more favorable at every time point compared with the baseline values (P < 0.05). Inflammatory lesions responded better than non-inflammatory lesions (P < 0.05). Adverse effects such as pinpoint bleeding, pain and erythema were noted, but were transient and not severe enough to stop treatment. Fractional radiofrequency microneedling is a safe and effective treatment for acne vulgaris. © 2014 Japanese Dermatological Association.

Tetanus vaccination with a dissolving microneedle patch confers protective immune responses in pregnancy.

PubMed

Esser, E Stein; Romanyuk, AndreyA; Vassilieva, Elena V; Jacob, Joshy; Prausnitz, Mark R; Compans, Richard W; Skountzou, Ioanna

2016-08-28

Maternal and neonatal tetanus claim tens of thousands lives every year in developing countries, but could be prevented by hygienic practices and improved immunization of pregnant women. This study tested the hypothesis that skin vaccination can overcome the immunologically transformed state of pregnancy and enhance protective immunity to tetanus in mothers and their newborns. To achieve this goal, we developed microneedle patches (MNPs) that efficiently delivered unadjuvanted tetanus toxoid to skin of pregnant mice and demonstrated that this route induced superior immune responses in female mice conferring 100% survival to tetanus toxin challenge when compared to intramuscular vaccination. Mice born to MNP-vaccinated mothers showed detectable tetanus-specific IgG antibodies up to 12weeks of age and complete protection to tetanus toxin challenge up at 6weeks of age. In contrast, none of the 6-week old mice born to intramuscularly vaccinated mothers survived challenge. Although pregnant mice vaccinated with unadjuvanted tetanus toxoid had 30% lower IgG and IgG1 titers than mice vaccinated intramuscularly with Alum®-adjuvanted tetanus toxoid vaccine, IgG2a titers and antibody affinity maturation were similar between these groups. We conclude that skin immunization with MNPs containing unadjuvanted tetanus toxoid can confer potent protective efficacy to mothers and their offspring using a delivery method well suited for expanding vaccination coverage in developing countries. Copyright © 2016 Elsevier B.V. All rights reserved.

Integrated hollow microneedle-optofluidic biosensor for therapeutic drug monitoring in sub-nanoliter volumes

NASA Astrophysics Data System (ADS)

Ranamukhaarachchi, Sahan A.; Padeste, Celestino; Dübner, Matthias; Häfeli, Urs O.; Stoeber, Boris; Cadarso, Victor J.

2016-07-01

Therapeutic drug monitoring (TDM) typically requires painful blood drawn from patients. We propose a painless and minimally-invasive alternative for TDM using hollow microneedles suitable to extract extremely small volumes (<1 nL) of interstitial fluid to measure drug concentrations. The inner lumen of a microneedle is functionalized to be used as a micro-reactor during sample collection to trap and bind target drug candidates during extraction, without requirements of sample transfer. An optofluidic device is integrated with this microneedle to rapidly quantify drug analytes with high sensitivity using a straightforward absorbance scheme. Vancomycin is currently detected by using volumes ranging between 50-100 μL with a limit of detection (LoD) of 1.35 μM. The proposed microneedle-optofluidic biosensor can detect vancomycin with a sample volume of 0.6 nL and a LoD of <100 nM, validating this painless point of care system with significant potential to reduce healthcare costs and patients suffering.

Integrated hollow microneedle-optofluidic biosensor for therapeutic drug monitoring in sub-nanoliter volumes

PubMed Central

Ranamukhaarachchi, Sahan A.; Padeste, Celestino; Dübner, Matthias; Häfeli, Urs O.; Stoeber, Boris; Cadarso, Victor J.

2016-01-01

Therapeutic drug monitoring (TDM) typically requires painful blood drawn from patients. We propose a painless and minimally-invasive alternative for TDM using hollow microneedles suitable to extract extremely small volumes (<1 nL) of interstitial fluid to measure drug concentrations. The inner lumen of a microneedle is functionalized to be used as a micro-reactor during sample collection to trap and bind target drug candidates during extraction, without requirements of sample transfer. An optofluidic device is integrated with this microneedle to rapidly quantify drug analytes with high sensitivity using a straightforward absorbance scheme. Vancomycin is currently detected by using volumes ranging between 50–100 μL with a limit of detection (LoD) of 1.35 μM. The proposed microneedle-optofluidic biosensor can detect vancomycin with a sample volume of 0.6 nL and a LoD of <100 nM, validating this painless point of care system with significant potential to reduce healthcare costs and patients suffering. PMID:27380889

Handheld Microneedle-Based Electrolyte Sensing Platform.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Miller, Philip R.; Rivas, Rhiana; Johnson, David

2015-11-01

Sandia National Laboratories will provide technical assistance, within time and budget, to Requester on testing and analyzing a microneedle-based electrolyte sensing platform. Hollow microneedles will be fabricated at Sandia and integrated with a fluidic chip using plastic laminate prototyping technology available at Sandia. In connection with commercial ion selective electrodes the sensing platform will be tested for detection of electrolytes (sodium and/or potassium) within physiological relevant concent ration ranges.

Optimization of impedance spectroscopy techniques for measuring cutaneous micropore formation after microneedle treatment in an elderly population.

PubMed

Kelchen, Megan N; Holdren, Grant O; Farley, Matthew J; Zimmerman, M Bridget; Fairley, Janet A; Brogden, Nicole K

2014-12-01

The objective of this study was to optimize a reproducible impedance spectroscopy method in elderly subjects as a means to evaluate the effects of microneedles on aging skin. Human volunteers were treated with microneedles at six sites on the upper arm. Repeated impedance measurements were taken pre- and post-microneedle insertion. Two electrode types were evaluated (dry vs. gel), using either light or direct pressure to maintain contact between the electrode and skin surface. Transepidermal water loss (TEWL) was measured as a complementary technique. Five control subjects and nine elderly subjects completed the study. Microneedle insertion produced a significant decrease in impedance from baseline in all subjects (p < 0.05, regardless of electrode type or pressure application), confirming micropore formation. This was supported by a complementary significant increase in TEWL (p < 0.05). The gel*direct condition produced the lowest variability between measurements, as demonstrated by a coefficient of variation of 3.8% and 3.5% (control and elderly subjects, respectively). This was lower than variation between TEWL measurements at the same sites: 19.8% and 21.6% (control and elderly subjects, respectively). Impedance spectroscopy reproducibly measures micropore formation in elderly subjects, which will be essential for future studies describing microneedle-assisted transdermal delivery in aging populations.

Microfluidic valve with cored glass microneedle for microinjection.

PubMed

Lee, Sanghoon; Jeong, Wonje; Beebe, David J

2003-08-01

In this paper, a new microinjection device was constructed by fusing a glass microneedle and a PDMS-based microvalve. The microneedle was fabricated via traditional micropipette pulling. The PDMS-based microvalve regulates the fluid flow in the microchannel and microneedle. The 'ON/OFF' operation of the valve was controlled by manually supplied pneumatic pressure. The valve membrane utilized a two level geometry to improve control at low flow rates. The relation between pressure and flow was measured and the results showed that very small volumes of fluid (>1 nl) could be controlled. The valve operation was investigated by monitoring the tip of the needle and pneumatic pressure simultaneously and it demonstrated very stable 'ON/OFF' operation to the pressure change.

Combination of microneedling and glycolic acid peels for the treatment of acne scars in dark skin.

PubMed

Sharad, Jaishree

2011-12-01

  Acne scars can cause emotional and psychosocial disturbance to the patient. Various modalities have been used for the treatment of acne scars like punch excision, subcision, peels, microdermabrasion, unfractionated and fractioned lasers. The latest in the treatment armamentarium is microneedling. Acne scars commonly coexist with postinflammatory hyperpigmentation. A combination of microneedling and glycolic acid (GA) peels was found to give excellent results in the treatment of such scars. The aim was to study the efficacy of a combination of microneedling with glycolic peel for the treatment of acne scars in pigmented skin.   Thirty patients in the age group of 20-40 years with atrophic box type or rolling scars with postinflammatory hyperpigmentation were chosen for the study. Two groups were made. The first group comprised of 30 patients in whom only microneedling was performed once in 6 weeks for five sessions. In the second group of 30 patients, a combination of microneedling and 35% GA peels was carried out. Patients from both groups were evaluated on the basis of Echelle d'Evaluation clinique des Cicatrices d'acné classification.   Based on the objective scoring and its statistical analysis, there was significant improvement in superficial and moderately deep scars (grade 1-3). There was also improvement in skin texture, reduction in postacne pigmentation in the second group.   Microneedling is a simple, inexpensive office procedure with no downtime. It is safe in Indian skin (skin types III-IV). The combined sequential treatment with GA peel caused a significant improvement in the acne scars without increasing morbidity. © 2011 Wiley Periodicals, Inc.

Microneedles for enhanced transdermal and intraocular drug delivery.

PubMed

Moffatt, Kurtis; Wang, Yujing; Raj Singh, Thakur Raghu; Donnelly, Ryan F

2017-10-01

Microneedle mediated delivery based research has garnered great interest in recent years. In the past, the initial focus was delivery of macromolecules of biological origin, however the field has now broadened its scope to include transdermal delivery of conventional low molecular weight drug molecules. Great success has been demonstrated utilising this approach, particularly in the field of vaccine delivery. Current technological advances have permitted an enhancement in design formulation, allowing delivery of therapeutic doses of small molecule drugs and biomolecules, aided by larger patch sizes and scalable manufacture. In addition, it has been recently shown that microneedles are beneficial in localisation of drug delivery systems within targeted ocular tissues. Microneedles have the capacity to modify the means in which therapeutics and formulations are delivered to the eye. However, further research is still required due to potential drawbacks and challenges. Indeed, no true microneedle-based transdermal or ocular drug delivery system has yet been marketed. Some concerns have been raised regarding regulatory issues and manufacturing processes of such systems, and those in the field are now actively working to address them. Microneedle-based transdermal and ocular drug delivery systems have the potential to greatly impact not only patient benefits, but also industry, and through diligence, innovation and collaboration, their true potential will begin to be realised within the next 3-5 years. Copyright © 2017 Elsevier Ltd. All rights reserved.

Novel in situ forming hydrogel microneedles for transdermal drug delivery.

PubMed

Sivaraman, Arunprasad; Banga, Ajay K

2017-02-01

Novel in situ forming hydrogel microneedles were evaluated for transdermal drug delivery using a biocompatible non-ionic triblock amphiphilic thermosensitive copolymer. The transition property of poloxamer from solution at room temperature to gel at skin temperature (32 °C) was utilized in preparation of in situ forming hydrogel microneedles. Methotrexate has been used to treat solid tumors, but because of its narrow safety margin, it requires sustained delivery within the therapeutic window. Formulations with and without poloxamer at different methotrexate concentrations were prepared and evaluated for drug permeation across skin using vertical Franz diffusion cell for 72 h. Sol-gel transition, skin resistance and thickness, microneedles geometry, microchannel depth, shape, formation and uniformity, viscoelasticity of skin, and in vitro drug permeation were characterized and tested. An average cumulative drug amount of 32.2 ± 15.76 and 114.54 ± 40.89 μg/cm 2 for porcine ear skin and 3.89 ± 0.60 and 10.27 ± 6.98 μg/cm 2 for dermatomed human skin from 0.2 % w/w and 0.4 % w/w methotrexate formulations was delivered by the in situ forming hydrogel microneedles. These in situ hydrogel microneedles embedded within the porated site of the skin provided a steady and sustained drug delivery.

Polymer microneedles fabricated from alginate and hyaluronate for transdermal delivery of insulin.

PubMed

Yu, Weijiang; Jiang, Guohua; Zhang, Yang; Liu, Depeng; Xu, Bin; Zhou, Junyi

2017-11-01

To reduce the inconvenient and painful of subcutaneous needle injection, the polymer microneedle patches that fabricated from modified alginate and hyaluronate were prepared for transdermal delivery of insulin. The as-prepared microneedles (MNs) exhibited excellent mechanical strength to penetrate the skin and good degradability to release loaded insulin. In vitro skin insertion capability was determined by staining with tissue-marking dye after insertion, and the real-time penetration depth was monitored using optical coherence tomography. Confocal microscopy images revealed that the rhodamine B and fluorescein isothiocyanate-labeled insulin (FITC-insulin) can gradually diffuse from the puncture sites to deeper tissue. In vivo and pharmacodynamic studies were then conducted to estimate the feasibility of the administration of insulin-loaded microneedle patches on diabetic mice for glucose regulation. The relative pharmacologic availability (RPA) and relative bioavailability (RBA) of insulin from microneedle patches were 90.5±6.8% and 92.9±7%, respectively. These results suggests the MNs developed in this study have a promising application in diabetes treatment via transdermal delivery. Copyright © 2017 Elsevier B.V. All rights reserved.

Microneedle crystals of cyano-substituted thiophene/phenylene co-oligomer epitaxially grown on KCl surface

NASA Astrophysics Data System (ADS)

Torii, Kazuki; Dokiya, Shohei; Tanaka, Yosuke; Yoshinaga, Shohei; Yanagi, Hisao

2017-06-01

A cyno-substituted thiophene/phenylene co-oligomer (TPCO), 5,5‧-bis(4‧-cyanobiphenyl-4-yl)-2,2‧-bithiophene (BP2T-CN), is vapor-deposited on KCl (001) surface kept at 220 °C by the mask-shadowing method. Transmission electron microscopy and fluorescence microscopy reveal that the deposited BP2T-CN crystallizes in two types of morphologies: microneedles and thin film crystallites. In particular, the predominant microneedles epitaxially grow in four directions in the manner that the BP2T-CN molecules align along the [110]KCl or [-110]KCl. X-ray diffraction patterns indicate that the BP2T-CN molecules in the microneedle lie parallel while those in the thin film crystallite obliquely stand on the KCl surface.

Biodegradable 3D printed polymer microneedles for transdermal drug delivery.

PubMed

Luzuriaga, Michael A; Berry, Danielle R; Reagan, John C; Smaldone, Ronald A; Gassensmith, Jeremiah J

2018-04-17

Biodegradable polymer microneedle (MN) arrays are an emerging class of transdermal drug delivery devices that promise a painless and sanitary alternative to syringes; however, prototyping bespoke needle architectures is expensive and requires production of new master templates. Here, we present a new microfabrication technique for MNs using fused deposition modeling (FDM) 3D printing using polylactic acid, an FDA approved, renewable, biodegradable, thermoplastic material. We show how this natural degradability can be exploited to overcome a key challenge of FDM 3D printing, in particular the low resolution of these printers. We improved the feature size of the printed parts significantly by developing a post fabrication chemical etching protocol, which allowed us to access tip sizes as small as 1 μm. With 3D modeling software, various MN shapes were designed and printed rapidly with custom needle density, length, and shape. Scanning electron microscopy confirmed that our method resulted in needle tip sizes in the range of 1-55 μm, which could successfully penetrate and break off into porcine skin. We have also shown that these MNs have comparable mechanical strengths to currently fabricated MNs and we further demonstrated how the swellability of PLA can be exploited to load small molecule drugs and how its degradability in skin can release those small molecules over time.

A method to improve the efficacy of topical eflornithine hydrochloride cream.

PubMed

Kumar, Amit; Naguib, Youssef W; Shi, Yan-Chun; Cui, Zhengrong

2016-06-01

Facial hirsutism is a cosmetic concern for women and can lead to significant anxiety and lack of self-esteem. Eflornithine cream is indicated for the treatment of facial hirsutism. However, limited success rate and overall patient's satisfaction, even with a long-term and high-frequency application, leave room for improvement. The objective of this study is to test the effect of microneedle treatment on the in vitro skin permeation and the in vivo efficacy of eflornithine cream in a mouse model. In vitro permeation study of eflornithine was performed using Franz diffusion cell. In vivo efficacy study was performed in a mouse model by monitoring the re-growth of hair in the lower dorsal skin of mice after the eflornithine cream was applied onto an area pretreated with microneedles. The skin and the hair follicles in the treated area were also examined histologically. The hair growth inhibitory activity of eflornithine was significantly enhanced when the eflornithine cream was applied onto a mouse skin area pretreated with microneedles, most likely because the micropores created by microneedles allowed the permeation of eflornithine into the skin, as confirmed in an in vitro permeation study. Immunohistochemistry data revealed that cell proliferation in the skin and hair follicles was also significantly inhibited when the eflornithine cream was applied onto a skin area pretreated with microneedles. The integration of microneedle treatment into topical eflornithine therapy represents a potentially viable approach to increase eflornithine's ability to inhibit hair growth.

Assessment of the effects of skin microneedling as adjuvant therapy for facial melasma: a pilot study.

PubMed

Lima, Emerson V A; Lima, Mariana Modesto D A; Paixão, Mauricio Pedreira; Miot, Hélio Amante

2017-11-28

Melasma is a common chronic and relapsing acquired dyschromia. Skin microneedling was reported resulting sustained long-term improvement of recalcitrant melasma, however, the exact mechanism that promotes this skin lightening is not known. This study aimed to investigate clinical and histologic alterations promoted by skin microneedling in facial melasma. Open pilot trial including six women with facial refractory melasma submitted to two sessions of microneedling (1.5 mm) each 30 days followed by daily triple combination and broad-spectrum sunscreen. Comparison of pretreatment (T0) and 15 days after last microneedling procedure (T45) was made by standardized pictures, skin colorimetry, MASI, MELASQoL and histological parameters (haematoxylin-eosin, picrosirius-red, periodic acid Schiff and Fontana-Masson staining). The age of the subjects varied from 34 to 46 years-old, the phototypes were III and IV (Fitzpatrick), and age of melasma onset was 20 to 38 years. Improvement of melasma was perceived in all subjects. There was a significant reduction of MASI score (-70%), MELASQoL (-55%) and increase in L* (+13%) colorimetric value (p < 0.03). All cases evidenced epithelium thickening, decrease in melanin pigmentation and densification of upper dermis collagen (p = 0.03). Patients were followed by 6 months under broad-spectrum sunscreen and triple combination without relapse. In addition to classic treatment (broad-spectrum sunscreen and triple combination), skin microneedling promoted clinical and histological improvement of refractory facial melasma.

Increasing topical anesthetic efficacy with microneedle application.

PubMed

Buhsem, Ömer; Aksoy, Alper; Kececi, Yavuz; Sir, Emin; Güngör, Melike

2016-10-01

Since topical anesthetics alone seldom provide adequate analgesia for laser resurfacing procedures, injectable forms of anesthesia are often required. However, their application is uncomfortable for the patient. In this study, it is investigated whether microneedle application would enhance the efficacy of topical anesthetics. Forty-seven patients participated in the study. Topical anesthetic agent EMLA was applied to the whole face of the patients. Microneedle treatment was applied to one side of the face with a roller-type device. Whole-face carbon dioxide laser resurfacing therapy was carried out then. The pain that patients experienced was assessed by using visual analog scale (VAS) method. VAS scores of two sides of the face were compared by using Wilcoxon signed-rank test. The mean of VAS score of the microneedle treated side was 2.1 ± 1.1 while that of the untreated side was 5.9 ± 0.9 and this difference was statistically significant (Wilcoxon signed-rank test, the Z-value is - 5.9683 and the p-value is < 0.001). This study revealed that microneedle application, with a roller-type device, is a safe and easy procedure in providing sufficient anesthesia for facial laser resurfacing without the need for supplementary nerve blocks or injections.

A repeatable and scalable fabrication method for sharp, hollow silicon microneedles

NASA Astrophysics Data System (ADS)

Kim, H.; Theogarajan, L. S.; Pennathur, S.

2018-03-01

Scalability and manufacturability are impeding the mass commercialization of microneedles in the medical field. Specifically, microneedle geometries need to be sharp, beveled, and completely controllable, difficult to achieve with microelectromechanical fabrication techniques. In this work, we performed a parametric study using silicon etch chemistries to optimize the fabrication of scalable and manufacturable beveled silicon hollow microneedles. We theoretically verified our parametric results with diffusion reaction equations and created a design guideline for a various set of miconeedles (80-160 µm needle base width, 100-1000 µm pitch, 40-50 µm inner bore diameter, and 150-350 µm height) to show the repeatability, scalability, and manufacturability of our process. As a result, hollow silicon microneedles with any dimensions can be fabricated with less than 2% non-uniformity across a wafer and 5% deviation between different processes. The key to achieving such high uniformity and consistency is a non-agitated HF-HNO3 bath, silicon nitride masks, and surrounding silicon filler materials with well-defined dimensions. Our proposed method is non-labor intensive, well defined by theory, and straightforward for wafer scale mass production, opening doors to a plethora of potential medical and biosensing applications.

Multiphoton microscopy of transdermal quantum dot delivery using two photon polymerization-fabricated polymer microneedles

PubMed Central

Gittard, Shaun D; Miller, Philip R; Boehm, Ryan D; Ovsianikov, Aleksandr; Chichkov, Boris N; Heiser, Jeremy; Gordon, John; Monteiro-Riviere, Nancy A; Narayan, Roger J

2010-01-01

Due to their ability to serve as fluorophores and drug delivery vehicles, quantum dots are a powerful tool for theranostics-based clinical applications. In this study, microneedle devices for transdermal drug delivery were fabricated by means of two-photon polymerization of an acrylate-based polymer. We examined proliferation of cells on this polymer using neonatal human epidermal keratinocytes and human dermal fibroblasts. The microneedle device was used to inject quantum dots into porcine skin; imaging of the quantum dots was performed using multiphoton microscopy. PMID:21413181

Modification of microneedles using inkjet printing

NASA Astrophysics Data System (ADS)

Boehm, R. D.; Miller, P. R.; Hayes, S. L.; Monteiro-Riviere, N. A.; Narayan, R. J.

2011-06-01

In this study, biodegradable acid anhydride copolymer microneedles containing quantum dots were fabricated by means of visible light dynamic mask micro-stereolithography-micromolding and inkjet printing. Nanoindentation was performed to obtain the hardness and the Young's modulus of the biodegradable acid anhydride copolymer. Imaging of quantum dots within porcine skin was accomplished by means of multiphoton microscopy. Our results suggest that the combination of visible light dynamic mask micro-stereolithography-micromolding and inkjet printing enables fabrication of solid biodegradable microneedles with a wide range of geometries as well as a wide range of pharmacologic agent compositions.

Hydrodynamic gene delivery in human skin using a hollow microneedle device.

PubMed

Dul, M; Stefanidou, M; Porta, P; Serve, J; O'Mahony, C; Malissen, B; Henri, S; Levin, Y; Kochba, E; Wong, F S; Dayan, C; Coulman, S A; Birchall, J C

2017-11-10

Microneedle devices have been proposed as a minimally invasive delivery system for the intradermal administration of nucleic acids, both plasmid DNA (pDNA) and siRNA, to treat localised disease or provide vaccination. Different microneedle types and application methods have been investigated in the laboratory, but limited and irreproducible levels of gene expression have proven to be significant challenges to pre-clinical to clinical progression. This study is the first to explore the potential of a hollow microneedle device for the delivery and subsequent expression of pDNA in human skin. The regulatory approved MicronJet600® (MicronJet hereafter) device was used to deliver reporter plasmids (pCMVβ and pEGFP-N1) into viable excised human skin. Exogenous gene expression was subsequently detected at multiple locations that were distant from the injection site but within the confines of the bleb created by the intradermal bolus. The observed levels of gene expression in the tissue are at least comparable to that achieved by the most invasive microneedle application methods e.g. lateral application of a microneedle. Gene expression was predominantly located in the epidermis, although also evident in the papillary dermis. Optical coherence tomography permitted real time visualisation of the sub-surface skin architecture and, unlike a conventional intradermal injection, MicronJet administration of a 50μL bolus appears to create multiple superficial microdisruptions in the papillary dermis and epidermis. These were co-localised with expression of the pCMVβ reporter plasmid. We have therefore shown, for the first time, that a hollow microneedle device can facilitate efficient and reproducible gene expression of exogenous naked pDNA in human skin using volumes that are considered to be standard for intradermal administration, and postulate a hydrodynamic effect as the mechanism of gene delivery. Copyright © 2017 Elsevier B.V. All rights reserved.

A method to improve the efficacy of topical eflornithine hydrochloride cream

PubMed Central

Kumar, Amit; Naguib, Youssef W.; Shi, Yan-chun; Cui, Zhengrong

2015-01-01

Context Facial hirsutism is a cosmetic concern for women and can lead to significant anxiety and lack of self-esteem. Eflornithine cream is indicated for the treatment of facial hirsutism. However, limited success rate and overall patient’s satisfaction, even with a long-term and high frequency application, leave room for improvement. Objective The objective of this study is to test the effect of microneedle treatment on the in vitro skin permeation and the in vivo efficacy of eflornithine cream in a mouse model. Materials and method In vitro permeation study of eflornithine was performed using Franz diffusion cell. In vivo efficacy study was performed in a mouse model by monitoring the re-growth of hair in the lower dorsal skin of mice after the eflornithine cream was applied onto an area pretreated with microneedles. The skin and the hair follicles in the treated area were also examined histologically. Results and discussion The hair growth inhibitory activity of eflornithine was significantly enhanced when the eflornithine cream was applied onto a mouse skin area pretreated with microneedles, most likely because the micropores created by microneedles allowed the permeation of eflornithine into the skin, as confirmed in an in vitro permeation study. Immunohistochemistry data revealed that cell proliferation in the skin and hair follicles was also significantly inhibited when the eflornithine cream was applied onto a skin area pretreated with microneedles. Conclusion The integration of microneedle treatment into topical eflornithine therapy represents a potentially viable approach to increase eflornithine’s ability to inhibit hair growth. PMID:25182303

In vivo optical coherence tomography imaging of dissolution of hyaluronic acid microneedles in human skin (Conference Presentation)

NASA Astrophysics Data System (ADS)

Song, Seungri; Kim, Jung Dong; Bae, Jung-hyun; Chang, Sooho; Kim, Soocheol; Lee, Hyungsuk; Jeong, Dohyeon; Kim, Hong Kee; Joo, Chulmin

2017-02-01

Transdermal drug delivery (TDD) has been recently highlighted as an alternative to oral delivery and hypodermic injections. Among many methods, drug delivery using a microneedle (MN) is one of the promising administration strategies due to its high skin permeability, mininal invasiveness, and ease of injection. In addition, microneedle-based TDD is explored for cosmetic and therapeutic purposes, rapidly developing market of microneedle industry for general population. To date, visualization of microneedles inserted into biological tissue has primarily been performed ex vivo. MRI, CT and ultrasound imaging do not provide sufficient spatial resolution, and optical microscopy is not suitable because of their limited imaging depth; structure of microneedles located in 0.2 1mm into the skin cannot be visulalized. Optical coherence tomography (OCT) is a non-invasive, cross-sectional optical imaging modality for biological tissue with high spatial resolution and acquisition speed. Compared with ultrasound imaging, it exhibits superior spatial resolution (1 10 um) and high sensitivity, while providing an imaging depth of biological tissue down to 1 2 mm. Here, we present in situ imaging and analysis of the penetration and dissolution characteristics of hyaluronic acid based MNs (HA-MN) with various needle heights in human skin in vivo. In contrast to other studies, we measured the actual penetration depths of the HA-MNs by considering the experimentally measured refractive index of HA in the solid state. For the dissolution dynamics of the HA-MNs, time-lapse structural alteration of the MNs could be clearly visualized, and the volumetric changes of the MNs were measured with an image analysis algorithm.

Coating solid dispersions on microneedles via a molten dip coating method: development and in vitro evaluation for transdermal delivery of a water insoluble drug

PubMed Central

Ma, Yunzhe; Gill, Harvinder S.

2014-01-01

This study demonstrates for the first time the ability to coat solid dispersions on microneedles as a means to deliver water-insoluble drugs through the skin. Polyethylene glycol (PEG) was selected as the hydrophilic matrix, and lidocaine base was selected as the model hydrophobic drug to create the solid dispersion. First, thermal characterization and viscosity measurements of the PEG-lidocaine mixture at different mass fractions were performed. The results show that lidocaine can remain stable at temperatures up to ~130 °C, and that viscosity of the PEG-lidocaine molten solution increases as the mass fraction of lidocaine decreases. Differential scanning calorimetry demonstrated that at lidocaine mass fraction less than or equal to 50%, lidocaine is well dispersed in the PEG-lidocaine mixture. Uniform coatings were obtained on microneedle surfaces. In vitro dissolution studies in porcine skin showed that microneedles coated with PEG-lidocaine dispersions resulted in significantly higher delivery of lidocaine in just 3 min compared to 1 h topical application of 0.15 g EMLA®, a commercial lidocaine-prilocaine cream. In conclusion, the molten coating process we introduce here offers a practical approach to coat water-insoluble drugs on microneedles for transdermal delivery. PMID:25213295

Development of in vivo impedance spectroscopy techniques for measurement of micropore formation following microneedle insertion

PubMed Central

Brogden, Nicole K.; Ghosh, Priyanka; Hardi, Lucia; Crofford, Leslie J.; Stinchcomb, Audra L.

2013-01-01

Microneedles provide a minimally invasive means to enhance skin permeability by creating micron-scale channels (micropores) that provide a drug delivery pathway. Adequate formation of the micropores is critical to the success of this unique drug delivery technique. The objective of these studies was to develop sensitive and reproducible impedance spectroscopy techniques to monitor micropore formation in animal models and human subjects. Hairless guinea pigs, a Yucatan miniature pig, and human volunteers were treated with 100 microneedle insertions per site following an overnight pre-hydration period. Repeated measurements were made pre- and post-microneedle treatment using dry and gel Ag/AgCl electrodes applied with light vs. direct pressure to hold the electrode to the skin surface. Impedance measurements dropped significantly post-microneedle application at all sites (p < 0.05, irrespective of electrode type or gel application), confirming micropore formation. In the Yucatan pig and human subjects, gel electrodes with direct pressure yielded the lowest variability (demonstrated by lower %RSD), whereas dry electrodes with direct pressure were superior in the guinea pigs. These studies confirm that impedance measurements are suitable for use in both clinical and animal research environments to monitor formation of new micropores that will allow for drug delivery through the impermeable skin layers. PMID:23589356

An evaluation of the antiaging properties of strawberry hydrolysate treatment enriched with L-ascorbic acid applied with microneedle mesotherapy.

PubMed

Markiewicz, Agata; Zasada, Malwina; Erkiert-Polguj, Anna; Wieckowska-Szakiel, Marzena; Budzisz, Elzbieta

2018-04-16

Mature skin is characterized by a loss of elasticity, hyperpigmentation, and dehydration. L-ascorbic acid stimulates the synthesis of collagen type I, inhibits melanogenesis, and helps to maintain correct skin hydration. Combining microneedle mesotherapy with the application of preparations rich in vitamin C results in better therapeutic effects due to the improved absorption of active substances. The study evaluates the effectiveness of the application of strawberry hydrolysate enriched with L-ascorbic acid using microneedle mesotherapy. Seventeen volunteers aged 45-70 years underwent a series of four microneedle mesotherapy treatments with vitamin C serum, performed every 10 days. The 20% L-ascorbic acid solution (pH = 3.5) was prepared immediately before application. After the treatment, the participants gave a subjective assessment of the effectiveness. Cutometer ® was used to measure skin elasticity and firmness, Corneometer ® to measure skin hydration, and Mexameter ® skin tone. The results of the survey showed improvements in skin hydration and elasticity. In vivo studies confirmed the effectiveness of serum and the impact of the active substance on skin firmness and elasticity, the degree of hydration and skin tone. Microneedling with vitamin C improves skin tone, hydratation and firmness, and decreases the visibility of hyperpigmentation. © 2018 Wiley Periodicals, Inc.

Wearable Wireless Tyrosinase Bandage and Microneedle Sensors: Toward Melanoma Screening.

PubMed

Ciui, Bianca; Martin, Aida; Mishra, Rupesh K; Brunetti, Barbara; Nakagawa, Tatsuo; Dawkins, Thomas J; Lyu, Mengjia; Cristea, Cecilia; Sandulescu, Robert; Wang, Joseph

2018-04-01

Wearable bendable bandage-based sensor and a minimally invasive microneedle biosensor are described toward rapid screening of skin melanoma. These wearable electrochemical sensors are capable of detecting the presence of the tyrosinase (TYR) enzyme cancer biomarker in the presence of its catechol substrate, immobilized on the transducer surface. In the presence of the surface TYR biomarker, the immobilized catechol is rapidly converted to benzoquinone that is detected amperometrically, with a current signal proportional to the TYR level. The flexible epidermal bandage sensor relies on printing stress-enduring inks which display good resiliency against mechanical deformations, whereas the hollow microneedle device is filled with catechol-coated carbon paste for assessing tissue TYR levels. The bandage sensor can thus be used directly on the skin whereas microneedle device can reach melanoma tissues under the skin. Both wearable sensors are interfaced to an ultralight flexible electronic board, which transmits data wirelessly to a mobile device. The analytical performance of the resulting bandage and microneedle sensing systems are evaluated using TYR-containing agarose phantom gel and porcine skin. The new integrated conformal portable sensing platforms hold considerable promise for decentralized melanoma screening, and can be extended to the screening of other key biomarkers in skin moles. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Penetration and distribution of PLGA nanoparticles in the human skin treated with microneedles.

PubMed

Zhang, Wei; Gao, Jing; Zhu, Quangang; Zhang, Min; Ding, Xueying; Wang, Xiaoyu; Hou, Xuemei; Fan, Wei; Ding, Baoyue; Wu, Xin; Wang, Xiying; Gao, Shen

2010-12-15

This study was designed to investigate the penetration and the distribution of poly(d,l-lactic-co-glycolic acid) (PLGA) nanoparticles in the human skin treated with microneedles. Fluorescent nanoparticles were prepared to indicate the transdermal transport process of the nanoparticles. Permeation study was performed on Franz-type diffusion cells in vitro. The distribution of nanoparticles was visualized by confocal laser scanning microscopy (CLSM) and quantified by high performance liquid chromatography (HPLC). CLSM images showed that nanoparticles were delivered into the microconduits created by microneedles and permeated into the epidermis and the dermis. The quantitative determination showed that (i) the permeation of nanoparticles into the skin was enhanced by microneedles, but no nanoparticle reached the receptor solution; (ii) much more nanoparticles deposited in the epidermis than those in the dermis; (iii) the permeation was in a particle size-dependent manner; and (iv) the permeation increased with the nanoparticle concentration increasing until a limit value was reached. These results suggested that microneedles could enhance the intradermal delivery of PLGA nanoparticles. The biodegradable nanoparticles would sustain drug release in the skin and supply the skin with drug over a prolonged period. This strategy would prove to be useful for topical drug administration. Copyright © 2010 Elsevier B.V. All rights reserved.

Intradermal microneedle delivery of insulin lispro achieves faster insulin absorption and insulin action than subcutaneous injection.

PubMed

Pettis, Ronald J; Ginsberg, Barry; Hirsch, Laurence; Sutter, Diane; Keith, Steven; McVey, Elaine; Harvey, Noel G; Hompesch, Marcus; Nosek, Leszek; Kapitza, Christoph; Heinemann, Lutz

2011-04-01

This study compared insulin lispro (IL) pharmacokinetics (PK) and pharmacodynamics (PD) delivered via microneedle intradermal (ID) injection with subcutaneous (SC) injection under euglycemic glucose clamp conditions. Ten healthy male volunteers were administered 10 international units (IU) of IL at 3 microneedle lengths (1.25, 1.50, or 1.75 mm) in a randomized, crossover fashion on Days 1-3 followed by a repetitive ID 1.5-mm microneedle dose (Day 4) and an SC dose (Day 5). Microneedle ID delivery resulted in more rapid absorption of IL, with decreased time to maximum insulin concentration (ID vs. SC: 36.0-46.4 vs. 64.3 min, P < 0.05) and higher fractional availability at early postinjection times. ID produced more rapid effects on glucose uptake with shorter times to maximal and early half-maximal glucose infusion rates (GIRs) (ID vs. SC: time to maximum GIR, 106-112 vs. 130 min, P < 0.05; early half-maximal GIR, 29-35 vs. 42 min), increased early GIR area under the curve (AUC), and faster offset of insulin action (shorter time to late half-maximal GIR: 271-287 vs. 309 min). Relative total insulin bioavailability (AUC to 360 min and AUC to infinite measurement) did not significantly differ between administration routes. ID PK/PD parameters showed some variation as a function of needle length. Delivery of ID IL was generally well tolerated, although transient, localized wheal formation and redness were observed at injection sites. Microneedle ID insulin lispro delivery enables more rapid onset and offset of metabolic effect than SC therapy and is safe and well tolerated; further study for insulin therapy is warranted.

Host responses in human skin after conventional intradermal injection or microneedle administration of virus-like-particle influenza vaccine.

PubMed

Pearton, Marc; Pirri, Daniela; Kang, Sang-Moo; Compans, Richard W; Birchall, James C

2013-10-01

Miniaturized microneedle devices are being developed for painlessly targeting vaccines to the immune cell populations in skin. As skin immunization studies are generally restricted to animal models however, where skin architecture and immunity is greatly different to human, surprisingly little is known about the local human response to intradermal (ID) vaccines. Here surgically excised human skin is used to explore for the first time the complex molecular and cellular host responses to a candidate influenza vaccine comprising nanoparticulate virus-like-particles (VLPs), administered via conventional hypodermic injection or reduced scale microneedles. Responses at the molecular level are determined by microarray analysis (47,296 discrete transcripts) and validated by quantitative PCR (96 genes). Cellular response is probed through monitoring migration of dendritic cells in viable skin tissue. Gene expression mapping, ontological analysis, and qPCR reveal up-regulation of a host of genes responsible for key immunomodulatory processes and host viral response, including cell recruitment, activation, migration, and T cell interaction following both ID and microneedle injection of VLPs; the response from the microneedles being more subtle. Significant morphological and migratory changes to skin dendritic cells are also apparent following microneedle VLP delivery. This is the first study displaying the global, multifaceted immunological events that occur at the site of vaccine deposition in human skin and will subsequently influence the degree and nature of innate and adaptive immune responses. An increased understanding of the detailed similarities and differences in response against antigen administered via different delivery modalities will inform the development of improved vaccines and vaccine delivery systems. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Enhancement of Skin Permeation and Skin Immunization of Ovalbumin Antigen via Microneedles.

PubMed

Pamornpathomkul, Boonnada; Rojanarata, Theerasak; Opanasopit, Praneet; Ngawhirunpat, Tanasait

2017-10-01

The purpose of this study was to evaluate the use of different types of microneedles and doses of ovalbumin antigen for in vitro skin permeation and in vivo immunization. In vitro skin permeation experiments and confocal laser scanning microscopy revealed that hollow microneedles had a superior enhancing effect on skin permeation compared with a solid microneedle patch and untreated skin by efficiently delivering ovalbumin-fluorescein conjugate into the deep skin layers. The flux and cumulative amount of ovalbumin-fluorescein conjugate at 8 h after administering with various conditions could be ranked as follows: hollow MN; high dose > medium dose > low dose > MN patch; high dose > medium dose > low dose > untreated skin; high dose > medium dose > low dose > without ovalbumin-fluorescein conjugate. As the dose of ovalbumin-fluorescein conjugate was increased to 500 μg, the antigen accumulated in the skin to a greater extent, as evidenced by the increasing green fluorescence intensity. When the hollow microneedle was used for the delivery of ovalbumin into the skin of mice, it was capable of inducing a stronger immunoglobulin G immune response than conventional subcutaneous injection at the same antigen dose. Immunoglobulin G levels in the hollow MN group were 5.7, 11.6, and 13.3 times higher than those of the subcutaneous injection group for low, medium, and high doses, respectively. Furthermore, the mice immunized using the hollow microneedle showed no signs of skin infection or pinpoint bleeding. The results suggest that the hollow MN is an efficient device for delivering the optimal dose of antigen via the skin for successful immunization.

A Comparative Study of Microneedling with Platelet-rich Plasma Plus Topical Minoxidil (5%) and Topical Minoxidil (5%) Alone in Androgenetic Alopecia.

PubMed

Shah, Kaksha B; Shah, Aarti N; Solanki, Rekha B; Raval, Ranjan C

2017-01-01

There are very few studies evaluating efficacy of platelet-rich plasma (PRP) in hair restoration and its combination with microneedling. As far as ascertained, there is no study to evaluate efficacy of microneedling with PRP plus topical minoxidil (5%) versus topical minoxidil (5%) alone in androgenetic alopecia (AGA). This study aims (1) to compare the efficacy of (a) topical minoxidil (5%) alone and (b) topical minoxidil (5%) + microneedling with PRP in men between 18 and 50 years with AGA Grade III to V vertex (Norwood-Hamilton scale) and (2) to perform objective and subjective evaluation based on clinical improvement and photographic evidence. The study was conducted in the outpatient department of dermatology, venereology, and leprology in tertiary care hospital. It was open, prospective study. Fifty patients with AGA were selected on the basis of inclusion and exclusion criteria. These patients were randomly divided into two groups of 25 patients each and were given following treatment: (i) Group A: topical minoxidil (5%) alone and (ii) Group B: topical minoxidil (5%) + microneedling with platelet-rich plasma (PRP). Patients were assessed before starting the treatment and at the end of 6 months on the basis of (a) Patient's self-assessment based on standardized seven-point scale compared with baseline (b) Physician's assessment based on standardized seven-point scale of hair growth compared with baseline. There was a significant improvement ( P < 0.05) in both patients' assessment and investigator's assessment in Group B as compared to Group A at the end of 6 months. Microneedling with PRP is safe, effective, and a promising tool for the management of AGA.

FLUX OF IONIC DYES ACROSS MICRONEEDLE-TREATED SKIN: EFFECT OF DYE MOLECULAR CHARACTERISTICS

PubMed Central

Gomaa, Yasmine A.; Garland, Martin J.; McInnes, Fiona; Donnelly, Ryan F.; El-Khordagui, Labiba K.; Wilson, Clive

2014-01-01

Drug flux across microneedle (MN)-treated skin is influenced by the characteristics of the MN array, microconduits and drug molecules in addition to the overall diffusional resistance of microconduits and viable tissue. Relative implication of these factors has not been fully explored. In the present study, the in vitro permeation of a series of six structurally related ionic xanthene dyes with different molecular weights (MW) and chemical substituents, across polymer MN-pretreated full thickness porcine skin was investigated in relation of their molecular characteristics. Phosphate buffer saline pH 7.4, the medium used in skin permeation experiments, was used to determine the equilibrium solubility of the dyes and their partition coefficient both in the isotropic n-octanol/ aqueous system and porcine skin/ aqueous system. Additionally, dissociation constants were determined potentiometrically. Results indicated that for rhodamine dyes, skin permeation of the zwitterionic form which predominates at physiological pH, was significantly reduced by an increase in MW, the presence of the chemically reactive isothiocyanate substituent reported to interact with stratum corneum proteins and the skin thickness. These factors were generally shown to override aqueous solubility, an important determinant of drug diffusion in an aqueous milieu. Findings provided more insight into the mechanism of drug permeation across MN-treated skin, of importance to both the design of MN-based transdermal drug delivery systems and in vitro skin permeation research. PMID:22960319

A proposed model membrane and test method for microneedle insertion studies.

PubMed

Larrañeta, Eneko; Moore, Jessica; Vicente-Pérez, Eva M; González-Vázquez, Patricia; Lutton, Rebecca; Woolfson, A David; Donnelly, Ryan F

2014-09-10

A commercial polymeric film (Parafilm M(®), a blend of a hydrocarbon wax and a polyolefin) was evaluated as a model membrane for microneedle (MN) insertion studies. Polymeric MN arrays were inserted into Parafilm M(®) (PF) and also into excised neonatal porcine skin. Parafilm M(®) was folded before the insertions to closely approximate thickness of the excised skin. Insertion depths were evaluated using optical coherence tomography (OCT) using either a force applied by a Texture Analyser or by a group of human volunteers. The obtained insertion depths were, in general, slightly lower, especially for higher forces, for PF than for skin. However, this difference was not a large, being less than the 10% of the needle length. Therefore, all these data indicate that this model membrane could be a good alternative to biological tissue for MN insertion studies. As an alternative method to OCT, light microscopy was used to evaluate the insertion depths of MN in the model membrane. This provided a rapid, simple method to compare different MN formulations. The use of Parafilm M(®), in conjunction with a standardised force/time profile applied by a Texture Analyser, could provide the basis for a rapid MN quality control test suitable for in-process use. It could also be used as a comparative test of insertion efficiency between candidate MN formulations. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.

Electroencephalogram measurement using polymer-based dry microneedle electrode

NASA Astrophysics Data System (ADS)

Arai, Miyako; Nishinaka, Yuya; Miki, Norihisa

2015-06-01

In this paper, we report a successful electroencephalogram (EEG) measurement using polymer-based dry microneedle electrodes. The electrodes consist of needle-shaped substrates of SU-8, a silver film, and a nanoporous parylene protective film. Differently from conventional wet electrodes, microneedle electrodes do not require skin preparation and a conductive gel. SU-8 is superior as a structural material to poly(dimethylsiloxane) (PDMS; Dow Corning Toray Sylgard 184) in terms of hardness, which was used in our previous work, and facilitates the penetration of needles through the stratum corneum. SU-8 microneedles can be successfully inserted into the skin without breaking and could maintain a sufficiently low skin-electrode contact impedance for EEG measurement. The electrodes successfully measured EEG from the frontal pole, and the quality of acquired signals was verified to be as high as those obtained using commercially available wet electrodes without any skin preparation or a conductive gel. The electrodes are readily applicable to record brain activities for a long period with little stress involved in skin preparation to the users.

Skin pretreatment with microneedles prior to pilocarpine iontophoresis increases sweat production.

PubMed

Wing, David; Prausnitz, Mark R; Buono, Michael J

2013-11-01

Collection of sweat via pilocarpine iontophoresis is commonly used to diagnose cystic fibrosis (CF), with thousands of tests performed each day. The main source of resistance to the passage of pilocarpine ions to the sweat glands is the electrical resistance of the stratum corneum. It was hypothesized that pretreating the skin with 0·5 mm-long microneedles would significantly decrease this resistance, thus increasing pilocarpine's permeation into the skin. Improved permeation should result in significantly reduced time to sweat initiation, time to collection of a clinically meaningful amount of sweat, and increased total amount of sweat produced in 15 min. Subjects (n = 12) had two 5 cm(2) areas on the forearm measured, marked and randomized to experimental (microneedles + iontophoresis) or control (iontophoresis alone). Microneedle pretreatment was conducted using a 35-needle microneedle stamp in a manner that 20 applications completely covered the 5 cm(2) treatment area. This was repeated five times for a total of 100 applications. Both experimental and control sites were placed under iontophoresis (1·5 mA) for 5 min. Microneedle pretreatment significantly decreased mean skin resistance (260 ± 27 kΩ versus 160 ± 19 kΩ, P = 0·006), while significantly increasing mean sweat rate (0·76 ± 0·35 versus 0·54 ± 0·19 μl cm(2) min(-1) , P = 0·007). No significant difference was found concerning pain (P = 0·059), number of active sweat glands (P = 0·627) or the osmolality of the collected sweat (P = 0·636). The results of this study suggest that microneedle pretreatment prior to pilocarpine iontophoresis significantly increases sweat production. Such results have the potential to improve the methodology currently used to diagnose cystic fibrosis and, more broadly, to administer drugs via the skin. © 2013 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd.

Nanostructured lipid carrier-loaded hyaluronic acid microneedles for controlled dermal delivery of a lipophilic molecule

PubMed Central

Lee, Sang Gon; Jeong, Jae Han; Lee, Kyung Min; Jeong, Kyu Ho; Yang, Huisuk; Kim, Miroo; Jung, Hyungil; Lee, Sangkil; Choi, Young Wook

2014-01-01

Nanostructured lipid carriers (NLCs) were employed to formulate a lipophilic drug into hydrophilic polymeric microneedles (MNs). Hyaluronic acid (HA) was selected as a hydrophilic and bioerodible polymer to fabricate MNs, and nile red (NR) was used as a model lipophilic molecule. NR-loaded NLCs were consolidated into the HA-based MNs to prepare NLC-loaded MNs (NLC-MNs). A dispersion of NLCs was prepared by high-pressure homogenization after dissolving NR in Labrafil and mixing with melted Compritol, resulting in 268 nm NLCs with a polydispersity index of 0.273. The NLC dispersion showed a controlled release of NR over 24 hours, following Hixson–Crowell’s cube root law. After mixing the NLC dispersion with the HA solution, the drawing lithography method was used to fabricate NLC-MNs. The length, base diameter, and tip diameter of the NLC-MNs were approximately 350, 380, and 30 μm, respectively. Fluorescence microscopic imaging of the NLC-MNs helped confirm that the NR-loaded NLCs were distributed evenly throughout the MNs. In a skin permeation study performed using a Franz diffusion cell with minipig dorsal skin, approximately 70% of NR was localized in the skin after 24-hour application of NLC-MNs. Confocal laser scanning microscopy (z-series) of the skin at different depths showed strong fluorescence intensity in the epidermal layer, which appeared to spread out radially with the passage of time. This study indicated that incorporation of drug-loaded NLCs into MNs could represent a promising strategy for controlled dermal delivery of lipophilic drugs. PMID:24403833

Fabrication of a Polymer Micro Needle Array by Mask-Dragging X-Ray Lithography and Alignment X-Ray Lithography

NASA Astrophysics Data System (ADS)

Li, Yi-Gui; Yang, Chun-Sheng; Liu, Jing-Quan; Sugiyama, Susumu

2011-03-01

Polymer materials such as transparent thermoplastic poly(methyl methacrylate) (PMMA) have been of great interest in the research and development of integrated circuits and micro-electromechanical systems due to their relatively low cost and easy process. We fabricated PMMA-based polymer hollow microneedle arrays by mask-dragging and aligning x-ray lithography. Techniques for 3D micromachining by direct lithography using x-rays are developed. These techniques are based on using image projection in which the x-ray is used to illuminate an appropriate gold pattern on a polyimide film mask. The mask is imaged onto the PMMA sample. A pattern with an area of up to 100 × 100mm2 can be fabricated with sub-micron resolution and a highly accurate order of a few microns by using a dragging mask. The fabrication technology has several advantages, such as forming complex 3D micro structures, high throughput and low cost.

Microneedle pretreatment enhances the percutaneous permeation of hydrophilic compounds with high melting points

PubMed Central

2012-01-01

Background Two commercially available microneedle rollers with a needle length of 200 μm and 300 μm were selected to examine the influence of microneedle pretreatment on the percutaneous permeation of four non-steroidal anti-inflammatory drugs (diclofenac, ibuprofen, ketoprofen, paracetamol) with different physicochemical drug characteristics in Franz-type diffusion cells. Samples of the receptor fluids were taken at predefined times over 6 hours and were analysed by UV–VIS high-performance liquid-chromatography. Histological examinations after methylene blue application were additionally performed to gather information about barrier disruption. Results Despite no visible pores in the stratum corneum, the microneedle pretreatment resulted in a twofold (200 μm) and threefold higher (300 μm) flux through the pretreated skin samples compared to untreated skin samples for ibuprofen and ketoprofen (LogKow > 3, melting point < 100°C). The flux of the hydrophilic compounds diclofenac and paracetamol (logKow < 1, melting point > 100°C) increased their amount by four (200 μm) to eight (300 μm), respectively. Conclusion Commercially available microneedle rollers with 200–300 μm long needles enhance the drug delivery of topically applied non-steroidal anti-inflammatory drugs and represent a valuable tool for percutaneous permeation enhancement particularly for substances with poor permeability due to a hydrophilic nature and high melting points. PMID:22947102

Comparison between the efficacy of microneedling combined with 5-fluorouracil vs microneedling with tacrolimus in the treatment of vitiligo.

PubMed

Mina, Mary; Elgarhy, Lamia; Al-Saeid, Hanan; Ibrahim, Zeinab

2018-03-12

Several treatment modalities had been used for the treatment of vitiligo, but the optimal treatment has not yet been identified. To study the efficacy of microneedling with 5-flurouracil vs its efficacy with tacrolimus in the treatment of vitiligo. Twenty-five patients with vitiligo were subjected to microneedling of 2 patches of vitiligo with dermapen, then application of 5-fluorouracil to 1 patch and tacrolimus on the other patch. This procedure was repeated every 2 weeks for every patient for maximum 6 months (12 sessions). The patients were followed up for 3 months after the last session. The overall repigmentation was significantly higher in 5-fluorouracil-treated patches compared with tacrolimus. Excellent improvement occurred in 48% of 5- flurouracil-treated patches while only in 16% of tacrolimus-treated patches. In the acral parts, 40% of the patches treated with 5-fluorouracil achieved excellent improvement (repigmentation >75%), while no patch in the acral parts achieved excellent improvement with tacrolimus. However, there was significant difference between the 2 drugs,regarding inflammation, ulceration, and hyperpigmentation which occurred with 5-fluorouracil. Microneedling combined with 5-fluorouracil or tacrolimus is safe and effective treatment of vitiligo. However, 5-fluorouracil achieved a greater percentage of repigmentation than tacrolimus particularly in the acral parts. © 2018 Wiley Periodicals, Inc.

Microneedle pH Sensor: Direct, Label-Free, Real-Time Detection of Cerebrospinal Fluid and Bladder pH.

PubMed

Mani, Ganesh Kumar; Miyakoda, Kousei; Saito, Asuka; Yasoda, Yutaka; Kajiwara, Kagemasa; Kimura, Minoru; Tsuchiya, Kazuyoshi

2017-07-05

Acid-base homeostasis (body pH) inside the body is precisely controlled by the kidneys and lungs and buffer systems, such that even a minor pH change could severely affect many organs. Blood and urine pH tests are common in day-to-day clinical trials and require little effort for diagnosis. There is always a great demand for in vivo testing to understand more about body metabolism and to provide effective diagnosis and therapy. In this article, we report the simple fabrication of microneedle-based direct, label-free, and real-time pH sensors. The reference and working electrodes were Ag/AgCl thick films and ZnO thin films on tungsten (W) microneedles, respectively. The morphological and structural characteristics of microneedles were carefully investigated through various analytical methods. The developed sensor exhibited a Nernstian response of -46 mV/pH. Different conditions were used to test the sensor to confirm their accuracy and stability, such as various buffer solutions, with respect to time, and we compared the reading with commercial pH electrodes. Besides that, the fabricated microneedle sensor ability is proven by in vivo testing in mouse cerebrospinal fluid (CSF) and bladders. The pH sensor procedure reported here is totally reversible, and results were reproducible after several rounds of testing.

A minimally invasive micro sampler for quantitative sampling with an ultrahigh-aspect-ratio microneedle and a PDMS actuator.

PubMed

Liu, Long; Wang, Yan; Yao, Jinyuan; Yang, Cuijun; Ding, Guifu

2016-08-01

This study describes a novel micro sampler consisting of an ultrahigh-aspect-ratio microneedle and a PDMS actuator. The microneedle was fabricated by a new method which introduced reshaped photoresist technology to form a flow channel inside. The microneedle includes two parts: shaft and pedestal. In this study, the shaft length is 1500 μm with a 45° taper angle on the tip and pedestal is 1000 μm. Besides, the shaft and pedestal are connected by an arc connection structure with a length of 600 μm. The microneedles have sufficient mechanical strength to insert into skin with a wide safety margin which was proved by mechanics tests. Moreover, a PDMS actuator with a chamber inside was designed and fabricated in this study. The chamber, acting as a reservoir in sampling process as well as providing power, was optimized by finite element analysis (FEA) to decrease dead volume and improve sampling precision. The micro sampler just needs finger press to activate the sampling process as well as used for quantitative micro injection to some extent. And a volume of 31.5 ± 0.8 μl blood was successfully sampled from the ear artery of a rabbit. This micro sampler is suitable for micro sampling for diagnose or therapy in biomedical field.

Microneedles for Transdermal Biosensing: Current Picture and Future Direction.

PubMed

Ventrelli, Letizia; Marsilio Strambini, Lucanos; Barillaro, Giuseppe

2015-12-09

A novel trend is rapidly emerging in the use of microneedles, which are a miniaturized replica of hypodermic needles with length-scales of hundreds of micrometers, aimed at the transdermal biosensing of analytes of clinical interest, e.g., glucose, biomarkers, and others. Transdermal biosensing via microneedles offers remarkable opportunities for moving biosensing technologies and biochips from research laboratories to real-field applications, and envisages easy-to-use point-of-care microdevices with pain-free, minimally invasive, and minimal-training features that are very attractive for both developed and emerging countries. In addition to this, microneedles for transdermal biosensing offer a unique possibility for the development of biochips provided with end-effectors for their interaction with the biological system under investigation. Direct and efficient collection of the biological sample to be analyzed will then become feasible in situ at the same length-scale of the other biochip components by minimally trained personnel and in a minimally invasive fashion. This would eliminate the need for blood extraction using hypodermic needles and reduce, in turn, related problems, such as patient infections, sample contaminations, analysis artifacts, etc. The aim here is to provide a thorough and critical analysis of state-of-the-art developments in this novel research trend, and to bridge the gap between microneedles and biosensors. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Reusable High Aspect Ratio 3-D Nickel Shadow Mask

PubMed Central

Shandhi, M.M.H.; Leber, M.; Hogan, A.; Warren, D.J.; Bhandari, R.; Negi, S.

2017-01-01

Shadow Mask technology has been used over the years for resistless patterning and to pattern on unconventional surfaces, fragile substrate and biomaterial. In this work, we are presenting a novel method to fabricate high aspect ratio (15:1) three-dimensional (3D) Nickel (Ni) shadow mask with vertical pattern length and width of 1.2 mm and 40 μm respectively. The Ni shadow mask is 1.5 mm tall and 100 μm wide at the base. The aspect ratio of the shadow mask is 15. Ni shadow mask is mechanically robust and hence easy to handle. It is also reusable and used to pattern the sidewalls of unconventional and complex 3D geometries such as microneedles or neural electrodes (such as the Utah array). The standard Utah array has 100 active sites at the tip of the shaft. Using the proposed high aspect ratio Ni shadow mask, the Utah array can accommodate 300 active sites, 200 of which will be along and around the shaft. The robust Ni shadow mask is fabricated using laser patterning and electroplating techniques. The use of Ni 3D shadow mask will lower the fabrication cost, complexity and time for patterning out-of-plane structures. PMID:29056835

Mechanisms of sampling interstitial fluid from skin using a microneedle patch.

PubMed

Samant, Pradnya P; Prausnitz, Mark R

2018-05-01

Although interstitial fluid (ISF) contains biomarkers of physiological significance and medical interest, sampling of ISF for clinical applications has made limited impact due to a lack of simple, clinically useful techniques that collect more than nanoliter volumes of ISF. This study describes experimental and theoretical analysis of ISF transport from skin using microneedle (MN) patches and demonstrates collection of >1 µL of ISF within 20 min in pig cadaver skin and living human subjects using an optimized system. MN patches containing arrays of submillimeter solid, porous, or hollow needles were used to penetrate superficial skin layers and access ISF through micropores (µpores) formed upon insertion. Experimental studies in pig skin found that ISF collection depended on transport mechanism according to the rank order diffusion < capillary action < osmosis < pressure-driven convection, under the conditions studied. These findings were in agreement with independent theoretical modeling that considered transport within skin, across the interface between skin and µpores, and within µpores to the skin surface. This analysis indicated that the rate-limiting step for ISF sampling is transport through the dermis. Based on these studies and other considerations like safety and convenience for future clinical use, we designed an MN patch prototype to sample ISF using suction as the driving force. Using this approach, we collected ISF from human volunteers and identified the presence of biomarkers in the collected ISF. In this way, sampling ISF from skin using an MN patch could enable collection of ISF for use in research and medicine.

The effects of chemical and physical penetration enhancers on the percutaneous permeation of lidocaine through equine skin

PubMed Central

2014-01-01

Background The effect of physical and chemical permeation enhancers on in vitro transdermal permeation of lidocaine was investigated in the horse. Therefore, the effect of six vehicles (phosphate-buffered saline (PBS), 50% ethanol, 50% propylene glycol, 50% isopropylalcohol, 50% isopropylalcohol/isopropylmyristate and 50% dimethylsulfoxide) was examined as well as the effect of microneedle pretreatment with different needle lengths on transdermal drug delivery of lidocaine. The skin was obtained from the thorax of six Warmblood horses and was stored up to two weeks at - 20°C. Franz-type diffusion cells were used to study the transdermal permeation through split skin (600 μm thickness). The amount of lidocaine in the receptor fluid was determined by UV–VIS high-performance liquid chromatography. Results All investigated vehicle supplementations diminished the transdermal flux of lidocaine through equine skin in comparison to pure PBS except dimethylsulfoxide, which resulted in comparable permeation rates to PBS. The maximum flux (Jmax) was 1.6-1.8 fold lower for lidocaine applied in 50% ethanol, propylene glycol, isopropylalcohol and isopropylalcohol/isopropylmyristate. A significant higher Jmax of lidocaine was observed when lidocaine was applied in PBS onto microneedle pretreated skin with similar permeation rates in both needle lengths. After 6 hours, 1.7 fold higher recovery rates were observed in the microneedle pretreated skin samples than in the untreated control samples. The lagtimes were reduced to 20–50% in the microneedle pretreated skin samples. Conclusion Microneedles represent a promising tool for transdermal lidocaine application in the horse with a rapid systemic bioavailability. PMID:24950611

Microneedle-assisted permeation of lidocaine carboxymethylcellulose with gelatine co-polymer hydrogel.

PubMed

Nayak, Atul; Das, Diganta B; Vladisavljević, Goran T

2014-05-01

Lidocaine hydrochloride (LidH) was formulated in sodium carboxymethyl cellulose/ gelatine (NaCMC/GEL) hydrogel and a 'poke and patch' microneedle delivery method was used to enhance permeation flux of LidH. The microparticles were formed by electrostatic interactions between NaCMC and GEL macromolecules within a water/oil emulsion in paraffin oil and the covalent crosslinking was by glutaraldehyde. The GEL to NaCMC mass ratio was varied between 1.6 and 2.7. The LidH encapsulation yield was 1.2 to 7% w/w. LidH NaCMC/GEL was assessed for encapsulation efficiency, zeta potential, mean particle size and morphology. Subsequent in vitro skin permeation studies were performed via passive diffusion and microneedle assisted permeation of LidH NaCMC/GEL to determine the maximum permeation rate through full thickness skin. LidH 2.4% w/w NaCMC/GEL 1:1.6 and 1:2.3 respectively, possessed optimum zeta potential. LidH 2.4% w/w NaCMC/GEL 1:2.3 and 1:2.7 demonstrate higher pseudoplastic behaviour. Encapsulation efficiency (14.9-17.2%) was similar for LidH 2.4% w/w NaCMC/GEL 1:1.6-1:2.3. Microneedle assisted permeation flux was optimum for LidH 2.4% w/w NaCMC/GEL 1:2.3 at 6.1 μg/ml/h. LidH 2.4% w/w LidH NaCMC/GEL 1:2.3 crossed the minimum therapeutic drug threshold with microneedle skin permeation in less than 70 min.

Bacillus Calmette-Guérin Vaccination Using a Microneedle Patch

PubMed Central

Hiraishi, Yasuhiro; Nandakumar, Subhadra; Choi, Seong-O; Lee, Jeong Woo; Kim, Yeu-Chun; Posey, James E.; Sable, Suraj B.; Prausnitz, Mark R.

2011-01-01

Tuberculosis (TB) caused by Mycobacterium tuberculosis continues to be a leading cause of mortality among bacterial diseases, and the bacillus Calmette-Guerin (BCG) is the only licensed vaccine for human use against this disease. TB prevention and control would benefit from an improved method of BCG vaccination that simplifies logistics and eliminates dangers posed by hypodermic needles without compromising immunogenicity. Here, we report the design and engineering of a BCG-coated microneedle vaccine patch for a simple and improved intradermal delivery of the vaccine. The microneedle vaccine patch induced a robust cell-mediated immune response in both the lungs and spleen of guinea pigs. The response was comparable to the traditional hypodermic needle based intradermal BCG vaccination and was characterized by a strong antigen specific lymphocyte proliferation and IFN-γ levels with high frequencies of CD4+IFN-γ+, CD4+TNF-α+ and CD4+IFN-γ+TNF-α+ T cells. The BCG-coated microneedle vaccine patch was highly immunogenic in guinea pigs and supports further exploration of this new technology as a simpler, safer, and compliant vaccination that could facilitate increased coverage, especially in developing countries that lack adequate healthcare infrastructure. PMID:21277407

A high aspect ratio SU-8 fabrication technique for hollow microneedles for transdermal drug delivery and blood extraction

NASA Astrophysics Data System (ADS)

Chaudhri, Buddhadev Paul; Ceyssens, Frederik; De Moor, Piet; Van Hoof, Chris; Puers, Robert

2010-06-01

Protein drugs, e.g. hormonal drugs, cannot be delivered orally to a patient as they get digested in the gastro-intestinal (GI) tract. Thus, it is imperative that these kinds of drugs are delivered transdermally through the skin. To provide for real-time feedback as well as to test independently for various substances in the blood, we also need a blood sampling system. Microneedles can perform both these functions. Further, microneedles made of silicon or metal have the risk of breaking inside the skin thereby leading to complications. SU-8, being approved of as being biocompatible by the Food and Drug Agency (FDA) of the United States, is an attractive alternative because firstly it is a polymer material, thereby reducing the chances of breakages inside the skin, and secondly it is a negative photoresist, thereby leading to ease of fabrication. Thus, here we present very tall (around 1600 µm) SU-8 polymer-based hollow microneedles fabricated by a simple and repeatable process, which are a very good candidate for transdermal drug delivery as well as blood extraction. The paper elaborates on the details that allow the fabrication of such extreme aspect ratios (>100).

Cutaneous immunization: an evolving paradigm in influenza vaccines

PubMed Central

Gill, Harvinder S; Kang, Sang-Moo; Quan, Fu-Shi; Compans, Richard W

2014-01-01

Introduction Most vaccines are administered by intramuscular injection using a hypodermic needle and syringe. Some limitations of this procedure include reluctance to be immunized because of fear of needlesticks, and concerns associated with the safe disposal of needles after their use. Skin delivery is an alternate route of vaccination that has potential to be painless and could even lead to dose reduction of vaccines. Recently, microneedles have emerged as a novel painless approach for delivery of influenza vaccines via the skin. Areas covered In this review, we briefly summarize the approaches and devices used for skin vaccination, and then focus on studies of skin immunization with influenza vaccines using microneedles. We discuss both the functional immune response and the nature of this immune response following vaccination with microneedles. Expert opinion The cutaneous administration of influenza vaccines using microneedles offers several advantages: it is painless, elicits stronger immune responses in preclinical studies and could improve responses in high-risk populations. These dry formulations of vaccines provide enhanced stability, a property of high importance in enabling their rapid global distribution in response to possible outbreaks of pandemic influenza and newly emerging infectious diseases. PMID:24521050

Optimization of naltrexone diclofenac codrugs for sustained drug delivery across microneedle-treated skin.

PubMed

Ghosh, Priyanka; Lee, DoMin; Kim, Kyung Bo; Stinchcomb, Audra L

2014-01-01

The purpose of this work was to optimize the structure of codrugs for extended delivery across microneedle treated skin. Naltrexone, the model compound was linked with diclofenac, a nonspecific cyclooxygenase inhibitor to enhance the pore lifetime following microneedle treatment and develop a 7 day transdermal system for naltrexone. Four different codrugs of naltrexone and diclofenac were compared in terms of stability and solubility. Transdermal flux, permeability and skin concentration of both parent drugs and codrugs were quantified to form a structure permeability relationship. The results indicated that all codrugs bioconverted in the skin. The degree of conversion was dependent on the structure, phenol linked codrugs were less stable compared to the secondary alcohol linked structures. The flux of naltrexone across microneedle treated skin and the skin concentration of diclofenac were higher for the phenol linked codrugs. The polyethylene glycol link enhanced solubility of the codrugs, which translated into flux enhancement. The current studies indicated that formulation stability of codrugs and the flux of naltrexone can be enhanced via structure design optimization. The polyethylene glycol linked naltrexone diclofenac codrug is better suited for a 7 day drug delivery system both in terms of stability and drug delivery.

Design, fabrication and skin-electrode contact analysis of polymer microneedle-based ECG electrodes

NASA Astrophysics Data System (ADS)

O'Mahony, Conor; Grygoryev, Konstantin; Ciarlone, Antonio; Giannoni, Giuseppe; Kenthao, Anan; Galvin, Paul

2016-08-01

Microneedle-based ‘dry’ electrodes have immense potential for use in diagnostic procedures such as electrocardiography (ECG) analysis, as they eliminate several of the drawbacks associated with the conventional ‘wet’ electrodes currently used for physiological signal recording. To be commercially successful in such a competitive market, it is essential that dry electrodes are manufacturable in high volumes and at low cost. In addition, the topographical nature of these emerging devices means that electrode performance is likely to be highly dependent on the quality of the skin-electrode contact. This paper presents a low-cost, wafer-level micromoulding technology for the fabrication of polymeric ECG electrodes that use microneedle structures to make a direct electrical contact to the body. The double-sided moulding process can be used to eliminate post-process via creation and wafer dicing steps. In addition, measurement techniques have been developed to characterize the skin-electrode contact force. We perform the first analysis of signal-to-noise ratio dependency on contact force, and show that although microneedle-based electrodes can outperform conventional gel electrodes, the quality of ECG recordings is significantly dependent on temporal and mechanical aspects of the skin-electrode interface.

Fluorescence characteristics and biodegradability of dissolved organic matter in forest and wetland soils from coastal temperate watersheds in southeast Alaska

Treesearch

Jason B. Fellman; David V. D' Amore; Eran Hood; Richard D. Boone

2008-01-01

Understanding how the concentration and chemical quality of dissolved organic matter (DOM) varies in soils is critical because DOM influences an array of biological, chemical, and physical processes. We used PARAFAC modeling of excitation-emission fluorescence spectroscopy, specific UV absorbance (SUVA254) and biodegradable dissolved organic...

Ebola Vaccination Using a DNA Vaccine Coated on PLGA-PLL/γPGA Nanoparticles Administered Using a Microneedle Patch.

PubMed

Yang, Hung-Wei; Ye, Ling; Guo, Xin Dong; Yang, Chinglai; Compans, Richard W; Prausnitz, Mark R

2017-01-01

Ebola DNA vaccine is incorporated into PLGA-PLL/γPGA nanoparticles and administered to skin using a microneedle (MN) patch. The nanoparticle delivery system increases vaccine thermostability and immunogenicity compared to free vaccine. Vaccination by MN patch produces stronger immune responses than intramuscular administration. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Development of a Self-calibrating Dissolved Oxygen Microsensor Array for the Monitoring and Control of Plant Growth in a Space Environment

NASA Technical Reports Server (NTRS)

Kim, Chang-Soo; Brown, Christopher S.; Nagle, H. Troy

2004-01-01

Plant experiments in space will require active nutrient delivery concepts in which water and nutrients are replenished on a continuous basis for long-term growth. The goal of this study is to develop a novel microsensor array to provide information on the dissolved oxygen environment in the plant root zone for the optimum control of plant cultivation systems in the space environment. Control of water and oxygen is limited by the current state-of-the-art in sensor technology. Two capabilities of the new microsensor array were tested. First, a novel in situ self-diagnosis/self-calibration capability for the microsensor was explored by dynamically controlling the oxygen microenvironment in close proximity to an amperometric dissolved oxygen microsensors. A pair of integrated electrochemical actuator electrodes provided the microenvironments based on water electrolysis. Miniaturized thin film dissolved oxygen microsensors on a flexible polyimide (Kapton(Registered Trademark)? substrate were fabricated and their performances were tested. Secondly, measurements of dissolved oxygen in two representative plant growth systems were made, which had not been performed previously due to lack of proper sensing technology. The responses of the oxygen microsensor array on a flexible polymer substrate properly reflected the oxygen contents on the surface of a porous tube nutrient delivery system and within a particulate substrate system. Additionally, we demonstrated the feasibility of using a 4-point thin film microprobe for water contents measurements for both plant growth systems. mechanical flexibility, and self-diagnosis. The proposed technology is anticipated to provide a reliable sensor feedback plant growth nutrient delivery systems in both terrestrial environment and the microgravity environment during long term space missions. The unique features of the sensor include small size and volume, multiple-point sensing,

Targeted administration into the suprachoroidal space using a microneedle for drug delivery to the posterior segment of the eye.

PubMed

Patel, Samirkumar R; Berezovsky, Damian E; McCarey, Bernard E; Zarnitsyn, Vladimir; Edelhauser, Henry F; Prausnitz, Mark R

2012-07-01

This study seeks to determine the intraocular pharmacokinetics of molecules and particles injected into the suprachoroidal space of the rabbit eye in vivo using a hollow microneedle. Suprachoroidal injections of fluorescein and fluorescently tagged dextrans (40 and 250 kDa), bevacizumab, and polymeric particles (20 nm to 10 μm in diameter) were performed using microneedles in New Zealand white rabbits. The fluorescence intensity within the eye was monitored in each animal using an ocular fluorophotometer to determine the distribution of the injected material in the eye over time as compared with intravitreal injection of fluorescein. Fundus photography and histology were performed as well. Molecules and particles injected near the limbus using a microneedle flowed circumferentially around the eye within the suprachoroidal space. By targeting the suprachoroidal space, the concentration of injected materials was at least 10-fold higher in the back of the eye tissues than in anterior tissues. In contrast, intravitreal injection of fluorescein targeted the vitreous humor with no significant selectivity for posterior versus anterior segment tissues. Half-lives in the suprachoroidal space for molecules of molecular weight from 0.3 to 250 kDa ranged from 1.2 to 7.9 hours. In contrast, particles ranging in size from 20 nm to 10 μm remained primarily in the suprachoroidal space and choroid for a period of months and did not clear the eye. No adverse effects of injection into the suprachoroidal space were observed. Injection into the suprachoroidal space using a microneedle offers a simple and minimally invasive way to target the delivery of drugs to the choroid and retina.

Targeted Administration into the Suprachoroidal Space Using a Microneedle for Drug Delivery to the Posterior Segment of the Eye

PubMed Central

Patel, Samirkumar R.; Berezovsky, Damian E.; McCarey, Bernard E.; Zarnitsyn, Vladimir; Edelhauser, Henry F.; Prausnitz, Mark R.

2012-01-01

Purpose. This study seeks to determine the intraocular pharmacokinetics of molecules and particles injected into the suprachoroidal space of the rabbit eye in vivo using a hollow microneedle. Methods. Suprachoroidal injections of fluorescein and fluorescently tagged dextrans (40 and 250 kDa), bevacizumab, and polymeric particles (20 nm to 10 μm in diameter) were performed using microneedles in New Zealand white rabbits. The fluorescence intensity within the eye was monitored in each animal using an ocular fluorophotometer to determine the distribution of the injected material in the eye over time as compared with intravitreal injection of fluorescein. Fundus photography and histology were performed as well. Results. Molecules and particles injected near the limbus using a microneedle flowed circumferentially around the eye within the suprachoroidal space. By targeting the suprachoroidal space, the concentration of injected materials was at least 10-fold higher in the back of the eye tissues than in anterior tissues. In contrast, intravitreal injection of fluorescein targeted the vitreous humor with no significant selectivity for posterior versus anterior segment tissues. Half-lives in the suprachoroidal space for molecules of molecular weight from 0.3 to 250 kDa ranged from 1.2 to 7.9 hours. In contrast, particles ranging in size from 20 nm to 10 μm remained primarily in the suprachoroidal space and choroid for a period of months and did not clear the eye. No adverse effects of injection into the suprachoroidal space were observed. Conclusion. Injection into the suprachoroidal space using a microneedle offers a simple and minimally invasive way to target the delivery of drugs to the choroid and retina. PMID:22669719

Administration of a Sol-Gel Formulation of Phenylephrine Using Low-Temperature Hollow Microneedle for Treatment of Intermittent Fecal Incontinence.

PubMed

Lee, Hyunji; Park, Jung-Hwan; Park, Jung Ho

2017-12-01

A low temperature hollow microneedle system was devised to deliver sol-gel transition formulation near the surface of the skin for extended release and local delivery of drug by a non-invasive method. This new system can improve treatment of intermittent fecal incontinence. The low-temperature system was integrated with a hollow microneedle to maintain the low temperature of the sol formulation. Various sol-gel formulations using Pluronic F-127 (PF-127) and Hydroxy-propyl-methyl-cellulose (HPMC) were prepared, and their gelation temperature, flow property, and diffusion retardation were observed. Resting anal sphincter pressure in response to a phenylephrine (PE) sol-gel formulation was measured using an air-charged catheter. The biocompatibility of the sol-gel PE formulation was evaluated by observing the immunological response. When the PF-127 25%, HPMC 1% and PE formulation (PF25-HPMC1-PE) was injected through the peri-anal skin of the rat in vivo, the highest pressure on the anal sphincter muscle occurred at 6-8 h and anal pressure increased and lasted twice as long as with the phosphate-buffered saline (PBS)-PE formulation. There was no significant difference in the number of mast cells after administration into the rat in vivo between the PF25-HPMC1-PE formulation and the PBS-PE formulation. The combination of a low-pain hollow microneedle system and an injectable sol-gel formulation improved the efficacy of treatment of intermittent fecal incontinence. A low-temperature hollow microneedle system using a sol-gel formulation has many applications in medical treatments that require depot effect, local targeting, and pain control.

The efficacy and safety of combined microneedle fractional radiofrequency and sublative fractional radiofrequency for acne scars in Asian skin.

PubMed

Park, Jae Yang; Lee, Eo Gin; Yoon, Moon Soo; Lee, Hee Jung

2016-06-01

Microneedle fractional radiofrequency has been reported to be effective for improving wrinkles, enlarged pores and various scars. Sublative fractional radiofrequency has been shown to induce both fractional ablation of epidermis and upper dermal remodelling, which had rejuvenation effects in photoaged skin. Both modalities may have the potential synergy to improve acne scars. To evaluate the efficacy and safety of combined microneedle and sublative fractional radiofrequency for acne scars in Asian skin. Twenty subjects comprised 11 males and 9 females (mean age 23.65 ± 2.94, skin phototype III-IV) with moderate to severe acne scars. The subjects received three consecutive combined microneedle and sublative fractional radiofrequency at 4-week intervals over 12 weeks. Both blinded dermatologists and subjects assessed the clinical improvement based on the standardized photography and questionnaires, respectively. The quartile grading scale was utilized and defined as follows: grade 1, 0-25% improvement; grade 2, 26-50% improvement; grade 3, 51-75% improvement and grade 4, 76-100% improvement. All 20 subjects were assessed to have grade 2 or more clinical improvement by physicians; four (20%) had grade 4, 10 (50%) had grade 3, and six (30%) had grade 2 improvement. The subjects' grading also showed a good concordance as indicated by Kappa index of 0.695. The mean duration of post-therapy crusting was 5.2 days and post-therapy erythema lasted 2.5 days. Combined microneedle and sublative fractional radiofrequency can have a positive therapeutic effect with no serious complications and may provide a new therapeutic approach on acne scars in Asians. © 2015 Wiley Periodicals, Inc.

Microneedling: Advances and widening horizons

PubMed Central

Singh, Aashim; Yadav, Savita

2016-01-01

Microneedling is a very simple, safe, effective, and minimally invasive therapeutic technique. It was initially introduced for skin rejuvenation, however, now it is being used for a very wide range of indications including acne scar, acne, post-traumatic/burn scar, alopecia, skin rejuvenation, drug delivery, hyperhidrosis, stretch marks, and many more. Moreover, during the last 10 years, many new innovations have been made to the initial instrument, which was used for microneedling. This technique can be combined with other surgical techniques to provide better results. In particular, it is a very safe technique for dark skin types, where risk of postinflammatory pigmentation is very high with other techniques that damage the epidermis. In this review article, we are updating on the different instruments now available for this procedure, and its efficacy when performed alone or in combination with other techniques for various indications. PMID:27559496

Hybrid microneedles devices for diagnostic and therapeutic applications: fabrication and preliminary results

NASA Astrophysics Data System (ADS)

Dardano, P.; Caliò, A.; Politi, J.; Di Palma, V.; Bevilacqua, M. F.; Rea, I.; Casalino, M.; Di Matteo, A.; Rendina, I.; De Stefano, L.

2015-06-01

Microneedles are newly developed biomedical devices, whose advantages are mainly in the non-invasiveness, discretion and versatility of use both as diagnostics and as therapeutics tool. In fact, they can be used both for drugs delivery in the interstitial fluids and for the analysis of the interstitial fluid. In this work we present the preliminary results for two devices based on micro needles in PolyEthylene (Glycol). The first for the drugs delivery includes a membrane whose optical reflected wavelength is related to the concentration of drug. Here, we present our preliminary result in diffusion of drugs between the membrane and the microneedles. The second device is gold coated and it works as electrode for the electrochemical detection of species in the interstitial fluid. A preliminary result in detection of glucose will be shown.

Microneedle-mediated transcutaneous immunization with plasmid DNA coated on cationic PLGA nanoparticles

PubMed Central

Kumar, Amit; Wonganan, Piyanuch; Sandoval, Michael A.; Li, Xinran; Zhu, Saijie; Cui, Zhengrong

2012-01-01

Previously, it was shown that microneedle-mediated transcutaneous immunization with plasmid DNA can potentially induce a stronger immune response than intramuscular injection of the same plasmid DNA. In the present study, we showed that the immune responses induced by transcutaneous immunization by applying plasmid DNA onto a skin area pretreated with solid microneedles were significantly enhanced by coating the plasmid DNA on the surface of cationic nanoparticles. In addition, the net surface charge of the DNA-coated nanoparticles significantly affected their in vitro skin permeation and their ability to induce immune responses in vivo. Transcutaneous immunization with plasmid DNA-coated net positively charged anoparticles elicited a stronger immune response than with plasmid DNA-coated net negatively charged nanoparticles or by intramuscular immunization with plasmid DNA alone. Transcutaneous immunization with plasmid DNA-coated net positively charged nanoparticles induced comparable immune responses as intramuscular injection of them, but transcutaneous immunization was able to induce specific mucosal immunity and a more balanced T helper type 1 and type 2 response. The ability of the net positively charged DNA-coated nanoparticles to induce a strong immune response through microneedle-mediated transcutaneous immunization may be attributed to their ability to increase the expression of the antigen gene encoded by the plasmid and to more effectively stimulate the maturation of antigen-presenting cells. PMID:22921518

Tissue expansion and fluid absorption by skin tissue following intradermal injections through hollow microneedles

NASA Astrophysics Data System (ADS)

Shrestha, Pranav; Stoeber, Boris

2017-11-01

Hollow microneedles provide a promising alternative to conventional drug delivery techniques due to improved patient compliance and the dose sparing effect. The dynamics of fluid injected through hollow microneedles into skin, which is a heterogeneous and deformable porous medium, have not been investigated extensively in the past. We have introduced the use of Optical Coherence Tomography (OCT) for real-time visualization of fluid injections into excised porcine tissue. The results from ex-vivo experiments, including cross-sectional tissue images from OCT and pressure/flow-rate measurements, show a transient mode of high flow-rate into the tissue followed by a lower steady-state infusion rate. The injected fluid expands the underlying tissue and causes the external free surface of the skin to rise, forming a characteristic intradermal wheal. We have used OCT to visualize the evolution of tissue and free surface deformation, and advancement of the boundary between regions of expanding and stationary tissue. We will show the effect of different injection parameters such as fluid pressure, viscosity and microneedle retraction on the injected volume. This work has been supported through funding from the Collaborative Health Research Program by the Natural Science and Engineering Research Council of Canada and the Canadian Health Research Institute, and through the Canada Research Chairs program.

Microneedle and mucosal delivery of influenza vaccines

PubMed Central

Kang, Sang-Moo; Song, Jae-Min; Kim, Yeu-Chun

2017-01-01

In recent years with the threat of pandemic influenza and other public health needs, alternative vaccination methods other than intramuscular immunization have received great attention. The skin and mucosal surfaces are attractive sites probably because of both non-invasive access to the vaccine delivery and unique immunological responses. Intradermal vaccines using a microinjection system (BD Soluvia) and intranasal vaccines (FluMist) are licensed. As a new vaccination method, solid microneedles have been developed using a simple device that may be suitable for self-administration. Because coated micorneedle influenza vaccines are administered in the solid state, developing formulations maintaining the stability of influenza vaccines is an important issue to be considered. Marketable microneedle devices and clinical trials remain to be developed. Other alternative mucosal routes such as oral and intranasal delivery systems are also attractive for inducing cross protective mucosal immunity but effective non-live mucosal vaccines remain to be developed. PMID:22697052

Printing of small molecular medicines from the vapor phase

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shalev, Olga; Raghavan, Shreya; Mazzara, J. Maxwell

There is growing need to develop efficient methods for early-stage drug discovery, continuous manufacturing of drug delivery vehicles, and ultra-precise dosing of high potency drugs. Here we demonstrate the use of solvent-free organic vapor jet printing to deposit nanostructured films of small molecular pharmaceutical ingredients, including caffeine, paracetamol, ibuprofen, tamoxifen, BAY 11-7082 and fluorescein, with accuracy on the scale of micrograms per square centimeter, onto glass, Tegaderm, Listerine tabs, and stainless steel microneedles. The printed films exhibit similar crystallographic order and chemistry as the original powders; controlled, order-of-magnitude enhancements of dissolution rate are observed relative to powder-form particles. In vitromore » treatment of breast and ovarian cancer cell cultures in aqueous media by tamoxifen and BAY 11-7082 films shows similar behavior to drugs pre-dissolved in dimethyl sulfoxide. In conclusion, the demonstrated precise printing of medicines as films, without the use of solvents, can accelerate drug screening and enable continuous manufacturing, while enhancing dosage accuracy.« less

Printing of small molecular medicines from the vapor phase

DOE PAGES

Shalev, Olga; Raghavan, Shreya; Mazzara, J. Maxwell; ...

2017-09-27

There is growing need to develop efficient methods for early-stage drug discovery, continuous manufacturing of drug delivery vehicles, and ultra-precise dosing of high potency drugs. Here we demonstrate the use of solvent-free organic vapor jet printing to deposit nanostructured films of small molecular pharmaceutical ingredients, including caffeine, paracetamol, ibuprofen, tamoxifen, BAY 11-7082 and fluorescein, with accuracy on the scale of micrograms per square centimeter, onto glass, Tegaderm, Listerine tabs, and stainless steel microneedles. The printed films exhibit similar crystallographic order and chemistry as the original powders; controlled, order-of-magnitude enhancements of dissolution rate are observed relative to powder-form particles. In vitromore » treatment of breast and ovarian cancer cell cultures in aqueous media by tamoxifen and BAY 11-7082 films shows similar behavior to drugs pre-dissolved in dimethyl sulfoxide. In conclusion, the demonstrated precise printing of medicines as films, without the use of solvents, can accelerate drug screening and enable continuous manufacturing, while enhancing dosage accuracy.« less

Delivery of salmon calcitonin using a microneedle patch

PubMed Central

Tas, Cetin; Mansoor, Saffar; Kalluri, Haripriya; Zarnitsyn, Vladimir G.; Choi, Seong-O; Banga, Ajay K.; Prausnitz, Mark R.

2011-01-01

Peptides and polypeptides have important pharmacological properties but only a limited number have been exploited as therapeutics because of problems related to their delivery. Most of these drugs require a parenteral delivery system which introduces the problems of pain, possible infection, and expertise required to carry out an injection. The aim of this study was to develop a transdermal patch containing microneedles (MNs) coated with a peptide drug, salmon calcitonin (sCT), as an alternative to traditional subcutaneous and nasal delivery routes. Quantitative analysis of sCT after coating and drying onto microneedles was performed with a validated HPLC method. In vivo studies were carried out on hairless rats and serum levels of sCT were determined by ELISA. The AUC value of MNs coated with a trehalose-containing formulation (250 ± 83 ng/mL.min) was not significantly different as compared to subcutaneous injections (403 ± 253 ng/mL.min), but approximately 13 times higher than nasal administration (18.4 ± 14.5 ng/mL.min). Tmax (7.5 ± 5 min) values for MN mediated administration were 50% shorter than subcutaneous injections (15 min), possibly due to rapid sCT dissolution and absorption by dermal capillaries. These results suggest that with further optimization of coating formulations, microneedles may enable administration of sCT and other peptides without the need for hypodermic injections. PMID:22172290

Microneedle-mediated transcutaneous immunization with plasmid DNA coated on cationic PLGA nanoparticles.

PubMed

Kumar, Amit; Wonganan, Piyanuch; Sandoval, Michael A; Li, Xinran; Zhu, Saijie; Cui, Zhengrong

2012-10-28

Previously, it was shown that microneedle-mediated transcutaneous immunization with plasmid DNA can potentially induce a stronger immune response than intramuscular injection of the same plasmid DNA. In the present study, we showed that the immune responses induced by transcutaneous immunization by applying plasmid DNA onto a skin area pretreated with solid microneedles were significantly enhanced by coating the plasmid DNA on the surface of cationic nanoparticles. In addition, the net surface charge of the DNA-coated nanoparticles significantly affected their in vitro skin permeation and their ability to induce immune responses in vivo. Transcutaneous immunization with plasmid DNA-coated net positively charged nanoparticles elicited a stronger immune response than with plasmid DNA-coated net negatively charged nanoparticles or by intramuscular immunization with plasmid DNA alone. Transcutaneous immunization with plasmid DNA-coated net positively charged nanoparticles induced comparable immune responses as intramuscular injection of them, but transcutaneous immunization was able to induce specific mucosal immunity and a more balanced T helper type 1 and type 2 response. The ability of the net positively charged DNA-coated nanoparticles to induce a strong immune response through microneedle-mediated transcutaneous immunization may be attributed to their ability to increase the expression of the antigen gene encoded by the plasmid and to more effectively stimulate the maturation of antigen-presenting cells. Copyright © 2012 Elsevier B.V. All rights reserved.

Treatment of Décolletage Photoaging With Fractional Microneedling Radiofrequency.

PubMed

Lyons, Alexis; Roy, Jillian; Herrmann, Jennifer; Chipps, Lisa

2018-01-01

The objective of this study was to examine the efficacy and safety of a novel fractional microneedling radiofrequency device to improve the appearance of rhytides and skin laxity of the décolletage. Twelve subjects received a total of three fractional microneedling radiofrequency treatments with Endymed Intensif (EndyMed Ltd., Cesarea, Israel) at least three weeks apart. Primary outcome measure was clinical efficacy quantified by a patient survey to assess treatment satisfaction as well as a physician Global Aesthetic Improvement Scale (GAIS). Photos were taken before every treatment and at a follow-up appointment. Assessments by two board-certified dermatologists revealed an overall improvement in 67% of patients. Seventy percent of subjects rated their post-treatment skin laxity and rhytides as improved, while 60% of patients rated their skin texture as improved. Eighty percent of subjects were at least slightly satisfied with their treatment. Forty percent of subjects would recommend this treatment to others. Subjects in this study demonstrated an overall improvement in décolletage appearance in regard to skin tightening, wrinkles, and skin texture suggested by overall patient satisfaction (80%) and physician-rated GAIS improvement (67%). This study suggests that fractional microneedling radiofrequency devices are a safe and efficacious way to improve overall décolletage appearance with little down time.

J Drugs Dermatol. 2018;17(1):74-76.

Long-term Nasal and Peri-oral Tightening by a Single Fractional Noninsulated Microneedle Radiofrequency Treatment

PubMed Central

2017-01-01

Background: The skin tightening effects induced by non-insulated microneedle radiofrequency have proved long-lasting. Our previous three-dimensional volumetric assessment showed significant facial tightening for up to six months. However, nasal and peri-oral tightening effects lasted longer. The objective of this study was to investigate the distribution of the long-term volumetric reduction in facial area induced by a single fractional non-insulated microneedle radiofrequency treatment. Methods: Fifteen Asian patients underwent full facial skin tightening using a sharply tapered non-insulated microneedle radiofrequency applicator with a novel fractionated pulse mode. Three-dimensional volumetric assessments were performed at six and 12 months post-treatment. Patients rated their satisfaction using a 5-point scale at each follow up. Results: Objective assessments with superimposed three-dimensional color images showed significant volumetric reduction in the nasal and peri-oral areas at 12 months post-treatment in all patients. Median volumetric reductions at six and 12 months post-treatment were 13.1 and 12.3ml, respectively. All of the patients were satisfied with their results 12 months post-treatment. Side effects were not observed. Conclusions: This single fractional NIMNRF treatment provided long-lasting nasal and peri-oral tightening as shown via 3D volumetric assessment. Moreover, NIMNRF produced minimal complications, downtime, and few side effects. This approach provides safe and effective treatment of skin tightening. PMID:28367261

Collagen-based brain microvasculature model in vitro using three-dimensional printed template

PubMed Central

Kim, Jeong Ah; Kim, Hong Nam; Im, Sun-Kyoung; Chung, Seok

2015-01-01

We present an engineered three-dimensional (3D) in vitro brain microvasculature system embedded within the bulk of a collagen matrix. To create a hydrogel template for the functional brain microvascular structure, we fabricated an array of microchannels made of collagen I using microneedles and a 3D printed frame. By culturing mouse brain endothelial cells (bEnd.3) on the luminal surface of cylindrical collagen microchannels, we reconstructed an array of brain microvasculature in vitro with circular cross-sections. We characterized the barrier function of our brain microvasculature by measuring transendothelial permeability of 40 kDa fluorescein isothiocyanate-dextran (Stoke's radius of ∼4.5 nm), based on an analytical model. The transendothelial permeability decreased significantly over 3 weeks of culture. We also present the disruption of the barrier function with a hyperosmotic mannitol as well as a subsequent recovery over 4 days. Our brain microvasculature model in vitro, consisting of system-in-hydrogel combined with the widely emerging 3D printing technique, can serve as a useful tool not only for fundamental studies associated with blood-brain barrier in physiological and pathological settings but also for pharmaceutical applications. PMID:25945141

Needle-free and microneedle drug delivery in children: a case for disease-modifying antirheumatic drugs (DMARDs).

PubMed

Shah, Utpal U; Roberts, Matthew; Orlu Gul, Mine; Tuleu, Catherine; Beresford, Michael W

2011-09-15

Parenteral routes of drug administration have poor acceptability and tolerability in children. Advances in transdermal drug delivery provide a potential alternative for improving drug administration in this patient group. Issues with parenteral delivery in children are highlighted and thus illustrate the scope for the application of needle-free and microneedle technologies. This mini-review discusses the opportunities and challenges for providing disease-modifying antirheumatic drugs (DMARDs) currently prescribed to paediatric rheumatology patients using such technologies. The aim is to raise further awareness of the need for age-appropriate formulations and drug delivery systems and stimulate exploration of these options for DMARDs, and in particular, rapidly emerging biologics on the market. The ability of needle-free and microneedle technologies to deliver monoclonal antibodies and fusion proteins still remains largely untested. Such an understanding is crucial for future drug design opportunities. The bioavailability, safety and tolerance of delivering biologics into the viable epidermis also need to be studied. Copyright © 2011 Elsevier B.V. All rights reserved.

Microneedle-based analysis of the micromechanics of the metaphase spindle assembled in Xenopus laevis egg extracts

PubMed Central

Shimamoto, Yuta; Kapoor, Tarun M.

2014-01-01

SUMMARY To explain how micron-sized cellular structures generate and respond to forces we need to characterize their micromechanical properties. Here we provide a protocol to build and use a dual force-calibrated microneedle-based set-up to quantitatively analyze the micromechanics of a metaphase spindle assembled in Xenopus laevis egg extracts. This cell-free extract system allows for controlled biochemical perturbations of spindle components. We describe how the microneedles are prepared and how they can be used to apply and measure forces. A multi-mode imaging system allows tracking of microtubules, chromosomes and needle tips. This set-up can be used to analyze the viscoelastic properties of the spindle on time-scales ranging from minutes to sub-seconds. A typical experiment, along with data analysis, is also detailed. We anticipate that our protocol can be readily extended to analyze the micromechanics of other cellular structures assembled in cell-free extracts. The entire procedure can take 3-4 days. PMID:22538847

A pilot comparative study of topical latanoprost and tacrolimus in combination with narrow-band ultraviolet B phototherapy and microneedling for the treatment of nonsegmental vitiligo.

PubMed

Korobko, Igor V; Lomonosov, Konstantin M

2016-11-01

Prostaglandins and their analogues are beneficial as topical agents in vitiligo treatment, yet neither of the previous study addressed their comparative efficiency with conventional topical agents used in vitiligo treatment. In this pilot (24 patients) left-right comparative study we addressed efficiency of prostaglandin F2α analogue latanoprost versus tacrolimus when combined with narrow-band ultraviolet B and microneedling in repigmentation of nonsegmental vitiligo lesions. Our results confirm potency of prostaglandins, in particular, that of latanoprost, in inducing repigmentation, with the efficiency being at least comparable to that of tacrolimus, while contribution of microneedling remains unclear. In summary, results of our study provide further evidences for justified use of prostaglandins, in particular, latanoprost, in vitiligo treatment. In turn, this warrants future studies on the topic aiming to conclusively introduce prostaglandin-based formulations as conventional agents for vitiligo management. © 2016 Wiley Periodicals, Inc.

Silicon/SU8 multi-electrode micro-needle for in vivo neurochemical monitoring.

PubMed

Vasylieva, Natalia; Marinesco, Stéphane; Barbier, Daniel; Sabac, Andrei

2015-10-15

Simultaneous monitoring of glucose and lactate is an important challenge for understanding brain energetics in physiological or pathological states. We demonstrate here a versatile method based on a minimally invasive single implantation in the rat brain. A silicon/SU8-polymer multi-sensing needle-shaped biosensor, was fabricated and tested. The multi-electrode array design comprises three platinum planar microelectrodes with a surface area of 40 × 200 µm(2) and a spacing of 200 µm, which were micromachined on a single 3mm long micro-needle having a 100 × 50 µm(2) cross-section for reduced tissue damage during implantation. Platinum micro-electrodes were aligned at the bottom of micro-wells obtained by photolithography on a SU8 photoresist layer. After clean room processing, each micro-electrode was functionalized inside the micro-wells by means of a micro-dispensing device, either with glucose oxidase or with lactate oxidase, which were cross-linked on the platinum electrodes. The third electrode covered with Bovine Serum Albumin (BSA) was used for the control of non-specific currents. The thick SU8 photoresist layer has revealed excellent electrical insulation of the micro-electrodes and between interconnection lines, and ensured a precise localization and packaging of the sensing enzymes on platinum micro-electrodes. During in vitro calibration with concentrations of analytes in the mM range, the micro-wells patterned in the SU8 photoresist proved to be highly effective in eliminating cross-talk signals, caused by H2O2 diffusion from closely spaced micro-electrodes. Moreover, our biosensor was successfully assayed in the rat cortex for simultaneous monitoring of both glucose and lactate during insulin and glucose administration. Copyright © 2015 Elsevier B.V. All rights reserved.

Sustained reduction of intraocular pressure by supraciliary delivery of brimonidine-loaded poly(lactic acid) microspheres for the treatment of glaucoma

PubMed Central

Chiang, B.; Kim, Y.C.; Doty, A.C.; Grossniklaus, H.E.; Schwendeman, S.P.; Prausnitz, M.R.

2016-01-01

Although effective drugs that lower intraocular pressure (IOP) in the management of glaucoma exist, their efficacy is limited by poor patient adherence to the prescribed eye drop regimen. To replace the need for eye drops, in this study we tested the hypothesis that IOP can be reduced for one month after a single targeted injection using a microneedle for administration of a glaucoma medication (i.e., brimonidine) formulated for sustained release in the supraciliary space of the eye adjacent to the drug’s site of action at the ciliary body. To test this hypothesis, brimonidine-loaded microspheres were formulated using poly(lactic acid) (PLA) to release brimonidine at a constant rate for 35 days and microneedles were designed to penetrate through the sclera, without penetrating into the choroid/retina, in order to target injection into the supraciliary space. A single administration of these microspheres using a hollow microneedle was performed in the eye of New Zealand White rabbits and was found to reduce IOP initially by 6 mm Hg and then by progressively smaller amounts for more than one month. All administrations were well tolerated without significant adverse events, although histological examination showed a foreign-body reaction to the microspheres. This study demonstrates, for the first time, that the highly-targeted delivery of brimonidine-loaded microspheres into the supraciliary space using a microneedle is able to reduce IOP for one month as an alternative to daily eye drops. PMID:26930266

Microneedle-mediated immunization of an adenovirus-based malaria vaccine enhances antigen-specific antibody immunity and reduces anti-vector responses compared to the intradermal route.

PubMed

Carey, John B; Vrdoljak, Anto; O'Mahony, Conor; Hill, Adrian V S; Draper, Simon J; Moore, Anne C

2014-08-21

Substantial effort has been placed in developing efficacious recombinant attenuated adenovirus-based vaccines. However induction of immunity to the vector is a significant obstacle to its repeated use. Here we demonstrate that skin-based delivery of an adenovirus-based malaria vaccine, HAdV5-PyMSP1₄₂, to mice using silicon microneedles induces equivalent or enhanced antibody responses to the encoded antigen, however it results in decreased anti-vector responses, compared to intradermal delivery. Microneedle-mediated vaccine priming and resultant induction of low anti-vector antibody titres permitted repeated use of the same adenovirus vaccine vector. This resulted in significantly increased antigen-specific antibody responses in these mice compared to ID-treated mice. Boosting with a heterologous vaccine; MVA-PyMSP1₄₂ also resulted in significantly greater antibody responses in mice primed with HAdV5-PyMSP1₄₂ using MN compared to the ID route. The highest protection against blood-stage malaria challenge was observed when a heterologous route of immunization (MN/ID) was used. Therefore, microneedle-mediated immunization has potential to both overcome some of the logistic obstacles surrounding needle-and-syringe-based immunization as well as to facilitate the repeated use of the same adenovirus vaccine thereby potentially reducing manufacturing costs of multiple vaccines. This could have important benefits in the clinical ease of use of adenovirus-based immunization strategies.

Microneedle-mediated immunization of an adenovirus-based malaria vaccine enhances antigen-specific antibody immunity and reduces anti-vector responses compared to the intradermal route

PubMed Central

Carey, John B.; Vrdoljak, Anto; O'Mahony, Conor; Hill, Adrian V. S.; Draper, Simon J.; Moore, Anne C.

2014-01-01

Substantial effort has been placed in developing efficacious recombinant attenuated adenovirus-based vaccines. However induction of immunity to the vector is a significant obstacle to its repeated use. Here we demonstrate that skin-based delivery of an adenovirus-based malaria vaccine, HAdV5-PyMSP142, to mice using silicon microneedles induces equivalent or enhanced antibody responses to the encoded antigen, however it results in decreased anti-vector responses, compared to intradermal delivery. Microneedle-mediated vaccine priming and resultant induction of low anti-vector antibody titres permitted repeated use of the same adenovirus vaccine vector. This resulted in significantly increased antigen-specific antibody responses in these mice compared to ID-treated mice. Boosting with a heterologous vaccine; MVA-PyMSP142 also resulted in significantly greater antibody responses in mice primed with HAdV5-PyMSP142 using MN compared to the ID route. The highest protection against blood-stage malaria challenge was observed when a heterologous route of immunization (MN/ID) was used. Therefore, microneedle-mediated immunization has potential to both overcome some of the logistic obstacles surrounding needle-and-syringe-based immunization as well as to facilitate the repeated use of the same adenovirus vaccine thereby potentially reducing manufacturing costs of multiple vaccines. This could have important benefits in the clinical ease of use of adenovirus-based immunization strategies. PMID:25142082

3D printing applications for transdermal drug delivery.

PubMed

Economidou, Sophia N; Lamprou, Dimitrios A; Douroumis, Dennis

2018-06-15

The role of two and three-dimensional printing as a fabrication technology for sophisticated transdermal drug delivery systems is explored in literature. 3D printing encompasses a family of distinct technologies that employ a virtual model to produce a physical object through numerically controlled apparatuses. The applicability of several printing technologies has been researched for the direct or indirect printing of microneedle arrays or for the modification of their surface through drug-containing coatings. The findings of the respective studies are presented. The range of printable materials that are currently used or potentially can be employed for 3D printing of transdermal drug delivery (TDD) systems is also reviewed. Moreover, the expected impact and challenges of the adoption of 3D printing as a manufacturing technique for transdermal drug delivery systems, are assessed. Finally, this paper outlines the current regulatory framework associated with 3D printed transdermal drug delivery systems. Copyright © 2018 Elsevier B.V. All rights reserved.

The Introduction of Crystallographic Concepts Using Lap-Dissolve Slide Techniques.

ERIC Educational Resources Information Center

Bodner, George M.; And Others

1980-01-01

Describes a method using lap-dissolve slide techniques with two or more slide projectors focused on a single screen for presenting visual effects that show structural features in extended arrays of atoms, or ions involving up to several hundred atoms. Presents an outline of an introduction to the structures of crystalline solids. (CS)

A minimally invasive blood-extraction system: elastic self-recovery actuator integrated with an ultrahigh- aspect-ratio microneedle.

PubMed

Li, Cheng Guo; Lee, Kwang; Lee, Chang Yeol; Dangol, Manita; Jung, Hyungil

2012-08-28

A minimally invasive blood-extraction system is fabricated by the integration of an elastic self-recovery actuator and an ultrahigh-aspect-ratio microneedle. The simple elastic self-recovery actuator converts finger force to elastic energy to provide power for blood extraction and transport without requiring an external source of power. This device has potential utility in the biomedical field within the framework of complete micro-electromechanical systems. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Flexible Microsensor Array for the Monitoring and Control of Plant Growth System

NASA Technical Reports Server (NTRS)

Kim, Chang-Soo; Porterfield, D. Marshall; Nagle, H. Troy; Brown, Christopher S.

2004-01-01

Testing for plant experiments in space has begun to explore active nutrient delivery concepts in which water and nutrients are replenished on a continuous basis for long-term growth. The goal of this study is to develop a novel microsensor array to provide information on the dissolved oxygen environment in the plant root zone for the optimum control of hydroponics and solid substrate plant cultivation systems in the space environment. Miniaturized polarographic dissolved oxygen sensors have been designed and fabricated on a flexible Kapton (trademark) (polyimide) substrate. Two capabilities of the new microsensor array were explored. First, measurements of dissolved oxygen in the plant root zone in hydroponics and solid substrate culture systems were made. The microsensor array was fabricated on a flexible substrate, and then cut out into a mesh type to make a suspended array that could be placed either in a hydroponics system or in a solid substrate cultivation system to measure the oxygen environments. Second, the in situ self-diagnostic and self-calibration capability (two-point for oxygen) was adopted by dynamically controlling the microenvironment in close proximity to the microsensors. With a built-in generating electrode that surrounds the microsensor, two kinds of microenvironments (oxygen-saturated and oxygen-depleted phases) could be established by water electrolysis depending on the polarity of the generating electrode. The unique features of the new microsensor array (small size, multiple sensors, flexibility and self-diagnosis) can have exceptional benefits for the study and optimization of plant cultivation systems in both terrestrial and microgravity environments. The in situ self-diagnostic and self-calibration features of the microsensor array will also enable continuous verification of the operability during entire plant growth cycles. This concept of automated control of a novel chemical monitoring system will minimize crew time required for maintenance, as well as reduce volume, mass, and power consumption by eliminating bulky diagnosis systems including calibrant (fluid and gas) reservoir and flow system hardware.

Biofabricated Structures Reconstruct Functional Urinary Bladders in Radiation-injured Rat Bladders.

PubMed

Imamura, Tetsuya; Shimamura, Mitsuru; Ogawa, Teruyuki; Minagawa, Tomonori; Nagai, Takashi; Silwal Gautam, Sudha; Ishizuka, Osamu

2018-05-08

The ability to repair damaged urinary bladders through the application of bone marrow-derived cells is in the earliest stages of development. We investigated the application of bone marrow-derived cells to repair radiation-injured bladders. We used a three-dimensional (3D) bioprinting robot system to biofabricate bone marrow-derived cell structures. We then determined if the biofabricated structures could restore the tissues and functions of radiation-injured bladders. The bladders of female 10-week-old Sprague-Dawley (SD) rats were irradiated with 2-Gy once a week for 5 weeks. Adherent and proliferating bone marrow-derived cells harvested from the femurs of male 17-week-old green fluorescence protein-transfected Tg-SD rats were cultured in collagen-coated flasks. Bone marrow-derived cell spheroids were formed in 96-well plates. Three layers of spheroids were assembled by the bioprinter onto a 9x9 microneedle array. The assembled spheroids were perfusion cultured for 7 days, and then the microneedle array was removed. Two weeks after the last radiation treatment, the biofabricated structures were transplanted into an incision on the anterior wall of the bladders (n=10). Control rats received the same surgery but without the biofabricated structures (sham-structure, n=12). At 2 and 4 weeks after surgery, the sham-structure control bladder tissues exhibited disorganized smooth muscle layers, decreased nerve cells, and significant fibrosis with increased presence of fibrosis-marker P4HB-positive cells and hypoxia-marker HIF1α-positive cells. The transplanted structures survived within the recipient tissues, and blood vessels extended within them from the recipient tissues. The bone marrow-derived cells in the structures differentiated into smooth muscle cells and formed smooth muscle clusters. The recipient tissues near the transplanted structures had distinct smooth muscle layers and reconstructed nerve cells, and only minimal fibrosis with decreased presence of P4HB- and HIF1α-positive cells. At 4 weeks after surgery, the sham-structure control rats exhibited significant urinary frequency symptoms with irregular and short voiding intervals, and low micturition volumes. In contrast, the structure-transplanted rats had regular micturition with longer voiding intervals and higher micturition volumes compared to the control rats. Further, the residual volume of the structure-transplanted rats was lower than for the controls. Therefore, transplantation of biofabricated bone marrow-derived cell structures reconstructed functional bladders.

In-vitro perforation of the round window membrane via direct 3-D printed microneedles.

PubMed

Aksit, Aykut; Arteaga, Daniel N; Arriaga, Miguel; Wang, Xun; Watanabe, Hirobumi; Kasza, Karen E; Lalwani, Anil K; Kysar, Jeffrey W

2018-06-08

The cochlea, or inner ear, is a space fully enclosed within the temporal bone of the skull, except for two membrane-covered portals connecting it to the middle ear space. One of these portals is the round window, which is covered by the Round Window Membrane (RWM). A longstanding clinical goal is to reliably and precisely deliver therapeutics into the cochlea to treat a plethora of auditory and vestibular disorders. Standard of care for several difficult-to-treat diseases calls for injection of a therapeutic substance through the tympanic membrane into the middle ear space, after which a portion of the substance diffuses across the RWM into the cochlea. The efficacy of this technique is limited by an inconsistent rate of molecular transport across the RWM. A solution to this problem involves the introduction of one or more microscopic perforations through the RWM to enhance the rate and reliability of diffusive transport. This paper reports the use of direct 3D printing via Two-Photon Polymerization (2PP) lithography to fabricate ultra-sharp polymer microneedles specifically designed to perforate the RWM. The microneedle has tip radius of 500 nm and shank radius of 50 μ m, and perforates the guinea pig RWM with a mean force of 1.19 mN. The resulting perforations performed in vitro are lens-shaped with major axis equal to the microneedle shank diameter and minor axis about 25% of the major axis, with mean area 1670 μ m 2 . The major axis is aligned with the direction of the connective fibers within the RWM. The fibers were separated along their axes without ripping or tearing of the RWM suggesting the main failure mechanism to be fiber-to-fiber decohesion. The small perforation area along with fiber-to-fiber decohesion are promising indicators that the perforations would heal readily following in vivo experiments. These results establish a foundation for the use of Two-Photon Polymerization lithography as a means to fabricate microneedles to perforate the RWM and other similar membranes.

Treatment of acute posterior uveitis in a porcine model by injection of triamcinolone acetonide into the suprachoroidal space using microneedles.

PubMed

Gilger, Brian C; Abarca, Eva M; Salmon, Jacklyn H; Patel, Samirkumar

2013-04-03

To evaluate the effect of triamcinolone acetonide (TA) administered into the suprachoroidal space (SCS) using a microneedle and compare it with intravitreal (IVT) TA injections in a porcine model of acute posterior segment inflammation. An IVT injection of balanced salt solution (BSS) or lipopolysaccharide (LPS) was followed 24 hours later with an injection of 0.2 mg or 2.0 mg of TA into the SCS or IVT. The SCS was accessed using microneedles in a minimally invasive procedure. Ocular inflammatory scores and IOP measurements were collected daily, whereas electroretinography, optical coherence tomography, and wide-field ocular fundus photography was performed on -1, 0, and 3 days after treatment. Aqueous and vitreous humor cell counts and protein levels and histopathology were also compared. Delivery of TA to the SCS using microneedles was simple, effective, and not associated with adverse effects or toxicity. SCS injection of low (0.2 mg) and high doses (2.0 mg) of TA was as effective in reducing acute inflammation in the ocular posterior segment as high-dose IVT injection. Low-dose SCS TA was also effective in reducing inflammation; however, low-dose IVT TA was not. Results from this study suggest that 0.2 mg and 2.0 mg of SCS TA was as effective in reducing inflammation as 2.0 mg IVT TA injection in a model of acute posterior segment inflammation. There were no adverse effects, increased IOP, or evidence of procedural or drug toxicity following injection of TA into the SCS in porcine eyes.

A protective role of murine langerin+ cells in immune responses to cutaneous vaccination with microneedle patches

PubMed Central

Pulit-Penaloza, Joanna A.; Esser, E. Stein; Vassilieva, Elena V.; Lee, Jeong Woo; Taherbhai, Misha T.; Pollack, Brian P.; Prausnitz, Mark R.; Compans, Richard W.; Skountzou, Ioanna

2014-01-01

Cutaneous vaccination with microneedle patches offers several advantages over more frequently used approaches for vaccine delivery, including improved protective immunity. However, the involvement of specific APC subsets and their contribution to the induction of immunity following cutaneous vaccine delivery is not well understood. A better understanding of the functions of individual APC subsets in the skin will allow us to target specific skin cell populations in order to further enhance vaccine efficacy. Here we use a Langerin-EGFP-DTR knock-in mouse model to determine the contribution of langerin+ subsets of skin APCs in the induction of adaptive immune responses following cutaneous microneedle delivery of influenza vaccine. Depletion of langerin+ cells prior to vaccination resulted in substantial impairment of both Th1 and Th2 responses, and decreased post-challenge survival rates, in mice vaccinated cutaneously but not in those vaccinated via the intramuscular route or in non-depleted control mice. Our results indicate that langerin+ cells contribute significantly to the induction of protective immune responses following cutaneous vaccination with a subunit influenza vaccine. PMID:25130187

Multi-Center Pilot Study to Evaluate the Safety Pro le of High Energy Fractionated Radiofrequency With Insulated Microneedles to Multiple Levels of the Dermis.

PubMed

Cohen, Joel L; Weiner, Steven F; Pozner, Jason N; Ibrahimi, Omar A; Vasily, David B; Ross, E Victor; Gabriel, Zena

2016-11-01

In this multi-center pilot study, the safety pro le of high intensity focused radiofrequency (RF) delivered to the dermis was evaluated for safety in the treatment of the aging neck and face. A newly designed insulated microneedle system delivers a signi cant coagulative thermal injury into the dermis while sparing the epidermis from RF injury. Thirty- ve healthy subjects from seven aesthetic practices were evaluated, and data from each were incorporated in this case report. The subjects received a single treatment using settings that delivered the highest RF energies suggested from the new recommended protocols. The depth of thermal delivery was adjusted before each pass and all subjects received a minimum of two to three passes to the treated areas. Before and after photographs along with adverse effects were recorded. This case report demonstrates the ability to deliver significant RF thermal injury to several layers of the dermis with insulated microneedles safely with little injury to the epidermis and minimum downtime. J Drugs Dermatol. 2016;15(11):1308-1312..

Clinical and Histologic Effects of Fractional Microneedling Radiofrequency Treatment on Rosacea.

PubMed

Park, Seon Yong; Kwon, Hyuck Hoon; Yoon, Ji Young; Min, Seonguk; Suh, Dae Hun

2016-12-01

Fractional microneedling radiofrequency (FMR) is an emerging treatment modality, but its effect on rosacea has not been studied yet. To investigate the potential impact of FMR treatment on clinical improvement and histologic changes in rosacea patients. A 12-week, prospective, randomized, split-face clinical trial was conducted. Two sessions of FMR were performed on one side of the cheeks with 4-week interval and the other side remained untreated. Erythema index from DermaSpectrometer and a* value from Spectrophotometer CM-2002 were measured at each visit for the objective measurement of erythema. Histologic analysis of skin samples was also carried out. Clinical evaluation and photometric measurement revealed the reduction of redness in the treated side compared with untreated side and baseline. Erythema index decreased 13.6% and a* value decreased 6.8% at Week 12 compared with baseline. Reduced expression of markers related to inflammation, innate immunity, and angiogenesis was observed in immunohistochemical staining of tissue obtained after FMR treatment. Fractional microneedling radiofrequency treatment showed modest clinical and histologic improvement of rosacea, and it might be used as an alternative or in combination with other treatment methods.

Combined therapy for resistant vitiligo lesions: NB-UVB, microneedling, and topical latanoprost, showed no enhanced efficacy compared to topical latanoprost and NB-UVB.

PubMed

Stanimirovic, Andrija; Kovacevic, Maja; Korobko, Igor; Šitum, Mirna; Lotti, Torello

2016-09-01

Vitiligo is depigmenting disorder of the skin and mucous membranes but despite various therapeutic options, complete and satisfactory treatment of vitiligo still remains a challenge. Therapeutic success also varies depending on the localization of lesions; hands and bony prominents are considered to be resistant to treatment. We investigated feasibility of treating resistant bilateral symmetrical vitiligo vulgaris and acrofacialis lesions with combination of narrowband UVB and topical prostaglandins (0.005% latanoprost solution) with or without Dermaroller 0.5 mm needle length-assisted microneedling. Frequency of repigmentation onset was generally low (37.8%) and pronounced repigmentation was infrequently seen (26-50% repigmentation in 20.8%, and >50% repigmentation in only 8.8% of repigmenting lesions). Our study, however, showed that latanoprost can be used in combination with NB-UVB phototherapy to induce repigmentation in some vitiligo lesions in resistant-to-treatment location, while addition of skin microneedling seems not to improve the treatment outcome and possibly needs modification. © 2016 Wiley Periodicals, Inc.

Curative effects of microneedle fractional radiofrequency system on skin laxity in Asian patients: A prospective, double-blind, randomized, controlled face-split study.

PubMed

Lu, Wenli; Wu, Pinru; Zhang, Zhen; Chen, Jinan; Chen, Xiangdong; Ewelina, Biskup

2017-04-01

To date, no studies compared curative effects of thermal lesions in deep and superficial dermal layers in the same patient (face-split study). To evaluate skin laxity effects of microneedle fractional radiofrequency induced thermal lesions in different dermal layers. 13 patients underwent three sessions of a randomized face-split microneedle fractional radiofrequency system (MFRS) treatment of deep dermal and superficial dermal layer. Skin laxity changes were evaluated objectively (digital images, 2 independent experts) and subjectively (patients' satisfaction numerical rating). 12 of 13 subjects completed a course of 3 treatments and a 1-year follow-up. Improvement of nasolabial folds in deep dermal approach was significantly better than that in superficial approach at three months (P=.0002) and 12 months (P=.0057) follow-up. Effects on infraorbital rhytides were only slightly better (P=.3531). MFRS is an effective method to improve skin laxity. Thermal lesion approach seems to provide better outcomes when applied to deep dermal layers. It is necessary to consider the skin thickness of different facial regions when choosing the treatment depth.

Survival of sheep demi-embryos in vivo and in vitro.

PubMed

Shelton, J N; Szell, A

1988-01-01

Sheep embryos (morulae and blastocysts) were bisected either by microscalpel or by microneedle after dissolving the zona pellucida with acidified Tyrode's solution. Fourteen and 11 cryopreserved demi-embryos failed to develop when transferred to recipients or placed in culture, respectively. When fresh demi-embryos were cultured in Dulbecco's phosphate buffered saline (DPBS) plus fetal calf serum (FCS) or Whitten's medium, the survival rate was 26% compared to 68% for whole embryos (P<0.01), and there was a suggestion that the presence of a zona pellucida was beneficial to survival. When two demi-embryos each within a zona pellucida were transferred into each of 10 ewes, six of them lambed to produce a total of eight lambs, including two sets of identical twins. Of 10 ewes receiving two demi-embryos without zonae pellucidae, three lambed to produce a total of four lambs, including one set of identical twins. Of 10 ewes that each received two whole embryos, 10 lambed to produce a total of 16 lambs. There was a suggestion that the zona pellucida might enhance the survival of demi-morulae but not demi-blastocysts.

Effective and lesion-free cutaneous influenza vaccination

PubMed Central

Wang, Ji; Li, Bo; Wu, Mei X.

2015-01-01

The current study details efficient lesion-free cutaneous vaccination via vaccine delivery into an array of micropores in the skin, instead of bolus injection at a single site. Such delivery effectively segregated vaccine-induced inflammation, resulting in rapid resolution of the inflammation, provided that distances between any two micropores were sufficient. When the inoculation site was treated by FDA-approved nonablative fractional laser (NAFL) before insertion of a PR8 model influenza vaccine-packaged, biodegradable microneedle array (MNs), mice displayed vigorous antigen-uptake, eliciting strong Th1-biased immunity. These animals were completely protected from homologous viral challenges, and fully or partially protected from heterologous H1N1 and H3N2 viral challenges, whereas mice receiving MNs alone suffered from severe illnesses or died of similar viral challenges. NAFL-mediated adjuvanicity was ascribed primarily to dsDNA and other “danger” signals released from laser-damaged skin cells. Thus, mice deficient in dsDNA-sensing pathway, but not Toll like receptor (TLR) or inflammasome pathways, showed poor responses to NAFL. Importantly, with this novel approach both mice and swine exhibited strong protective immunity without incurring any appreciable skin irritation, in sharp contrast to the overt skin irritation caused by intradermal injections. The effective lesion-free cutaneous vaccination merits further clinical studies. PMID:25848020

Targeted Delivery of Antiglaucoma Drugs to the Supraciliary Space Using Microneedles

PubMed Central

Kim, Yoo C.; Edelhauser, Henry F.; Prausnitz, Mark R.

2014-01-01

Purpose. In this work, we tested the hypothesis that highly targeted delivery of antiglaucoma drugs to the supraciliary space by using a hollow microneedle allows dramatic dose sparing of the drug compared to topical eye drops. The supraciliary space is the most anterior portion of the suprachoroidal space, located below the sclera and above the choroid and ciliary body. Methods. A single, hollow 33-gauge microneedle, 700 to 800 μm in length, was inserted into the sclera and used to infuse antiglaucoma drugs into the supraciliary space of New Zealand white rabbits (N = 3–6 per group). Sulprostone, a prostaglandin analog, and brimonidine, an α2-adrenergic agonist, were delivered via supraciliary and topical administration at various doses. The drugs were delivered unilaterally, and intraocular pressure (IOP) of both eyes was measured by rebound tonometry for 9 hours after injection to assess the pharmacodynamic responses. To assess safety of the supraciliary injection, IOP change immediately after intravitreal and supraciliary injection were compared. Results. Supraciliary delivery of both sulprostone and brimonidine reduced IOP by as much as 3 mm Hg bilaterally in a dose-related response; comparison with topical administration at the conventional human dose showed approximately 100-fold dose sparing by supraciliary injection for both drugs. A safety study showed that the kinetics of IOP elevation immediately after supraciliary and intravitreal injection of placebo formulations were similar. Conclusions. This study introduced the use of targeted drug delivery to the supraciliary space by using a microneedle and demonstrated dramatic dose sparing of antiglaucoma therapeutic agents compared to topical eye drops. Targeted delivery in this way can increase safety by reducing side effects and could allow a single injection to contain enough drug for long-term sustained delivery. PMID:25212782

Substrate Deformation Predicts Neuronal Growth Cone Advance

PubMed Central

Athamneh, Ahmad I.M.; Cartagena-Rivera, Alexander X.; Raman, Arvind; Suter, Daniel M.

2015-01-01

Although pulling forces have been observed in axonal growth for several decades, their underlying mechanisms, absolute magnitudes, and exact roles are not well understood. In this study, using two different experimental approaches, we quantified retrograde traction force in Aplysia californica neuronal growth cones as they develop over time in response to a new adhesion substrate. In the first approach, we developed a novel method, to our knowledge, for measuring traction forces using an atomic force microscope (AFM) with a cantilever that was modified with an Aplysia cell adhesion molecule (apCAM)-coated microbead. In the second approach, we used force-calibrated glass microneedles coated with apCAM ligands to guide growth cone advance. The traction force exerted by the growth cone was measured by monitoring the microneedle deflection using an optical microscope. Both approaches showed that Aplysia growth cones can develop traction forces in the 100–102 nN range during adhesion-mediated advance. Moreover, our results suggest that the level of traction force is directly correlated to the stiffness of the microneedle, which is consistent with a reinforcement mechanism previously observed in other cell types. Interestingly, the absolute level of traction force did not correlate with growth cone advance toward the adhesion site, but the amount of microneedle deflection did. In cases of adhesion-mediated growth cone advance, the mean needle deflection was 1.05 ± 0.07 μm. By contrast, the mean deflection was significantly lower (0.48 ± 0.06 μm) when the growth cones did not advance. Our data support a hypothesis that adhesion complexes, which can undergo micron-scale elastic deformation, regulate the coupling between the retrogradely flowing actin cytoskeleton and apCAM substrates, stimulating growth cone advance if sufficiently abundant. PMID:26445437

Thickness and Closure Kinetics of the Suprachoroidal Space Following Microneedle Injection of Liquid Formulations

PubMed Central

Chiang, Bryce; Venugopal, Nitin; Grossniklaus, Hans E.; Jung, Jae Hwan; Edelhauser, Henry F.; Prausnitz, Mark R.

2017-01-01

Purpose To determine the effect of injection volume and formulation of a microneedle injection into the suprachoroidal space (SCS) on SCS thickness and closure kinetics. Methods Microneedle injections containing 25 to 150 μL Hanks' balanced salt solution (HBSS) were performed in the rabbit SCS ex vivo. Distribution of SCS thickness was measured by ultrasonography and three-dimensional (3D) cryo-reconstruction. Microneedle injections were performed in the rabbit SCS in vivo using HBSS, Discovisc, and 1% to 5% carboxymethyl cellulose (CMC) in HBSS. Ultrasonography was used to track SCS thickness over time. Results Increasing HBSS injection volume increased the area of expanded SCS, but did not increase SCS thickness ex vivo. With SCS injections in vivo, the SCS initially expanded to thicknesses of 0.43 ± 0.06 mm with HBSS, 1.5 ± 0.4 mm with Discovisc, and 0.69 to 2.1 mm with 1% to 5% CMC. After injection with HBSS, Discovisc, and 1% CMC solution, the SCS collapsed to baseline with time constants of 19 minutes, 6 hours, and 2.4 days, respectively. In contrast, injections with 3% to 5% CMC solution resulted in SCS expansion to 2.3 to 2.8 mm over the course of 2.8 to 9.1 hours, after which the SCS collapsed to baseline with time constants of 4.5 to 9.2 days. Conclusions With low-viscosity formulations, SCS expands to a thickness that remains roughly constant, independent of the volume of fluid injected. Increasing injection fluid viscosity significantly increased SCS thickness. Expansion of the SCS is hypothesized to be controlled by a balance between the viscous forces of the liquid formulation and the resistive biomechanical forces of the tissue. PMID:28125842

Thickness and Closure Kinetics of the Suprachoroidal Space Following Microneedle Injection of Liquid Formulations.

PubMed

Chiang, Bryce; Venugopal, Nitin; Grossniklaus, Hans E; Jung, Jae Hwan; Edelhauser, Henry F; Prausnitz, Mark R

2017-01-01

To determine the effect of injection volume and formulation of a microneedle injection into the suprachoroidal space (SCS) on SCS thickness and closure kinetics. Microneedle injections containing 25 to 150 μL Hanks' balanced salt solution (HBSS) were performed in the rabbit SCS ex vivo. Distribution of SCS thickness was measured by ultrasonography and three-dimensional (3D) cryo-reconstruction. Microneedle injections were performed in the rabbit SCS in vivo using HBSS, Discovisc, and 1% to 5% carboxymethyl cellulose (CMC) in HBSS. Ultrasonography was used to track SCS thickness over time. Increasing HBSS injection volume increased the area of expanded SCS, but did not increase SCS thickness ex vivo. With SCS injections in vivo, the SCS initially expanded to thicknesses of 0.43 ± 0.06 mm with HBSS, 1.5 ± 0.4 mm with Discovisc, and 0.69 to 2.1 mm with 1% to 5% CMC. After injection with HBSS, Discovisc, and 1% CMC solution, the SCS collapsed to baseline with time constants of 19 minutes, 6 hours, and 2.4 days, respectively. In contrast, injections with 3% to 5% CMC solution resulted in SCS expansion to 2.3 to 2.8 mm over the course of 2.8 to 9.1 hours, after which the SCS collapsed to baseline with time constants of 4.5 to 9.2 days. With low-viscosity formulations, SCS expands to a thickness that remains roughly constant, independent of the volume of fluid injected. Increasing injection fluid viscosity significantly increased SCS thickness. Expansion of the SCS is hypothesized to be controlled by a balance between the viscous forces of the liquid formulation and the resistive biomechanical forces of the tissue.

Ways of Noninvasive Facial Skin Tightening and Fat Reduction.

PubMed

Fritz, Klaus; Salavastru, Carmen

2016-06-01

For skin tightening, ablative and nonablative lasers have been used with various parameters full or fractionated. Currently, other energy-based technologies have been developed such as radiofrequency (RF) from mono- to multipolar, microneedling RF, and high-intensity focused ultrasound. They heat up the tissue to a clinical endpoint. Temperatures above 42°C stimulate fibroblasts to produce more collagen and some technologies produce small coagulation points that allow to shrink and to tighten the tissue with less downtime or side effects. Alternative treatments not based on heat can be chemical peels from light to deep and microneedling without RF. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Vehicle influence on permeation through intact and compromised skin.

PubMed

Gujjar, Meera; Banga, Ajay K

2014-09-10

The purpose of this study was to compare the transdermal permeation of a model compound, diclofenac diethylamine, from a hydrophilic and lipophilic vehicle across in vitro models simulating compromised skin. Mineral oil served as a lipophilic vehicle while 10mM phosphate buffered saline served as a hydrophilic vehicle. Compromised skin was simulated by tape stripping, delipidization, or microneedle application and compared with intact skin as a control. Transepidermal water loss was measured to assess barrier function. Skin compromised with tape stripping and delipidization significantly (p<0.05) increased permeation of diclofenac diethylamine compared to intact and microneedle treated skin with phosphate buffered saline vehicle. A similar trend in permeation was observed with mineral oil as the vehicle. For both vehicles, permeation across skin increased in the same order and correlated with degree of barrier impairment as indicated by transepidermal water loss values: intact

Hypoxia and H2O2 Dual-Sensitive Vesicles for Enhanced Glucose-Responsive Insulin Delivery.

PubMed

Yu, Jicheng; Qian, Chenggen; Zhang, Yuqi; Cui, Zheng; Zhu, Yong; Shen, Qundong; Ligler, Frances S; Buse, John B; Gu, Zhen

2017-02-08

A glucose-responsive closed-loop insulin delivery system mimicking pancreas activity without long-term side effect has the potential to improve diabetic patients' health and quality of life. Here, we developed a novel glucose-responsive insulin delivery device using a painless microneedle-array patch containing insulin-loaded vesicles. Formed by self-assembly of hypoxia and H 2 O 2 dual-sensitive diblock copolymer, the glucose-responsive polymersome-based vesicles (d-GRPs) can disassociate and subsequently release insulin triggered by H 2 O 2 and hypoxia generated during glucose oxidation catalyzed by glucose specific enzyme. Moreover, the d-GRPs were able to eliminate the excess H 2 O 2 , which may lead to free radical-induced damage to skin tissue during the long-term usage and reduce the activity of GOx. In vivo experiments indicated that this smart insulin patch could efficiently regulate the blood glucose in the chemically induced type 1 diabetic mice for 10 h.

Evaluation of postprandial glucose excursion using a novel minimally invasive glucose area-under-the-curve monitoring system.

PubMed

Kuranuki, Sachi; Sato, Toshiyuki; Okada, Seiki; Hosoya, Samiko; Seko, Akinobu; Sugihara, Kaya; Nakamura, Teiji

2013-01-01

To develop a minimally invasive interstitial fluid extraction technology (MIET) to monitor postprandial glucose area under the curve (AUC) without blood sampling, we evaluated the accuracy of glucose AUC measured by MIET and compared with that by blood sampling after food intake. Interstitial fluid glucose AUC (IG-AUC) following consumption of 6 different types of foods was measured by MIET. MIET consisted of stamping microneedle arrays, placing hydrogel patches on the areas, and calculating IG-AUC based on glucose levels in the hydrogels. Glycemic index (GI) was determined using IG-AUC and reference AUC measured by blood sampling. IG-AUC strongly correlated with reference AUC (R = 0.91), and GI determined using IG-AUC showed good correlation with that determined by reference AUC (R = 0.88). IG-AUC obtained by MIET can accurately predict the postprandial glucose excursion without blood sampling. In addition, feasibility of GI measurement by MIET was confirmed.

Derivation of habitat-specific dissolved oxygen criteria for Chesapeake Bay and its tidal tributaries

USGS Publications Warehouse

Batiuk, Richard A.; Breitburg, Denise L.; Diaz, Robert J.; Cronin, Thomas M.; Secor, David H.; Thursby, Glen

2009-01-01

The Chesapeake 2000 Agreement committed its state and federal signatories to “define the water quality conditions necessary to protect aquatic living resources” in the Chesapeake Bay (USA) and its tidal tributaries. Hypoxia is one of the key water quality issues addressed as a result of the above Agreement. This paper summarizes the protection goals and specific criteria intended to achieve those goals for addressing hypoxia. The criteria take into account the variety of Bay habitats and the tendency towards low dissolved oxygen in some areas of the Bay. Stressful dissolved oxygen conditions were characterized for a diverse array of living resources of the Chesapeake Bay by different aquatic habitats: migratory fish spawning and nursery, shallow-water, open-water, deep-water, and deep-channel. The dissolved oxygen criteria derived for each of these habitats are intended to protect against adverse effects on survival, growth, reproduction and behavior. The criteria accommodate both spatial and temporal aspects of low oxygen events, and have been adopted into the Chesapeake Bay states – Maryland, Virginia, and Delaware – and the District of Columbia's water quality standards regulations. These criteria, now in the form of state regulatory standards, are driving an array of land-based and wastewater pollution reduction actions across the six-watershed.

Large Plasma Membrane Disruptions Are Rapidly Resealed by Ca2+-dependent Vesicle–Vesicle Fusion Events

PubMed Central

Terasaki, Mark; Miyake, Katsuya; McNeil, Paul L.

1997-01-01

A microneedle puncture of the fibroblast or sea urchin egg surface rapidly evokes a localized exocytotic reaction that may be required for the rapid resealing that follows this breach in plasma membrane integrity (Steinhardt, R.A,. G. Bi, and J.M. Alderton. 1994. Science (Wash. DC). 263:390–393). How this exocytotic reaction facilitates the resealing process is unknown. We found that starfish oocytes and sea urchin eggs rapidly reseal much larger disruptions than those produced with a microneedle. When an ∼40 by 10 μm surface patch was torn off, entry of fluorescein stachyose (FS; 1,000 mol wt) or fluorescein dextran (FDx; 10,000 mol wt) from extracellular sea water (SW) was not detected by confocal microscopy. Moreover, only a brief (∼5–10 s) rise in cytosolic Ca2+ was detected at the wound site. Several lines of evidence indicate that intracellular membranes are the primary source of the membrane recruited for this massive resealing event. When we injected FS-containing SW deep into the cells, a vesicle formed immediately, entrapping within its confines most of the FS. DiI staining and EM confirmed that the barrier delimiting injected SW was a membrane bilayer. The threshold for vesicle formation was ∼3 mM Ca2+ (SW is ∼10 mM Ca2+). The capacity of intracellular membranes for sealing off SW was further demonstrated by extruding egg cytoplasm from a micropipet into SW. A boundary immediately formed around such cytoplasm, entrapping FDx or FS dissolved in it. This entrapment did not occur in Ca2+-free SW (CFSW). When egg cytoplasm stratified by centrifugation was exposed to SW, only the yolk platelet–rich domain formed a membrane, suggesting that the yolk platelet is a critical element in this response and that the ER is not required. We propose that plasma membrane disruption evokes Ca2+ regulated vesicle–vesicle (including endocytic compartments but possibly excluding ER) fusion reactions. The function in resealing of this cytoplasmic fusion reaction is to form a replacement bilayer patch. This patch is added to the discontinuous surface bilayer by exocytotic fusion events. PMID:9314529

Rapid Intradermal Delivery of Liquid Formulations Using a Hollow Microstructured Array

PubMed Central

Burton, Scott A.; Ng, Chin-Yee; Simmers, Ryan; Moeckly, Craig; Brandwein, David; Gilbert, Tom; Johnson, Nathan; Brown, Ken; Alston, Tesha; Prochnow, Gayatri; Siebenaler, Kris

2010-01-01

ABSTRACT Purpose The purpose of this work is to demonstrate rapid intradermal delivery of up to 1.5 mL of formulation using a hollow microneedle delivery device designed for self-application. Methods 3M’s hollow Microstructured Transdermal System (hMTS) was applied to domestic swine to demonstrate delivery of a variety of formulations including small molecule salts and proteins. Blood samples were collected after delivery and analyzed via HPLC or ELISA to provide a PK profile for the delivered drug. Site evaluations were conducted post delivery to determine skin tolerability. Results Up to 1.5 mL of formulation was infused into swine at a max rate of approximately 0.25 mL/min. A red blotch, the size of the hMTS array, was observed immediately after patch removal, but had faded so as to be almost indistinguishable 10 min post-patch removal. One-mL deliveries of commercial formulations of naloxone hydrochloride and human growth hormone and a formulation of equine anti-tetanus toxin were completed in swine. With few notable differences, the resulting PK profiles were similar to those achieved following subcutaneous injection of these formulations. Conclusions 3M’s hMTS can provide rapid, intradermal delivery of 300–1,500 µL of liquid formulations of small molecules salts and proteins, compounds not typically compatible with passive transdermal delivery. PMID:20582455

Development of blood extraction system for health monitoring system

NASA Astrophysics Data System (ADS)

Tsuchiya, Kazuyoshi; Nakanishi, Naoyuki; Nakamachi, Eiji

2004-03-01

The purpose of this research is to develop the compact human blood sampling device applied for a health monitoring system(HMS), which is called "Mobile Hospital". The HMS consists of (1) a micro electrical pumping system for blood extraction, (2) a bio-sensor to detect and evaluate an amount of Glucose, Cholesterol and Urea in extracted blood, by using enzyme such as Glucoseoxidase (GOD), Cholesteroloxidase and Urease. The mechanical design elements of the device are bio-compatible microneedle, indentation unit using a shape memory alloy(SMA) actuator and pumping unit using a piezoelectric microactuator. The design concept is the biomimetic micromachine of female mosquito"s blood sampling mechanism. The performances of the main mechanical elements such as indentation force of the microneedle, actual stroke of the indentation unit using a SMA actuator and liquid sampling ability of the pumping unit using PZT piezoelectric microactuator were measured. The 3 mm stroke of the indentation load generated by SMA actuator was 0.8mN. The amount of imitation blood extracted by using bimorph PZT actuators was about 0.5 microliters for 10 sec. A 60-micrometer outer diameter and 25-micrometer inner diameter Titanium microneedle, which size is same as female mosquito"s labium, was produced by sputter deposition.

A Dual Wedge Microneedle for sampling of perilymph solution via round window membrane

PubMed Central

Watanabe, Hirobumi; Cardoso, Luis; Lalwani, Anil K.; Kysar, Jeffrey W.

2017-01-01

Objective Precision medicine for inner-ear disease is hampered by the absence of a methodology to sample inner-ear fluid atraumatically. The round window membrane (RWM) is an attractive portal for accessing cochlear fluids as it heals spontaneously. In this study, we report on the development of a microneedle for perilymph sampling that minimizes size of RWM perforation, facilitates quick aspiration, and provides precise volume control. Methods Considering the mechanical anisotropy of the RWM and hydrodynamics through a microneedle, a 31G stainless steel pipe was machined into wedge-shaped design via electrical discharge machining. Guinea pig RWM was penetrated in vitro, and 1 μ1 of perilymph was sampled and analyzed via UV-vis spectroscopy. Results The prototype wedge shaped needle created oval perforation with minor and major diameter of 143 and 344 μm (n=6). The sampling duration and standard deviation of aspirated volume were seconds and 6.8% respectively. The protein concentration was 1.74 mg/mL. Conclusion The prototype needle facilitated precise perforation of RWMs and rapid aspiration of cochlear fluid with precise volume control. The needle design is promising and requires testing in human cadaveric temporal bone and further optimization to become clinically viable. PMID:26888440

Effect of Osmotic Pressure on the Stability of Whole Inactivated Influenza Vaccine for Coating on Microneedles

PubMed Central

Choi, Hyo-Jick; Song, Jae-Min; Bondy, Brian J.; Compans, Richard W.; Kang, Sang-Moo; Prausnitz, Mark R.

2015-01-01

Enveloped virus vaccines can be damaged by high osmotic strength solutions, such as those used to protect the vaccine antigen during drying, which contain high concentrations of sugars. We therefore studied shrinkage and activity loss of whole inactivated influenza virus in hyperosmotic solutions and used those findings to improve vaccine coating of microneedle patches for influenza vaccination. Using stopped-flow light scattering analysis, we found that the virus underwent an initial shrinkage on the order of 10% by volume within 5 s upon exposure to a hyperosmotic stress difference of 217 milliosmolarity. During this shrinkage, the virus envelope had very low osmotic water permeability (1 – 6×10−4 cm s–1) and high Arrhenius activation energy (E a = 15.0 kcal mol–1), indicating that the water molecules diffused through the viral lipid membranes. After a quasi-stable state of approximately 20 s to 2 min, depending on the species and hypertonic osmotic strength difference of disaccharides, there was a second phase of viral shrinkage. At the highest osmotic strengths, this led to an undulating light scattering profile that appeared to be related to perturbation of the viral envelope resulting in loss of virus activity, as determined by in vitro hemagglutination measurements and in vivo immunogenicity studies in mice. Addition of carboxymethyl cellulose effectively prevented vaccine activity loss in vitro and in vivo, believed to be due to increasing the viscosity of concentrated sugar solution and thereby reducing osmotic stress during coating of microneedles. These results suggest that hyperosmotic solutions can cause biphasic shrinkage of whole inactivated influenza virus which can damage vaccine activity at high osmotic strength and that addition of a viscosity enhancer to the vaccine coating solution can prevent osmotically driven damage and thereby enable preparation of stable microneedle coating formulations for vaccination. PMID:26230936

Stability of whole inactivated influenza virus vaccine during coating onto metal microneedles

PubMed Central

Choi, Hyo-Jick; Bondy, Brian J.; Yoo, Dae-Goon; Compans, Richard W.; Kang, Sang-Moo; Prausnitz, Mark R.

2012-01-01

Immunization using a microneedle patch coated with vaccine offers the promise of simplified vaccination logistics and increased vaccine immunogenicity. This study examined the stability of influenza vaccine during the microneedle coating process, with a focus on the role of coating formulation excipients. Thick, uniform coatings were obtained using coating formulations containing a viscosity enhancer and surfactant, but these formulations retained little functional vaccine hemagglutinin (HA) activity after coating. Vaccine coating in a trehalose-only formulation retained about 40 – 50% of vaccine activity, which is a significant improvement. The partial viral activity loss observed in the trehalose-only formulation was hypothesized to come from osmotic pressure-induced vaccine destabilization. We found that inclusion of a viscosity enhancer, carboxymethyl cellulose, overcame this effect and retained full vaccine activity on both washed and plasma-cleaned titanium surfaces. The addition of polymeric surfactant, Lutrol® micro 68, to the trehalose formulation generated phase transformations of the vaccine coating, such as crystallization and phase separation, which was correlated to additional vaccine activity loss, especially when coating on hydrophilic, plasma-cleaned titanium. Again, the addition of a viscosity enhancer suppressed the surfactant-induced phase transformations during drying, which was confirmed by in vivo assessment of antibody response and survival rate after immunization in mice. We conclude that trehalose and a viscosity enhancer are beneficial coating excipients, but the inclusion of surfactant is detrimental to vaccine stability. PMID:23246470

Skin Vaccination against Rotavirus Using Microneedles: Proof of Concept in Gnotobiotic Piglets.

PubMed

Wang, Yuhuan; Vlasova, Anastasia; Velasquez, Daniel E; Saif, Linda J; Kandasamy, Sukumar; Kochba, Efrat; Levin, Yotam; Jiang, Baoming

2016-01-01

Live-attenuated oral rotavirus (RV) vaccines have lower efficacy in low income countries, and additionally are associated with a rare but severe adverse event, intussusception. We have been pursuing the development of an inactivated rotavirus vaccine (IRV) using the human rotavirus strain CDC-9 (G1P[8]) through parenteral immunization and previously demonstrated dose sparing and enhanced immunogenicity of intradermal (ID) unadjuvanted IRV using a coated microneedle patch in comparison with intramuscular (IM) administration in mice. The aim of this study was to evaluate the immune response and protection against RV infection and diarrhea conferred by the administration of the ID unadjuvanted IRV using the microneedle device MicronJet600® in neonatal gnotobiotic (Gn) piglets challenged with virulent Wa G1P[8] human RV. Three doses of 5 μg IRV when administered intradermally and 5 μg IRV formulated with aluminum hydroxide [Al(OH)3] when administered intramuscularly induced comparable rotavirus-specific antibody titers of IgA, IgG, IgG avidity index and neutralizing activity in sera of neonatal piglets. Both IRV vaccination regimens protected against RV antigen shedding in stools, and reduced the cumulative diarrhea scores in the piglets. This study demonstrated that the ID and IM administrations of IRV are immunogenic and protective against RV-induced diarrhea in neonatal piglets. Our findings highlight the potential value of an adjuvant sparing effect of the IRV ID delivery route.

Wind driven vertical transport in a vegetated, wetland water column with air-water gas exchange

NASA Astrophysics Data System (ADS)

Poindexter, C.; Variano, E. A.

2010-12-01

Flow around arrays of cylinders at low and intermediate Reynolds numbers has been studied numerically, analytically and experimentally. Early results demonstrated that at flow around randomly oriented cylinders exhibits reduced turbulent length scales and reduced diffusivity when compared to similarly forced, unimpeded flows (Nepf 1999). While horizontal dispersion in flows through cylinder arrays has received considerable research attention, the case of vertical dispersion of reactive constituents has not. This case is relevant to the vertical transfer of dissolved gases in wetlands with emergent vegetation. We present results showing that the presence of vegetation can significantly enhance vertical transport, including gas transfer across the air-water interface. Specifically, we study a wind-sheared air-water interface in which randomly arrayed cylinders represent emergent vegetation. Wind is one of several processes that may govern physical dispersion of dissolved gases in wetlands. Wind represents the dominant force for gas transfer across the air-water interface in the ocean. Empirical relationships between wind and the gas transfer coefficient, k, have been used to estimate spatial variability of CO2 exchange across the worlds’ oceans. Because wetlands with emergent vegetation are different from oceans, different model of wind effects is needed. We investigated the vertical transport of dissolved oxygen in a scaled wetland model built inside a laboratory tank equipped with an open-ended wind tunnel. Plastic tubing immersed in water to a depth of approximately 40 cm represented emergent vegetation of cylindrical form such as hard-stem bulrush (Schoenoplectus acutus). After partially removing the oxygen from the tank water via reaction with sodium sulfite, we used an optical probe to measure dissolved oxygen at mid-depth as the tank water re-equilibrated with the air above. We used dissolved oxygen time-series for a range of mean wind speeds to estimate the gas transfer coefficient, k, for both a vegetated condition and a control condition (no cylinders). The presence of cylinders in the tank substantially increased the rate of the gas transfer. For the highest wind speed, the gas transfer coefficient was several times higher when cylinders were present compared to when they were not. The gas transfer coefficient for the vegetated condition also proved sensitive to wind speed, increasing markedly with increasing mean wind speeds. Profiles of dissolved oxygen revealed well-mixed conditions in the bulk water column following prolonged air-flow above the water surface, suggesting application of the thin-film model is appropriate. The enhanced gas exchange observed might be explained by increased turbulent kinetic energy within the water column and the anisotropy of the cylinder array, which constrains horizontal motions more than vertical motions. Improved understanding of gas exchange in vegetated water columns may be of particularly use to investigations of carbon fluxes and soil accretion in wetlands. Reference: Nepf, H. (1999), Drag, turbulence, and diffusion in flow through emergent vegetation, Water Resour. Res., 35(2), 479-489.

Unsteady jet in designing innovative drug delivery system

NASA Astrophysics Data System (ADS)

Wang, Cong; Mazur, Paul; Cosse, Julia; Rider, Stephanie; Gharib, Morteza

2014-11-01

Micro-needle injections, a promising pain-free drug delivery method, is constrained by its limited penetration depth. This deficiency can be overcome by implementing fast unsteady jet that can penetrate sub-dermally. The development of a faster liquid jet would increase the penetration depth and delivery volume of micro-needles. In this preliminary work, the nonlinear transient behavior of an elastic tube balloon in providing fast discharge is analyzed. A physical model that combines the Mooney Rivlin Material model and Young-Lapalce's Law was developed and used to investigate the fast discharging dynamic phenomenon. A proof of concept prototype was constructed to demonstrate the feasibility of a simple thumb-sized delivery system to generate liquid jet with desired speed in the range of 5-10 m/s. This work is supported by ZCUBE Corporation.

A 32-Channel Phased-Array Receive with Asymmetric Birdcage Transmit RF Coil for Hyperpolarized Xenon-129 Lung Imaging

PubMed Central

Dregely, Isabel; Ruset, Iulian C.; Wiggins, Graham; Mareyam, Azma; Mugler, John P.; Altes, Talissa A.; Meyer, Craig; Ruppert, Kai; Wald, Lawrence L.; Hersman, F. William

2012-01-01

Hyperpolarized xenon-129 (HP Xe) has the potential to become a non-invasive contrast agent for lung MRI. In addition to its utility for imaging of ventilated airspaces, the property of xenon to dissolve in lung tissue and blood upon inhalation provides the opportunity to study gas exchange. Implementations of imaging protocols for obtaining regional parameters that exploit the dissolved phase are limited by the available signal-to-noise ratio (SNR), excitation homogeneity, and length of acquisition times. To address these challenges, a 32-channel receive-array coil complemented by an asymmetric birdcage transmit coil tuned to the HP Xe resonance at 3T was developed. First results of spin-density imaging in healthy subjects and subjects with obstructive lung disease demonstrated the improvements in image quality by high resolution ventilation images with high SNR. Parallel imaging performance of the phased-array coil was demonstrated by acceleration factors up to three in 2D acquisitions and up to six in 3D acquisitions. Transmit-field maps showed a regional variation of only 8% across the whole lung. The newly developed phased-array receive coil with the birdcage transmit coil will lead to an improvement in existing imaging protocols, but moreover enable the development of new, functional lung imaging protocols based on the improvements in excitation homogeneity, SNR, and acquisition speed. PMID:23132336

The influence of dissolved oxygen on winter habitat selection by largemouth bass: an integration of field biotelemetry studies and laboratory experiments.

PubMed

Hasler, C T; Suski, C D; Hanson, K C; Cooke, S J; Tufts, B L

2009-01-01

In this study, field biotelemetry and laboratory physiology approaches were coupled to allow understanding of the behavioral and physiological responses of fish to winter hypoxia. The biotelemetry study compared dissolved oxygen levels measured throughout the winter period with continually tracked locations of nine adult largemouth bass obtained from a whole-lake submerged telemetry array. Fish habitat usage was compared with habitat availability to assess whether fish were selecting for specific dissolved oxygen concentrations. The laboratory study examined behavioral and physiological responses to progressive hypoxia in juvenile largemouth bass acclimated to winter temperatures. Results from the dissolved oxygen measurements made during the biotelemetry study showed high variance in under-ice dissolved oxygen levels. Avoidance of water with dissolved oxygen <2.0 mg/L by telemetered fish was demonstrated, but significant use of water with intermediate dissolved oxygen levels was also found. Results from the lab experiments showed marked changes in behavior (i.e., yawning and vertical movement) at <2.0 mg/L of dissolved oxygen but no change in tissue lactate, an indicator of anaerobic metabolism. Combined results of the biotelemetry and laboratory studies demonstrate that a dissolved oxygen content of 2.0 mg/L may be a critical threshold that induces behavioral responses by largemouth bass during the winter. In addition, the use by fish of areas with intermediate levels of dissolved oxygen suggests that there are multiple environmental factors influencing winter behavior.

Hydrogel-Forming Microneedle Arrays Allow Detection of Drugs and Glucose In Vivo: Potential for Use in Diagnosis and Therapeutic Drug Monitoring

PubMed Central

Caffarel-Salvador, Ester; Brady, Aaron J.; Eltayib, Eyman; Meng, Teng; Alonso-Vicente, Ana; Gonzalez-Vazquez, Patricia; Torrisi, Barbara M.; Vicente-Perez, Eva Maria; Mooney, Karen; Jones, David S.; Bell, Steven E. J.; McCoy, Colin P.; McCarthy, Helen O.; McElnay, James C.; Donnelly, Ryan F.

2015-01-01

We describe, for the first time the use of hydrogel-forming microneedle (MN) arrays for minimally-invasive extraction and quantification of drug substances and glucose from skin in vitro and in vivo. MN prepared from aqueous blends of hydrolysed poly(methyl-vinylether-co-maleic anhydride) (11.1% w/w) and poly(ethyleneglycol) 10,000 daltons (5.6% w/w) and crosslinked by esterification swelled upon skin insertion by uptake of fluid. Post-removal, theophylline and caffeine were extracted from MN and determined using HPLC, with glucose quantified using a proprietary kit. In vitro studies using excised neonatal porcine skin bathed on the underside by physiologically-relevant analyte concentrations showed rapid (5 min) analyte uptake. For example, mean concentrations of 0.16 μg/mL and 0.85 μg/mL, respectively, were detected for the lowest (5 μg/mL) and highest (35 μg/mL) Franz cell concentrations of theophylline after 5 min insertion. A mean concentration of 0.10 μg/mL was obtained by extraction of MN inserted for 5 min into skin bathed with 5 μg/mL caffeine, while the mean concentration obtained by extraction of MN inserted into skin bathed with 15 μg/mL caffeine was 0.33 μg/mL. The mean detected glucose concentration after 5 min insertion into skin bathed with 4 mmol/L was 19.46 nmol/L. The highest theophylline concentration detected following extraction from a hydrogel-forming MN inserted for 1 h into the skin of a rat dosed orally with 10 mg/kg was of 0.363 μg/mL, whilst a maximum concentration of 0.063 μg/mL was detected following extraction from a MN inserted for 1 h into the skin of a rat dosed with 5 mg/kg theophylline. In human volunteers, the highest mean concentration of caffeine detected using MN was 91.31 μg/mL over the period from 1 to 2 h post-consumption of 100 mg Proplus® tablets. The highest mean blood glucose level was 7.89 nmol/L detected 1 h following ingestion of 75 g of glucose, while the highest mean glucose concentration extracted from MN was 4.29 nmol/L, detected after 3 hours skin insertion in human volunteers. Whilst not directly correlated, concentrations extracted from MN were clearly indicative of trends in blood in both rats and human volunteers. This work strongly illustrates the potential of hydrogel-forming MN in minimally-invasive patient monitoring and diagnosis. Further studies are now ongoing to reduce clinical insertion times and develop mathematical algorithms enabling determination of blood levels directly from MN measurements. PMID:26717198

Three dimensional transient multifield analysis of a piezoelectric micropump for drug delivery system for treatment of hemodynamic dysfunctions.

PubMed

Nisar, Asim; Afzulpurkar, Nitin; Tuantranont, Adisorn; Mahaisavariya, Banchong

2008-12-01

In this paper, we present design of a transdermal drug delivery system for treatment of cardiovascular or hemodynamic disorders such as hypertension. The system comprises of integrated control electronics and microelectromechanical system devices such as micropump, micro blood pressure sensor and microneedle array. The objective is to overcome the limitations of oral therapy such as variable absorption profile and the need for frequent dosing, by fabricating a safe, reliable and cost effective transdermal drug delivery system to dispense various pharmacological agents through the skin for treatment of hemodynamic dysfunction such as hypertension. Moreover, design optimization of a piezoelectrically actuated valveless micropump is presented for the drug delivery system. Because of the complexity in analysis of piezoelectric micropump, which involves structural and fluid field couplings in a complicated geometrical arrangement, finite element (FE) numerical simulation rather than an analytical system has been used. The behavior of the piezoelectric actuator with biocompatible polydimethylsiloxane membrane is first studied by conducting piezoelectric analysis. Then the performance of the valveless micropump is analyzed by building a three dimensional electric-solid-fluid model of the micropump. The effect of geometrical dimensions on micropump characteristics and efficiency of nozzle/diffuser elements of a valveless micropump is investigated in the transient analysis using multiple code coupling method. The deformation results of the membrane using multifield code coupling analysis are in good agreement with analytical as well as results of single code coupling analysis of a piezoelectric micropump. The analysis predicts that to enhance the performance of the micropump, diffuser geometrical dimensions such as diffuser length, diffuser neck width and diffuser angle need to be optimized. Micropump flow rate is not strongly affected at low excitation frequencies from 10 to 200 Hz. The excitation voltage is the more dominant factor that affects the flow rate of the micropump as compared with the excitation frequency. However, at extremely high excitation frequencies beyond 8,000 Hz, the flow rate drops as the membrane exhibits multiple bending peaks which is not desirable for fluid flow. Following the extensive numerical analysis, actual fabrication and performance characterization of the micropump is presented. The performance of the micropump is characterized in terms of piezoelectric actuator deflection and micropump flow rate at different operational parameters. The set of multifield simulations and experimental measurement of deflection and flow rate at varying voltage and excitation frequency is a significant advance in the study of the electric-solid-fluid coupled field effects as it allows transient, three dimensional piezoelectric and fluid analysis of the micropump thereby facilitating a more realistic multifield analysis. The results of the present study will also help to conduct relevant strength duration tests of integrated drug delivery device with micropump and microneedle array in future.

Enabling skin vaccination using new delivery technologies

PubMed Central

Kim, Yeu-Chun; Prausnitz, Mark R.

2011-01-01

The skin is known to be a highly immunogenic site for vaccination, but few vaccines in clinical use target skin largely because conventional intradermal injection is difficult and unreliable to perform. Now, a number of new or newly adapted delivery technologies have been shown to administer vaccine to the skin either by non-invasive or minimally invasive methods. Non-invasive methods include high-velocity powder and liquid jet injection, as well as diffusion-based patches in combination with skin abrasion, thermal ablation, ultrasound, electroporation, and chemical enhancers. Minimally invasive methods are generally based on small needles, including solid microneedle patches, hollow microneedle injections, and tattoo guns. The introduction of these advanced delivery technologies can make the skin a site for simple, reliable vaccination that increases vaccine immunogenicity and offers logistical advantages to improve the speed and coverage of vaccination. PMID:21799951

Enabling skin vaccination using new delivery technologies

PubMed Central

Kim, Yeu-Chun; Prausnitz, Mark R.

2011-01-01

The skin is known to be a highly immunogenic site for vaccination, but few vaccines in clinical use target skin largely because conventional intradermal injection is difficult and unreliable to perform. Now, a number of new or newly adapted delivery technologies have been shown to administer vaccine to the skin either by non-invasive or minimally invasive methods. Non-invasive methods include high-velocity powder and liquid jet injection, as well as diffusion-based patches in combination with skin abrasion, thermal ablation, ultrasound, electroporation, and chemical enhancers. Minimally invasive methods are generally based on small needles, including solid microneedle patches, hollow microneedle injections and tattoo guns. The introduction of these advanced delivery technologies can make the skin a site for simple, reliable vaccination that increases vaccine immunogenicity and offers logistical advantages to improve the speed and coverage of vaccination. PMID:21472533

Axillary hyperhidrosis: A review of the extent of the problem and treatment modalities.

PubMed

Singh, Sanjay; Davis, Harriet; Wilson, Paul

2015-10-01

The purpose of this review is to summarize the extent of the problem of axillary hyperhidrosis and treatment modalities available. The benefits and disadvantages of various treatments are reflected on with the hope of providing a starting point to investigate new ways of treating hyperhidrosis. A literature search was conducted using various databases and search criteria. Current treatments include aluminium chloride antiperspirants, iontophoresis, botox injections and endoscopic thoracic sympathectomy. Botox therapy is usually the most effective treatment, without surgery or unpleasant side effects. However it has to be administered by a skilled clinician and involves around 20 injections to treat axillary hyperhidrosis. Other ways of giving Botox are being developed, the most promising one being the use of microneedles which are able to penetrate the skin and deliver drugs to the target area of the dermis without causing pain. In comparison to the temporary effects of microneedles, laser and microwave therapies are also assessed as they offer the hope of permanent relief from hyperhidrosis. There is a considerable dearth in the literature on the management of axillary hyperhidrosis. Further study in larger populations with longer follow up times is critical to access the long term effects of treatment. Microneedles could be the future treatment of choice with the potential to deliver drugs in a safe and pain free way. Copyright © 2015 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.

Skin Vaccination against Rotavirus Using Microneedles: Proof of Concept in Gnotobiotic Piglets

PubMed Central

Wang, Yuhuan; Vlasova, Anastasia; Velasquez, Daniel E.; Saif, Linda J.; Kandasamy, Sukumar; Kochba, Efrat; Levin, Yotam; Jiang, Baoming

2016-01-01

Live-attenuated oral rotavirus (RV) vaccines have lower efficacy in low income countries, and additionally are associated with a rare but severe adverse event, intussusception. We have been pursuing the development of an inactivated rotavirus vaccine (IRV) using the human rotavirus strain CDC-9 (G1P[8]) through parenteral immunization and previously demonstrated dose sparing and enhanced immunogenicity of intradermal (ID) unadjuvanted IRV using a coated microneedle patch in comparison with intramuscular (IM) administration in mice. The aim of this study was to evaluate the immune response and protection against RV infection and diarrhea conferred by the administration of the ID unadjuvanted IRV using the microneedle device MicronJet600® in neonatal gnotobiotic (Gn) piglets challenged with virulent Wa G1P[8] human RV. Three doses of 5 μg IRV when administered intradermally and 5 μg IRV formulated with aluminum hydroxide [Al(OH)3] when administered intramuscularly induced comparable rotavirus-specific antibody titers of IgA, IgG, IgG avidity index and neutralizing activity in sera of neonatal piglets. Both IRV vaccination regimens protected against RV antigen shedding in stools, and reduced the cumulative diarrhea scores in the piglets. This study demonstrated that the ID and IM administrations of IRV are immunogenic and protective against RV-induced diarrhea in neonatal piglets. Our findings highlight the potential value of an adjuvant sparing effect of the IRV ID delivery route. PMID:27824918

Microneedle Coating Techniques for Transdermal Drug Delivery

PubMed Central

Haj-Ahmad, Rita; Khan, Hashim; Arshad, Muhammad Sohail; Rasekh, Manoochehr; Hussain, Amjad; Walsh, Susannah; Li, Xiang; Chang, Ming-Wei; Ahmad, Zeeshan

2015-01-01

Drug administration via the transdermal route is an evolving field that provides an alternative to oral and parenteral routes of therapy. Several microneedle (MN) based approaches have been developed. Among these, coated MNs (typically where drug is deposited on MN tips) are a minimally invasive method to deliver drugs and vaccines through the skin. In this review, we describe several processes to coat MNs. These include dip coating, gas jet drying, spray coating, electrohydrodynamic atomisation (EHDA) based processes and piezoelectric inkjet printing. Examples of process mechanisms, conditions and tested formulations are provided. As these processes are independent techniques, modifications to facilitate MN coatings are elucidated. In summary, the outcomes and potential value for each technique provides opportunities to overcome formulation or dosage form limitations. While there are significant developments in solid degradable MNs, coated MNs (through the various techniques described) have potential to be utilized in personalized drug delivery via controlled deposition onto MN templates. PMID:26556364

Analysis of angle effect on particle flocculation in branch flow

NASA Astrophysics Data System (ADS)

Prasad, Karthik; Fink, Kathryn; Liepmann, Dorian

2014-11-01

Hollow point microneedle drug delivery systems are known to be highly susceptible to blockage, owing to their very small structures. This problem has been especially noted when delivering suspended particle solutions, such as vaccines. Attempts to reduce particle flocculation in such devices through surface treatments of the particles have been largely unsuccessful. Furthermore, the particle clog only forms at the mouths of the microneedle structures, leaving the downstream walls clear. This implies that the sudden change in length scales alter the hydrodynamic interactions, creating the conditions for particle flocculation. However, while it is known that particle flocculation occurs, the physics behind the event are obscure. We utilize micro-PIV to observe how the occurrence and formation of particle flocculation changes in relation to the angle encountered by particle laden flow into microfluidic branch structures. The results offer the ability to optimize particle flocculation in MEMS devices, increasing device efficacy and longevity.

A graphene-based electrochemical device with thermoresponsive microneedles for diabetes monitoring and therapy

NASA Astrophysics Data System (ADS)

Lee, Hyunjae; Choi, Tae Kyu; Lee, Young Bum; Cho, Hye Rim; Ghaffari, Roozbeh; Wang, Liu; Choi, Hyung Jin; Chung, Taek Dong; Lu, Nanshu; Hyeon, Taeghwan; Choi, Seung Hong; Kim, Dae-Hyeong

2016-06-01

Owing to its high carrier mobility, conductivity, flexibility and optical transparency, graphene is a versatile material in micro- and macroelectronics. However, the low density of electrochemically active defects in graphene synthesized by chemical vapour deposition limits its application in biosensing. Here, we show that graphene doped with gold and combined with a gold mesh has improved electrochemical activity over bare graphene, sufficient to form a wearable patch for sweat-based diabetes monitoring and feedback therapy. The stretchable device features a serpentine bilayer of gold mesh and gold-doped graphene that forms an efficient electrochemical interface for the stable transfer of electrical signals. The patch consists of a heater, temperature, humidity, glucose and pH sensors and polymeric microneedles that can be thermally activated to deliver drugs transcutaneously. We show that the patch can be thermally actuated to deliver Metformin and reduce blood glucose levels in diabetic mice.

Intradermal vaccination using the novel microneedle device MicronJet600: Past, present, and future.

PubMed

Levin, Yotam; Kochba, Efrat; Hung, Ivan; Kenney, Richard

2015-01-01

Intradermal immunization has become a forefront of vaccine improvement, both scientifically and commercially. Newer technologies are being developed to address the need to reduce the dose required for vaccination and to improve the reliability and ease of injection, which have been major hurdles in expanding the number of approved vaccines using this route of administration. In this review, 7 y of clinical experience with a novel intradermal delivery device, the MicronJet600, which is a registered hollow microneedle that simplifies the delivery of liquid vaccines, are summarized. This device has demonstrated both significant dose-sparing and superior immunogenicity in various vaccine categories, as well as in diverse subject populations and age groups. These studies have shown that intradermal delivery using this device is safe, effective, and preferred by the subjects. Comparison with other intradermal devices and potential new applications for intradermal delivery that could be pursued in the future are also discussed.

Polymer multilayer tattooing for enhanced DNA vaccination

NASA Astrophysics Data System (ADS)

Demuth, Peter C.; Min, Younjin; Huang, Bonnie; Kramer, Joshua A.; Miller, Andrew D.; Barouch, Dan H.; Hammond, Paula T.; Irvine, Darrell J.

2013-04-01

DNA vaccines have many potential benefits but have failed to generate robust immune responses in humans. Recently, methods such as in vivo electroporation have demonstrated improved performance, but an optimal strategy for safe, reproducible, and pain-free DNA vaccination remains elusive. Here we report an approach for rapid implantation of vaccine-loaded polymer films carrying DNA, immune-stimulatory RNA, and biodegradable polycations into the immune-cell-rich epidermis, using microneedles coated with releasable polyelectrolyte multilayers. Films transferred into the skin following brief microneedle application promoted local transfection and controlled the persistence of DNA and adjuvants in the skin from days to weeks, with kinetics determined by the film composition. These ‘multilayer tattoo’ DNA vaccines induced immune responses against a model HIV antigen comparable to electroporation in mice, enhanced memory T-cell generation, and elicited 140-fold higher gene expression in non-human primate skin than intradermal DNA injection, indicating the potential of this strategy for enhancing DNA vaccination.

Transdermal drug delivery

PubMed Central

Prausnitz, Mark R.; Langer, Robert

2009-01-01

Transdermal drug delivery has made an important contribution to medical practice, but has yet to fully achieve its potential as an alternative to oral delivery and hypodermic injections. First-generation transdermal delivery systems have continued their steady increase in clinical use for delivery of small, lipophilic, low-dose drugs. Second-generation delivery systems using chemical enhancers, non-cavitational ultrasound and iontophoresis have also resulted in clinical products; the ability of iontophoresis to control delivery rates in real time provides added functionality. Third-generation delivery systems target their effects to skin’s barrier layer of stratum corneum using microneedles, thermal ablation, microdermabrasion, electroporation and cavitational ultrasound. Microneedles and thermal ablation are currently progressing through clinical trials for delivery of macromolecules and vaccines, such as insulin, parathyroid hormone and influenza vaccine. Using these novel second- and third-generation enhancement strategies, transdermal delivery is poised to significantly increase impact on medicine. PMID:18997767

Flexible Microsensor Array for the Root Zone Monitoring of Porous Tube Plant Growth System

NASA Technical Reports Server (NTRS)

Sathyan, Sandeep; Kim, Chang-Soo; Porterfield, D. Marshall; Nagle, H. Troy; Brown, Christopher S.

2004-01-01

Control of oxygen and water in the root zone is vital to support plant growth in the microgravity environment. The ability to control these sometimes opposing parameters in the root zone is dependent upon the availability of sensors to detect these elements and provide feedback for control systems. In the present study we demonstrate the feasibility of using microsensor arrays on a flexible substrate for dissolved oxygen detection, and a 4-point impedance microprobe for surface wetness detection on the surface of a porous tube (PT) nutrient delivery system. The oxygen microsensor reported surface oxygen concentrations that correlated with the oxygen concentrations of the solution inside the PT when operated at positive pressures. At negative pressures the microsensor shows convergence to zero saturation (2.2 micro mol/L) values due to inadequate water film formation on porous tube surface. The 4-point microprobe is useful as a wetness detector as it provides a clear differentiation between dry and wet surfaces. The unique features of the dissolved oxygen microsensor array and 4-point microprobe include small and simple design, flexibility and multipoint sensing. The demonstrated technology is anticipated to provide low cost, and highly reliable sensor feedback monitoring plant growth nutrient delivery system in both terrestrial and microgravity environments.

Formation and dissolution of microbubbles on highly-ordered plasmonic nanopillar arrays

PubMed Central

Liu, Xiumei; Bao, Lei; Dipalo, Michele; De Angelis, Francesco; Zhang, Xuehua

2015-01-01

Bubble formation from plasmonic heating of nanostructures is of great interest in many applications. In this work, we study experimentally the intrinsic effects of the number of three-dimensional plasmonic nanostructures on the dynamics of microbubbles, largely decoupled from the effects of dissolved air. The formation and dissolution of microbubbles is observed on exciting groups of 1, 4, and 9 nanopillars. Our results show that the power threshold for the bubble formation depends on the number density of the nanopillars in highly-ordered arrays. In the degassed water, both the growth rate and the maximal radius of the plasmonic microbubbles increase with an increase of the illuminated pillar number, due to the heat balance between the heat loss across the bubble and the collective heating generated from the nanopillars. Interestingly, our results show that the bubble dissolution is affected by the spatial arrangement of the underlying nanopillars, due to the pinning effect on the bubble boundary. The bubbles on nanopillar arrays dissolve in a jumping mode with step-wise features on the dissolution curves, prior to a smooth dissolution phase for the bubble pinned by a single pillar. The insight from this work may facilitate the design of nanostructures for efficient energy conversion. PMID:26687143

A pilot split-scalp study of combined fractional radiofrequency microneedling and 5% topical minoxidil in treating male pattern hair loss.

PubMed

Yu, A-J; Luo, Y-J; Xu, X-G; Bao, L-L; Tian, T; Li, Z-X; Dong, Y-X; Li, Y-H

2018-06-27

Various trials have been conducted on the management of male pattern hair loss (MPHL), but the outcomes often seem to be limited. Adjuvant therapies are urgently needed. To evaluate the efficacy and safety of combined fractional radiofrequency microneedling (FRM) and 5% topical minoxidil in the treatment of male pattern hair loss. In total, 19 Chinese men were enrolled in this randomized, controlled, split-scalp trial. Participants received monotherapy with 5% topical minoxidil twice daily to one half of the scalp, while on the other half of the scalp the treatment with twice-daily 5% topical minoxidil was combined with five sessions of FRM at 4-week intervals. Mean hair count and hair thickness, global assessment by the investigators, subject self-assessment and adverse effects were assessed. After 5 months of treatment, mean hair count increased from 44.12 ± 21.58 to 73.14 ± 25.45 on the combined-therapy side and from 46.22 ± 18.77 to 63.21 ± 19.22 on the monotherapy side, while mean hair thickness increased from 53 ± 13 μm to 71 ± 15 μm and from 52 ± 16 μm to 66 ± 14 μm, respectively. Compared with the monotherapy side, the combined-therapy side had a higher degree of improvement in both hair count (P = 0.01) and hair thickness (P = 0.02). Combined treatment with fractional radiofrequency microneedle and 5% topical minoxidil could be an effective and safe treatment option for male pattern hair loss. © 2018 British Association of Dermatologists.

MEMS for medical technology applications

NASA Astrophysics Data System (ADS)

Frisk, Thomas; Roxhed, Niclas; Stemme, Göran

2007-01-01

This paper gives an in-depth description of two recent projects at the Royal Institute of Technology (KTH) which utilize MEMS and microsystem technology for realization of components intended for specific applications in medical technology and diagnostic instrumentation. By novel use of the DRIE fabrication technology we have developed side-opened out-of-plane silicon microneedles intended for use in transdermal drug delivery applications. The side opening reduces clogging probability during penetration into the skin and increases the up-take area of the liquid in the tissue. These microneedles offer about 200µm deep and pain-free skin penetration. We have been able to combine the microneedle chip with an electrically and heat controlled liquid actuator device where expandable microspheres are used to push doses of drug liquids into the skin. The entire unit is made of low cost materials in the form of a square one cm-sized patch. Finally, the design, fabrication and evaluation of an integrated miniaturized Quartz Crystal Microbalance (QCM) based "electronic nose" microsystem for detection of narcotics is described. The work integrates a novel environment-to-chip sample interface with the sensor element. The choice of multifunctional materials and the geometric features of a four-component microsystem allow a functional integration of a QCM crystal, electrical contacts, fluidic contacts and a sample interface in a single system with minimal assembly effort, a potential for low-cost manufacturing, and a few orders of magnitude reduced in system size (12*12*4 mm 3) and weight compared to commercially available instruments. The sensor chip was successfully used it for the detection of 200 ng of narcotics sample.

Process for alloying uranium and niobium

DOEpatents

Holcombe, Cressie E.; Northcutt, Jr., Walter G.; Masters, David R.; Chapman, Lloyd R.

1991-01-01

Alloys such as U-6Nb are prepared by forming a stacked sandwich array of uraniun sheets and niobium powder disposed in layers between the sheets, heating the array in a vacuum induction melting furnace to a temperature such as to melt the uranium, holding the resulting mixture at a temperature above the melting point of uranium until the niobium dissolves in the uranium, and casting the uranium-niobium solution. Compositional uniformity in the alloy product is enabled by use of the sandwich structure of uranium sheets and niobium powder.

The fabrication of Ag nanoflake arrays via self-assembly on the surface of an anodic aluminum oxide template

NASA Astrophysics Data System (ADS)

Li, Xueming; Dong, Kun; Tang, Libin; Wu, Yongjun; Yang, Peizhi; Zhang, Pengxiang

2010-02-01

Vertical-aligned Ag nanoflake arrays are fabricated on the surface of an anodic aluminum oxide (AAO) template under a hydrothermal condition for the first time. The porous surface of AAO templates and the precursor solution may play key roles in the process of fabricating Ag nanoflakes. The rim of pores can provide many active sites for nucleation and growth, and then nanoflake arrays gradually form through self-assembly of Ag on the surface of AAO membranes. The product is characterized by X-ray diffraction (XRD) and scanning electron microscopy (SEM), and a growth mechanism of nanoflake is deduced. This work demonstrates that it is possible to make ordered nanoarrays without dissolving templates using the hydrothermal method, and this interesting Ag nanoflake arrays may provide a wider range of nanoscale applications.

Comparison of Physical Pretreatment Regimens to Enhance Protoporphyrin IX Uptake in Photodynamic Therapy: A Randomized Clinical Trial.

PubMed

Bay, Christiane; Lerche, Catharina Margrethe; Ferrick, Bradford; Philipsen, Peter Alshede; Togsverd-Bo, Katrine; Haedersdal, Merete

2017-04-01

Skin pretreatment is recommended for adequate penetration of topical photosensitizing agents and subsequent protoporphyrin IX (PPIX) accumulation in photodynamic therapy (PDT). To compare the relative potential of different physical pretreatments to enhance PPIX fluorescence in normal skin. This intraindividual, randomized clinical trial was performed from November 28 to December 20, 2014, at Bispebjerg Hospital, Copenhagen, Denmark, among 12 healthy volunteers 18 years or older. Analysis was based on intention to treat. All participants completed the study protocol. Participants were each exposed to standardized skin preparation with curettage, microdermabrasion with abrasive pads, microneedling with dermarollers, ablative fractional laser (AFXL), non-AFXL, and no pretreatment, followed by 3 hours of methyl aminolevulinate hydrochloride incubation and subsequent red light illumination. The primary outcome measure was methyl aminolevulinate-induced PPIX fluorescence accumulation. Secondary outcome measures were PPIX photobleaching and clinical local skin reactions, supported by noninvasive reflectance measurements of percentage of skin redness, transepidermal water loss, and participant-assessed pain. Among the 12 healthy study participants (8 men; 4 women; mean [SD] age, 33 [15] years), histologic findings confirmed standardization of interventions with partial removal of the stratum corneum after curettage and microdermabrasion and similar vertical penetration depths for microneedling, AFXL, and non-AFXL (median, 125 μm). PPIX fluorescence reached highest intensities in skin pretreated with AFXL (median, 8661 arbitrary units [AU]) compared with microdermabrasion (median, 6731 AU), microneedling (median, 5609 AU), and curettage (median, 4765 AU) (P < .001), among which similar enhancement was shown. Comparatively lower fluorescence levels were demonstrated for skin pretreated with non-AFXL (median, 2898 AU), methyl aminolevulinate-treated controls (median, 2254 AU), and untreated controls (median, 239 AU) (P < .03). Increasing laser densities (2% vs 4% vs 6%) and the number of pretreatment passes (1, 2, and 3 passes) did not enhance PPIX fluorescence. Local skin reactions were most intensified in AFXL-pretreated skin and correlated with PPIX fluorescence and degree of PPIX photobleaching. Under standardized conditions, PPIX accumulation was most enhanced after AFXL pretreatment, followed by microdermabrasion, microneedling, and curettage. Increasing the number of pretreatment passes and laser densities did not further augment PPIX accumulation. These results may indicate relatively enhanced PDT response by AFXL pretreatment in diseased skin. clinicaltrials.gov Identifier: NCT02372370.

Novel drug delivery strategies for porphyrins and porphyrin precursors

NASA Astrophysics Data System (ADS)

Morrow, D. I. J.; Donnelly, R. F.

2009-06-01

superficial lesions, such as actinic keratosis. In addition, photodynamic antimicrobial chemotherapy (PACT) is attracting increasing interest for the treatment of infection. However, delivery strategies for topical PDT and PACT are still based on application of rather simplistic cream and solution formulations, with little consideration given to thermodynamics, targeting or the physicochemical properties of the active agent. Purpose-designed dosage forms for topical delivery of aminolevulinic acid or its esters include creams containing penetration enhancers and/or iron chelators, pressure sensitive patches and bioadhesive patches. Such systems aim to enhance drug delivery across the stratum corneum and keratinised debris overlying neoplastic lesions and improve subsequent protoporphyrin IX (PpIX) production. The alternative to using porphyrin precursors is the use of pre-formed photosensitisers. However, owing to their relatively high molecular weights, conventional topical application is not appropriate. Innovative strategies, such as the use of needle-free injections and microneedle arrays, bypass the stratum corneum, enabling rapid and targeted delivery not only porphyrin precursors but also pre-formed photosensitisers. This presentation will review drug delivery work published to date in the fields of PDT and PACT. In addition, the benefits of employing the latest advances in pharmaceutical technology will be highlighted.

A Magnetic Microbead Occlusion Model to Induce Ocular Hypertension-Dependent Glaucoma in Mice

PubMed Central

Cueva Vargas, Jorge L.; Di Polo, Adriana

2016-01-01

The use of rodent models of glaucoma has been essential to understand the molecular mechanisms that underlie the pathophysiology of this multifactorial neurodegenerative disease. With the advent of numerous transgenic mouse lines, there is increasing interest in inducible murine models of ocular hypertension. Here, we present an occlusion model of glaucoma based on the injection of magnetic microbeads into the anterior chamber of the eye using a modified microneedle with a facetted bevel. The magnetic microbeads are attracted to the iridocorneal angle using a handheld magnet to block the drainage of aqueous humour from the anterior chamber. This disruption in aqueous dynamics results in a steady elevation of intraocular pressure, which subsequently leads to the loss of retinal ganglion cells, as observed in human glaucoma patients. The microbead occlusion model presented in this manuscript is simple compared to other inducible models of glaucoma and also highly effective and reproducible. Importantly, the modifications presented here minimize common issues that often arise in occlusion models. First, the use of a bevelled glass microneedle prevents backflow of microbeads and ensures that minimal damage occurs to the cornea during the injection, thus reducing injury-related effects. Second, the use of magnetic microbeads ensures the ability to attract most beads to the iridocorneal angle, effectively reducing the number of beads floating in the anterior chamber avoiding contact with other structures (e.g., iris, lens). Lastly, the use of a handheld magnet allows flexibility when handling the small mouse eye to efficiently direct the magnetic microbeads and ensure that there is little reflux of the microbeads from the eye when the microneedle is withdrawn. In summary, the microbead occlusion mouse model presented here is a powerful investigative tool to study neurodegenerative changes that occur during the onset and progression of glaucoma. PMID:27077732

Protective Immunity in Mice Achieved with Dry Powder Formulation and Alternative Delivery of Plague F1-V Vaccine▿

PubMed Central

Huang, Joanne; D'Souza, Ajit J.; Alarcon, Jason B.; Mikszta, John A.; Ford, Brandi M.; Ferriter, Matthew S.; Evans, Michelle; Stewart, Todd; Amemiya, Kei; Ulrich, Robert G.; Sullivan, Vincent J.

2009-01-01

The potential use of Yersinia pestis as a bioterror agent is a great concern. Development of a stable powder vaccine against Y. pestis and administration of the vaccine by minimally invasive methods could provide an alternative to the traditional liquid formulation and intramuscular injection. We evaluated a spray-freeze-dried powder vaccine containing a recombinant F1-V fusion protein of Y. pestis for vaccination against plaque in a mouse model. Mice were immunized with reconstituted spray-freeze-dried F1-V powder via intramuscular injection, microneedle-based intradermal delivery, or noninvasive intranasal administration. By intramuscular injection, the reconstituted powder induced serum antibody responses and provided protection against lethal subcutaneous challenge with 1,000 50% lethal doses of Y. pestis at levels equivalent to those elicited by unprocessed liquid formulations (70 to 90% protection). The feasibility of intradermal and intranasal delivery of reconstituted powder F1-V vaccine was also demonstrated. Overall, microneedle-based intradermal delivery was shown to be similar in efficacy to intramuscular injection, while intranasal administration required an extra dose of vaccine to achieve similar protection. In addition, the results suggest that seroconversion against F1 may be a better predictor of protection against Y. pestis challenge than seroconversion against either F1-V or V. In summary, we demonstrate the preclinical feasibility of using a reconstituted powder F1-V formulation and microneedle-based intradermal delivery to provide protective immunity against plague in a mouse model. Intranasal delivery, while feasible, was less effective than injection in this study. The potential use of these alternative delivery methods and a powder vaccine formulation may result in substantial health and economic benefits. PMID:19261773

Protective immunity in mice achieved with dry powder formulation and alternative delivery of plague F1-V vaccine.

PubMed

Huang, Joanne; D'Souza, Ajit J; Alarcon, Jason B; Mikszta, John A; Ford, Brandi M; Ferriter, Matthew S; Evans, Michelle; Stewart, Todd; Amemiya, Kei; Ulrich, Robert G; Sullivan, Vincent J

2009-05-01

The potential use of Yersinia pestis as a bioterror agent is a great concern. Development of a stable powder vaccine against Y. pestis and administration of the vaccine by minimally invasive methods could provide an alternative to the traditional liquid formulation and intramuscular injection. We evaluated a spray-freeze-dried powder vaccine containing a recombinant F1-V fusion protein of Y. pestis for vaccination against plaque in a mouse model. Mice were immunized with reconstituted spray-freeze-dried F1-V powder via intramuscular injection, microneedle-based intradermal delivery, or noninvasive intranasal administration. By intramuscular injection, the reconstituted powder induced serum antibody responses and provided protection against lethal subcutaneous challenge with 1,000 50% lethal doses of Y. pestis at levels equivalent to those elicited by unprocessed liquid formulations (70 to 90% protection). The feasibility of intradermal and intranasal delivery of reconstituted powder F1-V vaccine was also demonstrated. Overall, microneedle-based intradermal delivery was shown to be similar in efficacy to intramuscular injection, while intranasal administration required an extra dose of vaccine to achieve similar protection. In addition, the results suggest that seroconversion against F1 may be a better predictor of protection against Y. pestis challenge than seroconversion against either F1-V or V. In summary, we demonstrate the preclinical feasibility of using a reconstituted powder F1-V formulation and microneedle-based intradermal delivery to provide protective immunity against plague in a mouse model. Intranasal delivery, while feasible, was less effective than injection in this study. The potential use of these alternative delivery methods and a powder vaccine formulation may result in substantial health and economic benefits.

Recent advances of controlled drug delivery using microfluidic platforms.

PubMed

Sanjay, Sharma T; Zhou, Wan; Dou, Maowei; Tavakoli, Hamed; Ma, Lei; Xu, Feng; Li, XiuJun

2018-03-15

Conventional systematically-administered drugs distribute evenly throughout the body, get degraded and excreted rapidly while crossing many biological barriers, leaving minimum amounts of the drugs at pathological sites. Controlled drug delivery aims to deliver drugs to the target sites at desired rates and time, thus enhancing the drug efficacy, pharmacokinetics, and bioavailability while maintaining minimal side effects. Due to a number of unique advantages of the recent microfluidic lab-on-a-chip technology, microfluidic lab-on-a-chip has provided unprecedented opportunities for controlled drug delivery. Drugs can be efficiently delivered to the target sites at desired rates in a well-controlled manner by microfluidic platforms via integration, implantation, localization, automation, and precise control of various microdevice parameters. These features accordingly make reproducible, on-demand, and tunable drug delivery become feasible. On-demand self-tuning dynamic drug delivery systems have shown great potential for personalized drug delivery. This review presents an overview of recent advances in controlled drug delivery using microfluidic platforms. The review first briefly introduces microfabrication techniques of microfluidic platforms, followed by detailed descriptions of numerous microfluidic drug delivery systems that have significantly advanced the field of controlled drug delivery. Those microfluidic systems can be separated into four major categories, namely drug carrier-free micro-reservoir-based drug delivery systems, highly integrated carrier-free microfluidic lab-on-a-chip systems, drug carrier-integrated microfluidic systems, and microneedles. Microneedles can be further categorized into five different types, i.e. solid, porous, hollow, coated, and biodegradable microneedles, for controlled transdermal drug delivery. At the end, we discuss current limitations and future prospects of microfluidic platforms for controlled drug delivery. Copyright © 2017 Elsevier B.V. All rights reserved.

Peri-tumor administration of 5-fluorouracil sol-gel using a hollow microneedle for treatment of gastric cancer.

PubMed

Jung, Yoon Suk; Koo, Dong-Hoe; Yang, Jeong-Yoon; Lee, Hee-Young; Park, Jung-Hwan; Park, Jung Ho

2018-11-01

The aim of this study was to investigate the effectiveness of treating gastric cancer by injecting a pluronic F-127 sol-gel formulation of 5-fluorouracil (5-FU) into normal tissue surrounding the tumor using a hollow microneedle. The MTS tetrazolium assay was performed to assess the cytotoxicity of 5-FU after application to gastric cancer cells at different concentrations for 1, 5 and 10 h. Gastric cancer cells were inoculated subcutaneously into 30 male nude mice (CrjBALB/c-nu/nu mice, male); the inoculated mouse were divided into three groups. One group received no treatment, whereas the two other groups received free 5-FU gel (40 mg/kg) and 5-FU gel (40 mg/kg) for 4 days, respectively. Mean tumor volume, apoptotic index (TUNEL) and proliferative index (Ki 67) were evaluated in all groups. Cell viability was 77.3% when 1.22 g of free 5-FU was administered, whereas cell viability was 37.4% and 43.5% when 0.122 g of free 5-FU was administered per hour for 10 h and 0.244 g of free 5-FU was administered for 5 h (p < .01). The 5-FU sol-gel induced apoptosis and significantly inhibited cell proliferation compared to the free 5-FU (p < .01). In addition, xenografted tumor growth was significantly suppressed by administration of the 5-FU sol-gel formulation to inoculated mice (p < .01), and 71% (5/7) of xenografted tumors disappeared after 4 weeks. In conclusion, peri-tumor injection of a 5-FU sol-gel formulation into normal tissue surrounding the tumor mass using a hollow microneedle is an effective method for treating gastric cancer.

Immunogenicity of diphtheria toxoid and poly(I:C) loaded cationic liposomes after hollow microneedle-mediated intradermal injection in mice.

PubMed

Du, Guangsheng; Leone, Mara; Romeijn, Stefan; Kersten, Gideon; Jiskoot, Wim; Bouwstra, Joke A

2018-06-02

In this study, we aimed to investigate the immunogenicity of cationic liposomes loaded with diphtheria toxoid (DT) and poly(I:C) after hollow microneedle-mediated intradermal vaccination in mice. The following liposomal formulations were studied: DT loaded liposomes, a mixture of free DT and poly(I:C)-loaded liposomes, a mixture of DT-loaded liposomes and free poly(I:C), and liposomal formulations with DT and poly(I:C) either individually or co-encapsulated in the liposomes. Reference groups were DT solution adjuvanted with or without poly(I:C) (DT/poly(I:C)). The liposomal formulations were characterized in terms of particle size, zeta potential, loading and release of DT and poly(I:C). After intradermal injection of BALB/c mice with the formulations through a hollow microneedle, the immunogenicity was assessed by DT-specific ELISAs. All formulations induced similar total IgG and IgG1 titers. However, all the liposomal groups containing both DT and poly(I:C) showed enhanced IgG2a titers compared to DT/poly(I:C) solution, indicating that the immune response was skewed towards a Th1 direction. This enhancement was similar for all liposomal groups that contain both DT and poly(I:C) in the formulations. Our results reveal that a mixture of DT encapsulated liposomes and poly(I:C) encapsulated liposomes have a similar effect on the antibody responses as DT and poly(I:C) co-encapsulated liposomes. These findings may have implications for future design of liposomal vaccine delivery systems. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Microsensor Technologies for Plant Growth System Monitoring

NASA Technical Reports Server (NTRS)

Kim, Chang-Soo

2004-01-01

This document covered the following: a) demonstration of feasibility of microsensor for tube and particulate growth systems; b) Dissolved oxygen; c)Wetness; d) Flexible microfluidic substrate with microfluidic channels and microsensor arrays; e)Dynamic root zone control/monitoring in microgravity; f)Rapid prototyping of phytoremediation; and g) A new tool for root physiology and pathology.

Integrated Arrays of Ion-Sensitive Electrodes

NASA Technical Reports Server (NTRS)

Buehler, Martin; Kuhlman, Kimberly

2003-01-01

The figure depicts an example of proposed compact water-quality sensors that would contain integrated arrays of ion-sensitive electrodes (ISEs). These sensors would serve as electronic "tongues": they would be placed in contact with water and used to "taste" selected dissolved ions (that is, they would be used to measure the concentrations of the ions). The selected ions could be any or all of a variety of organic and inorganic cations and anions that could be regarded as contaminants or analytes, depending on the specific application. In addition, some of the ISEs could be made sensitive to some neutral analytes

Major structural components in freshwater dissolved organic matter.

PubMed

Lam, Buuan; Baer, Andrew; Alaee, Mehran; Lefebvre, Brent; Moser, Arvin; Williams, Antony; Simpson, André J

2007-12-15

Dissolved organic matter (DOM) contains a complex array of chemical components that are intimately linked to many environmental processes, including the global carbon cycle, and the fate and transport of chemical pollutants. Despite its importance, fundamental aspects, such as the structural components in DOM remain elusive, due in part to the molecular complexity of the material. Here, we utilize multidimensional nuclear magnetic resonance spectroscopy to demonstrate the major structural components in Lake Ontario DOM. These include carboxyl-rich alicyclic molecules (CRAM), heteropolysaccharides, and aromatic compounds, which are consistent with components recently identified in marine dissolved organic matter. In addition, long-range proton-carbon correlations are obtained for DOM, which support the existence of material derived from linear terpenoids (MDLT). It is tentatively suggested that the bulk of freshwater dissolved organic matter is aliphatic in nature, with CRAM derived from cyclic terpenoids, and MDLT derived from linear terpenoids. This is in agreement with previous reports which indicate terpenoids as major precursors of DOM. At this time it is not clear in Lake Ontario whether these precursors are of terrestrial or aquatic origin or whether transformations proceed via biological and/ or photochemical processes.

Polymer multilayer tattooing for enhanced DNA vaccination

PubMed Central

DeMuth, Peter C.; Min, Younjin; Huang, Bonnie; Kramer, Joshua A.; Miller, Andrew D.; Barouch, Dan H.; Hammond, Paula T.; Irvine, Darrell J.

2014-01-01

DNA vaccines have many potential benefits but have failed to generate robust immune responses in humans. Recently, methods such as in vivo electroporation have demonstrated improved performance, but an optimal strategy for safe, reproducible, and pain-free DNA vaccination remains elusive. Here we report an approach for rapid implantation of vaccine-loaded polymer films carrying DNA, immune-stimulatory RNA, and biodegradable polycations into the immune-cell-rich epidermis, using microneedles coated with releasable polyelectrolyte multilayers. Films transferred into the skin following brief microneedle application promoted local transfection and controlled the persistence of DNA and adjuvants in the skin from days to weeks, with kinetics determined by the film composition. These “multilayer tattoo” DNA vaccines induced immune responses against a model HIV antigen comparable to electroporation in mice, enhanced memory T-cell generation, and elicited 140-fold higher gene expression in non-human primate skin than intradermal DNA injection, indicating the potential of this strategy for enhancing DNA vaccination. PMID:23353628

Intanza® 9 µg intradermal seasonal influenza vaccine for adults 18 to 59 years of age

PubMed Central

Leroux-Roels, Isabel; Weber, Françoise

2013-01-01

Seasonal influenza in healthy working-age adults accounts for a substantial part of the socioeconomic burden of this disease. Intanza® 9 μg (sanofi pasteur) is a microneedle-delivered intradermal trivalent inactivated influenza vaccine approved in 2009 for the prevention of seasonal influenza in adults 18 to 59 y of age. The microneedle system reliably and reproducibly delivers the vaccine to the dermis. Clinical studies show that Intanza 9 μg is as immunogenic and as well tolerated in working-age adults as a reference intramuscular trivalent inactivated vaccine. Local reactions to Intanza 9 μg, mainly erythema, are transient, mostly mild or moderate, and do not affect acceptability. Intanza 9 μg is considered satisfactory by at least 95% of both vaccinees and prescribers, especially because of the short needle and rapid administration. Because Intanza® 9 μg offers an alternative to intramuscular vaccines, it might help increase influenza vaccine coverage rates. PMID:23442585

Intradermal Vaccination With Adjuvanted Ebola Virus Soluble Glycoprotein Subunit Vaccine by Microneedle Patches Protects Mice Against Lethal Ebola Virus Challenge.

PubMed

Liu, Ying; Ye, Ling; Lin, Fang; Gomaa, Yasmine; Flyer, David; Carrion, Ricardo; Patterson, Jean L; Prausnitz, Mark R; Smith, Gale; Glenn, Gregory; Wu, Hua; Compans, Richard W; Yang, Chinglai

2018-06-08

In this study, we investigated immune responses induced by purified Ebola virus (EBOV) soluble glycoprotein (sGP) subunit vaccines via intradermal immunization with microneedle (MN) patches in comparison with intramuscular (IM) injection in mice. Our results showed that MN delivery of EBOV sGP was superior to IM injection in eliciting higher levels and longer lasting antibody responses against EBOV sGP and GP antigens. Moreover, sGP-specific immune responses induced by MN or IM immunizations were effectively augmented by formulating sGP with a saponin-based adjuvant, and they were shown to confer complete protection of mice against lethal mouse-adapted EBOV (MA-EBOV) challenge. In comparison, mice that received sGP without adjuvant by MN or IM immunizations succumbed to lethal MA-EBOV challenge. These results show that immunization with EBOV sGP subunit vaccines with adjuvant by MN patches, which have been shown to provide improved safety and thermal stability, is a promising approach to protect against EBOV infection.

Microneedles: A New Frontier in Nanomedicine Delivery.

PubMed

Larrañeta, Eneko; McCrudden, Maelíosa T C; Courtenay, Aaron J; Donnelly, Ryan F

2016-05-01

This review aims to concisely chart the development of two individual research fields, namely nanomedicines, with specific emphasis on nanoparticles (NP) and microparticles (MP), and microneedle (MN) technologies, which have, in the recent past, been exploited in combinatorial approaches for the efficient delivery of a variety of medicinal agents across the skin. This is an emerging and exciting area of pharmaceutical sciences research within the remit of transdermal drug delivery and as such will undoubtedly continue to grow with the emergence of new formulation and fabrication methodologies for particles and MN. Firstly, the fundamental aspects of skin architecture and structure are outlined, with particular reference to their influence on NP and MP penetration. Following on from this, a variety of different particles are described, as are the diverse range of MN modalities currently under development. The review concludes by highlighting some of the novel delivery systems which have been described in the literature exploiting these two approaches and directs the reader towards emerging uses for nanomedicines in combination with MN.

Intradermal vaccination using the novel microneedle device MicronJet600: Past, present, and future

PubMed Central

Levin, Yotam; Kochba, Efrat; Hung, Ivan; Kenney, Richard

2015-01-01

Intradermal immunization has become a forefront of vaccine improvement, both scientifically and commercially. Newer technologies are being developed to address the need to reduce the dose required for vaccination and to improve the reliability and ease of injection, which have been major hurdles in expanding the number of approved vaccines using this route of administration. In this review, 7 y of clinical experience with a novel intradermal delivery device, the MicronJet600, which is a registered hollow microneedle that simplifies the delivery of liquid vaccines, are summarized. This device has demonstrated both significant dose-sparing and superior immunogenicity in various vaccine categories, as well as in diverse subject populations and age groups. These studies have shown that intradermal delivery using this device is safe, effective, and preferred by the subjects. Comparison with other intradermal devices and potential new applications for intradermal delivery that could be pursued in the future are also discussed. PMID:25745830

Clinical evaluation of a novel microneedle device for intradermal delivery of an influenza vaccine: are all delivery methods the same?

PubMed

Levin, Yotam; Kochba, Efrat; Kenney, Richard

2014-07-23

The skin provides the largest immune barrier to infection and is a readily accessible site for vaccination, although intradermal (ID) injection can be challenging. The MicronJet™ microneedle is a novel device that consistently injects antigens very close to the skin's dendritic cells. A dose-sparing ID injection study was conducted in 280 healthy adult volunteers using trivalent virosomal adjuvanted influenza vaccine. ID injection of 3 μg using the MicronJet™ was well tolerated and showed a statistically higher geometric mean fold rise than the same dose ID using a conventional needle (Mantoux technique) for the H1N1 and B strains or a 15 μg intramuscular (IM) injection for the H3N2 strain. Thus, the immune response appears to partially depend on the delivery device and route of injection. The MicronJet™ may allow dose-sparing, yet give a superior response in influenza vaccination and warrants further clinical evaluation. Copyright © 2014 Elsevier Ltd. All rights reserved.

Parallel nanomanufacturing via electrohydrodynamic jetting from microfabricated externally-fed emitter arrays

NASA Astrophysics Data System (ADS)

Ponce de Leon, Philip J.; Hill, Frances A.; Heubel, Eric V.; Velásquez-García, Luis F.

2015-06-01

We report the design, fabrication, and characterization of planar arrays of externally-fed silicon electrospinning emitters for high-throughput generation of polymer nanofibers. Arrays with as many as 225 emitters and with emitter density as large as 100 emitters cm-2 were characterized using a solution of dissolved PEO in water and ethanol. Devices with emitter density as high as 25 emitters cm-2 deposit uniform imprints comprising fibers with diameters on the order of a few hundred nanometers. Mass flux rates as high as 417 g hr-1 m-2 were measured, i.e., four times the reported production rate of the leading commercial free-surface electrospinning sources. Throughput increases with increasing array size at constant emitter density, suggesting the design can be scaled up with no loss of productivity. Devices with emitter density equal to 100 emitters cm-2 fail to generate fibers but uniformly generate electrosprayed droplets. For the arrays tested, the largest measured mass flux resulted from arrays with larger emitter separation operating at larger bias voltages, indicating the strong influence of electrical field enhancement on the performance of the devices. Incorporation of a ground electrode surrounding the array tips helps equalize the emitter field enhancement across the array as well as control the spread of the imprints over larger distances.

Carbon Nanotube Purification

NASA Technical Reports Server (NTRS)

Delzeit, Lance D. (Inventor); Delzeit, Clement J. (Inventor)

2005-01-01

A method for cleaning or otherwise removing amorphous carbon and other residues that arise in growth of a carbon nanotube (CNT) array. The CNT array is exposed to a plurality of hydroxyls or hydrogen, produced from a selected vapor or liquid source such as H2O or H2O2. and the hydroxyls or hydrogen (neutral or electrically charged) react with the residues to produce partly or fully dissolved or hydrogenated or hydroxylizated products that can be removed or separated from the CNT array. The hydroxyls or hydrogen can be produced by heating the CNT array, residue and selected vapor or liquid source or by application of an electromagnetic excitation signal with a selected frequency or range of frequencies to dissociate the selected vapor or liquid. The excitation frequency can be chirped to cover a selected range of frequencies corresponding to dissociation of the selected vapor or liquid. Sonication may be uscd to supplement dissociation of the H2O and/or H2O2.

Development of replication-deficient adenovirus malaria vaccines.

PubMed

Hollingdale, Michael R; Sedegah, Martha; Limbach, Keith

2017-03-01

Malaria remains a major threat to endemic populations and travelers, including military personnel to these areas. A malaria vaccine is feasible, as radiation attenuated sporozoites induce nearly 100% efficacy. Areas covered: This review covers current malaria clinical trials using adenoviruses and pre-clinical research. Heterologous prime-boost regimens, including replication-deficient human adenovirus 5 (HuAd5) carrying malaria antigens, are efficacious. However, efficacy appears to be adversely affected by pre-existing anti-HuAd5 antibodies. Current strategies focus on replacing HuAd5 with rarer human adenoviruses or adenoviruses isolated from non-human primates (NHPs). The chimpanzee adenovirus ChAd63 is undergoing evaluation in clinical trials including infants in malaria-endemic areas. Key antigens have been identified and are being used alone, in combination, or with protein subunit vaccines. Gorilla adenoviruses carrying malaria antigens are also currently being evaluated in preclinical models. These replacement adenovirus vectors will be successfully used to develop vaccines against malaria, as well as other infectious diseases. Expert commentary: Simplified prime-boost single shot regimens, dry-coated live vector vaccines or silicon microneedle arrays could be developed for malaria or other vaccines. Replacement vectors with similar or superior immunogenicity have rapidly advanced, and several are now in extensive Phase 2 and beyond in malaria as well as other diseases, notably Ebola.

Dissolved oxygen sensing using organometallic dyes deposited within a microfluidic environment

NASA Astrophysics Data System (ADS)

Chen, Q. L.; Ho, H. P.; Jin, L.; Chu, B. W.-K.; Li, M. J.; Yam, V. W.-W.

2008-02-01

This work primarily aims to integrate dissolved oxygen sensing capability with a microfluidic platform containing arrays of micro bio-reactors or bio-activity indicators. The measurement of oxygen concentration is of significance for a variety of bio-related applications such as cell culture and gene expression. Optical oxygen sensors based on luminescence quenching are gaining much interest in light of their low power consumption, quick response and high analyte sensitivity in comparison to similar oxygen sensing devices. In our microfluidic oxygen sensor device, a thin layer of oxygen-sensitive luminescent organometallic dye is covalently bonded to a glass slide. Micro flow channels are formed on the glass slide using patterned PDMS (Polydimethylsiloxane). Dissolved oxygen sensing is then performed by directing an optical excitation probe beam to the area of interest within the microfluidic channel. The covalent bonding approach for sensor layer formation offers many distinct advantages over the physical entrapment method including minimizing dye leaching, ensuring good stability and fabrication simplicity. Experimental results confirm the feasibility of the device.

Immunotherapeutic effect of BCG-polysaccharide nucleic acid powder on Mycobacterium tuberculosis-infected mice using microneedle patches.

PubMed

Yan, Qinying; Liu, Houming; Cheng, Zhigang; Xue, Yun; Cheng, Zhide; Dai, Xuyong; Shan, Wanshui; Chen, Fan

2017-11-01

Polysaccharide nucleic acid fractions of bacillus Calmette-Guérin, termed BCG-PSN, have traditionally been used as immunomodulators in the treatment of dermatitis and allergic diseases. While the sales of injectable BCG-PSN have shown steady growth in recent years, no reports of using BCG-PSN powder or its immunotherapeutic effects exist. Here, BCG-PSN powder was applied directly to the skin to evaluate the immunotherapeutic effects on mice infected with Mycobacterium tuberculosis (MTB). In total, 34 μg of BCG-PSN powder could be loaded into a microneedle patch (MNP). Mice receiving BCG-PSN powder delivered via MNP exhibited significantly increased IFN-γ and TNF-α production in peripheral blood CD4 + T cells and improved pathological changes in their lungs and spleens compared to control group mice. The immunotherapeutic effect of BCG-PSN powder delivered via MNP was better than that delivered via intramuscular injection to some extent. Furthermore, MNPs eliminate the side effects of syringes, and this study demonstrated that BCG-PSN can be clinically administrated in powder form.

Microneedle-based drug delivery systems for transdermal route.

PubMed

Pierre, Maria Bernadete Riemma; Rossetti, Fabia Cristina

2014-03-01

Transdermal delivery offers an attractive, noninvasive administration route but it is limited by the skin's barrier to penetration. Minimally invasive techniques, such as the use of microneedles (MNs), bypass the stratum corneum (SC) barrier to permit the drug's direct access to the viable epidermis. These novel micro devices have been developed to puncture the skin for the transdermal delivery of hydrophilic drugs and macromolecules, including peptides, DNA and other molecules, that would otherwise have difficulty passing the outermost layer of the skin, the SC. Using the tools of the microelectronics industry, MNs have been fabricated with a range of sizes, shapes and materials. MNs have been shown to be robust enough to penetrate the skin and dramatically increase the skin permeability of several drugs. Moreover, MNs have reduced needle insertion pain and tissue trauma and provided controlled delivery across the skin. This review focuses on the current state of the art in the transdermal delivery of drugs using various types of MNs and developments in the field of microscale devices, as well as examples of their uses and clinical safety.

Development of blood extraction system designed by female mosquito's blood sampling mechanism for bio-MEMS

NASA Astrophysics Data System (ADS)

Tsuchiya, Kazuyoshi; Nakanishi, Naoyuki; Nakamachi, Eiji

2005-02-01

A compact and wearable wristwatch type Bio-MEMS such as a health monitoring system (HMS) to detect blood sugar level for diabetic patient, was newly developed. The HMS consists of (1) a indentation unit with a microneedle to generate the skin penetration force using a shape memory alloy(SMA) actuator, (2) a pumping unit using a bimorph PZT piezoelectric actuator to extract the blood and (3) a gold (Au) electrode as a biosensor immobilized GOx and attached to the gate electrode of MOSFET to detect the amount of Glucose in extracted blood. GOx was immobilized on a self assembled spacer combined with an Au electrode by the cross-link method using BSA as an additional bonding material. The device can extract blood in a few microliter through a painless microneedle with the negative pressure by deflection of the bimorph PZT piezoelectric actuator produced in the blood chamber, by the similar way the female mosquito extracts human blood with muscle motion to flex or relax. The performances of the liquid sampling ability of the pumping unit through a microneedle (3.8mm length, 100μm internal diameter) using the bimorph PZT piezoelectric microactuator were measured. The blood extraction micro device could extract human blood at the speed of 2μl/min, and it is enough volume to measure a glucose level, compared to the amount of commercial based glucose level monitor. The electrode embedded in the blood extraction device chamber could detect electrons generated by the hydrolysis of hydrogen peroxide produced by the reaction between GOx and glucose in a few microliter extracted blood, using the constant electric current measurement system of the MOSFET type hybrid biosensor. The output voltage for the glucose diluted in the chamber was increased lineally with increase of the glucose concentration.

Microneedle-based minimally-invasive measurement of puncture resistance and fracture toughness of sclera.

PubMed

Park, Seung Hyun; Lee, Kang Ju; Lee, JiYong; Yoon, Jae Hyoung; Jo, Dong Hyun; Kim, Jeong Hun; Kang, Keonwook; Ryu, WonHyoung

2016-10-15

The sclera provides the structural support of the eye and protects the intraocular contents. Since it covers a large portion of the eye surface and has relatively high permeability for most drugs, the sclera has been used as a major pathway for drug administration. Recently, microneedle (MN) technology has shown the possibility of highly local and minimally-invasive drug delivery to the eye by MN insertion through the sclera or the suprachoroidal space. Although ocular MN needs to be inserted through the sclera, there has been no systematic study to understand the mechanical properties of the sclera, which are important to design ocular MNs. In this study, we investigated a MN-based method to measure the puncture resistance and fracture toughness of the sclera. To reflect the conditions of MN insertion into the sclera, force-displacement curves obtained from MN-insertion tests were used to estimate the puncture resistance and fracture toughness of sclera tissue. To understand the effect of the insertion conditions, dependency of the mechanical properties on insertion speeds, pre-strain of the sclera, and MN sizes were analyzed and discussed. Measurement of mechanical property of soft biological tissue is challenging due to variations between tissue samples or lack of well-defined measurement techniques. Although non-invasive measurement techniques such as nano/micro indentation were employed to locally measure the elastic modulus of soft biological materials, mechanical properties such as puncture resistance or fracture toughness, which requires "invasive" measurement and is important for the application of "microneedles or hypodermic needles", has not been well studied. In this work, we report minimally-invasive measurement of puncture resistance and fracture toughness of sclera using a double MN insertion method. Parametric studies showed that use of MN proved to be advantageous because of minimally-invasive insertion into tissue as well as higher sensitivity to sub-tissue architecture during the measurement. Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Fabrication of gold dot, ring, and corpuscle arrays from block copolymer templates via a simple modification of surface energy

NASA Astrophysics Data System (ADS)

Cho, Heesook; Choi, Sinho; Kim, Jin Young; Park, Soojin

2011-12-01

We demonstrate a simple method for tuning the morphologies of as-spun micellar thin films by modifying the surface energy of silicon substrates. When a polystyrene-block-poly(2-vinylpyridine) (PS-b-P2VP) copolymer dissolved in o-xylene was spin-coated onto a PS-modified surface, a dimple-type structure consisting of a thick PS shell and P2VP core was obtained. Subsequently, when the films were immersed in metal precursor solutions at certain periods of time and followed by plasma treatment, metal individual dots in a ring-shaped structure, metal nanoring, and metal corpuscle arrays were fabricated, depending on the loading amount of metal precursors. In contrast, when PS-b-P2VP films cast onto silicon substrates with a native oxide were used as templates, only metal dotted arrays were obtained. The combination of micellar thin film and surface energy modification offers an effective way to fabricate various nanostructured metal or metal oxide films.We demonstrate a simple method for tuning the morphologies of as-spun micellar thin films by modifying the surface energy of silicon substrates. When a polystyrene-block-poly(2-vinylpyridine) (PS-b-P2VP) copolymer dissolved in o-xylene was spin-coated onto a PS-modified surface, a dimple-type structure consisting of a thick PS shell and P2VP core was obtained. Subsequently, when the films were immersed in metal precursor solutions at certain periods of time and followed by plasma treatment, metal individual dots in a ring-shaped structure, metal nanoring, and metal corpuscle arrays were fabricated, depending on the loading amount of metal precursors. In contrast, when PS-b-P2VP films cast onto silicon substrates with a native oxide were used as templates, only metal dotted arrays were obtained. The combination of micellar thin film and surface energy modification offers an effective way to fabricate various nanostructured metal or metal oxide films. Electronic supplementary information (ESI) available: AFM images of Au nanorings prepared from a mixed solvent and characterization of PS-b-P2VP micellar films. See DOI: 10.1039/c1nr11075f

Revealing the properties of oils from their dissolved hydrocarbon compounds in water with an integrated sensor array system.

PubMed

Qi, Xiubin; Crooke, Emma; Ross, Andrew; Bastow, Trevor P; Stalvies, Charlotte

2011-09-21

This paper presents a system and method developed to identify a source oil's characteristic properties by testing the oil's dissolved components in water. Through close examination of the oil dissolution process in water, we hypothesise that when oil is in contact with water, the resulting oil-water extract, a complex hydrocarbon mixture, carries the signature property information of the parent oil. If the dominating differences in compositions between such extracts of different oils can be identified, this information could guide the selection of various sensors, capable of capturing such chemical variations. When used as an array, such a sensor system can be used to determine parent oil information from the oil-water extract. To test this hypothesis, 22 oils' water extracts were prepared and selected dominant hydrocarbons analyzed with Gas Chromatography-Mass Spectrometry (GC-MS); the subsequent Principal Component Analysis (PCA) indicates that the major difference between the extract solutions is the relative concentration between the volatile mono-aromatics and fluorescent polyaromatics. An integrated sensor array system that is composed of 3 volatile hydrocarbon sensors and 2 polyaromatic hydrocarbon sensors was built accordingly to capture the major and subtle differences of these extracts. It was tested by exposure to a total of 110 water extract solutions diluted from the 22 extracts. The sensor response data collected from the testing were processed with two multivariate analysis tools to reveal information retained in the response patterns of the arrayed sensors: by conducting PCA, we were able to demonstrate the ability to qualitatively identify and distinguish different oil samples from their sensor array response patterns. When a supervised PCA, Linear Discriminate Analysis (LDA), was applied, even quantitative classification can be achieved: the multivariate model generated from the LDA achieved 89.7% of successful classification of the type of the oil samples. By grouping the samples based on the level of viscosity and density we were able to reveal the correlation between the oil extracts' sensor array responses and their original oils' feature properties. The equipment and method developed in this study have promising potential to be readily applied in field studies and marine surveys for oil exploration or oil spill monitoring.

Elucidating mechanisms of toxic action of dissolved organic chemicals in oil sands process-affected water (OSPW).

PubMed

Morandi, Garrett D; Wiseman, Steve B; Guan, Miao; Zhang, Xiaowei W; Martin, Jonathan W; Giesy, John P

2017-11-01

Oil sands process-affected water (OSPW) is generated during extraction of bitumen in the surface-mining oil sands industry in Alberta, Canada, and is acutely and chronically toxic to aquatic organisms. It is known that dissolved organic compounds in OSPW are responsible for most toxic effects, but knowledge of the specific mechanism(s) of toxicity, is limited. Using bioassay-based effects-directed analysis, the dissolved organic fraction of OSPW has previously been fractionated, ultimately producing refined samples of dissolved organic chemicals in OSPW, each with distinct chemical profiles. Using the Escherichia coli K-12 strain MG1655 gene reporter live cell array, the present study investigated relationships between toxic potencies of each fraction, expression of genes and characterization of chemicals in each of five acutely toxic and one non-toxic extract of OSPW derived by use of effects-directed analysis. Effects on expressions of genes related to response to oxidative stress, protein stress and DNA damage were indicative of exposure to acutely toxic extracts of OSPW. Additionally, six genes were uniquely responsive to acutely toxic extracts of OSPW. Evidence presented supports a role for sulphur- and nitrogen-containing chemical classes in the toxicity of extracts of OSPW. Copyright © 2017 Elsevier Ltd. All rights reserved.

Investigation of a fiber optic surface plasmon spectroscopy in conjunction with conductivity as an in situ method for simultaneously monitoring changes in dissolved organic carbon and salinity in coastal waters.

PubMed

Kim, Yoon-Chang; Cramer, Jeffrey A; Booksh, Karl S

2011-10-21

A combination surface plasmon resonance (SPR) and conductivity sensor array was developed and implemented to demonstrate the ability to differentiate among changes in dissolved organic carbon (DOC) and salinity in coastal water. The array is capable of achieving sufficient spatial and temporal data density to better understand the cycling and fate of terrestrial DOC in coastal areas. DOC is the second largest source of bioreactive carbon in the environment and plays a key role in mediating microbial activity and generation of atmospheric CO(2). In the coastal areas, the salinity is also an important property in many applications, such as leak detection for landfill liners, saltwater intrusion to drinking water, marine environment monitoring, and seasonal climate prediction. Conductivity sensors are the industry standard for determining salinity in ocean systems. However, both conductivity and refractive index sensors, such as SPR spectroscopy based sensors, respond to salinity and DOC levels. To demonstrate the capability of the SPR sensor and a conductivity sensor to collect complimentary data useful in discrimination of salinity and DOC in coastal zone water, conductivity, SPR, and temperature data were collected during passage from the Juan de Fuca ridge area returning to the University of Washington docks.

Methane concentrations in water wells unrelated to proximity to existing oil and gas wells in northeastern Pennsylvania.

PubMed

Siegel, Donald I; Azzolina, Nicholas A; Smith, Bert J; Perry, A Elizabeth; Bothun, Rikka L

2015-04-07

Recent studies in northeastern Pennsylvania report higher concentrations of dissolved methane in domestic water wells associated with proximity to nearby gas-producing wells [ Osborn et al. Proc. Natl. Acad. Sci. U. S. A. 2011 , 108 , 8172 ] and [ Jackson et al. Proc. Natl. Acad. Sci. U. S. A. , 2013 , 110 , 11250 ]. We test this possible association by using Chesapeake Energy's baseline data set of over 11,300 dissolved methane analyses from domestic water wells, densely arrayed in Bradford and nearby counties (Pennsylvania), and near 661 pre-existing oil and gas wells. The majority of these, 92%, were unconventional wells, drilled with horizontal legs and hydraulically fractured. Our data set is hundreds of times larger than data sets used in prior studies. In contrast to prior findings, we found no statistically significant relationship between dissolved methane concentrations in groundwater from domestic water wells and proximity to pre-existing oil or gas wells. Previous analyses used small sample sets compared to the population of domestic wells available, which may explain the difference in prior findings compared to ours.

Acute in vivo testing of a conformal polymer microelectrode array for multi-region hippocampal recordings

NASA Astrophysics Data System (ADS)

Xu, Huijing; Weltman Hirschberg, Ahuva; Scholten, Kee; Berger, Theodore William; Song, Dong; Meng, Ellis

2018-02-01

Objective. The success of a cortical prosthetic device relies upon its ability to attain resolvable spikes from many neurons in particular neural networks over long periods of time. Traditionally, lifetimes of neural recordings are greatly limited by the body’s immune response against the foreign implant which causes neuronal death and glial scarring. This immune reaction is posited to be exacerbated by micromotion between the implant, which is often rigid, and the surrounding, soft brain tissue, and attenuates the quality of recordings over time. Approach. In an attempt to minimize the foreign body response to a penetrating neural array that records from multiple brain regions, Parylene C, a flexible, biocompatible polymer was used as the substrate material for a functional, proof-of-concept neural array with a reduced elastic modulus. This probe array was designed and fabricated to have 64 electrodes positioned to match the anatomy of the rat hippocampus and allow for simultaneous recordings between two cell-body layers of interest. A dissolvable brace was used for deep-brain penetration of the flexible array. Main results. Arrays were electrochemically characterized at the benchtop, and a novel insertion technique that restricts acute insertion injury enabled accurate target placement of four, bare, flexible arrays to greater than 4 mm deep into the rat brain. Arrays were tested acutely and in vivo recordings taken intra-operatively reveal spikes in both targeted regions of the hippocampus with spike amplitudes and noise levels similar to those recorded with microwires. Histological staining of a sham array implanted for one month reveals limited astrocytic scarring and neuronal death around the implant. Significance. This work represents one of the first examples of a penetrating polymer probe array that records from individual neurons in structures that lie deep within the brain.

77 FR 50089 - Notice of Intent To Grant Exclusive License of the United States Patent No. 7,837,654 B2, Issued...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-20

... Delivery Device for Promoting Healing in Living Tissue AGENCY: Department of the Army, DoD. ACTION: Notice... & Engineering Center, Attn: RDMR-CST (Dr. J.R. Alexander), 5400 Fowler Road, Redstone Arsenal, Alabama 35898... claims a microneedle insertable in a target cell tissue, including a manipulative end maintained exterior...

DNA vaccination for cervical cancer; a novel technology platform of RALA mediated gene delivery via polymeric microneedles.

PubMed

Ali, Ahlam A; McCrudden, Cian M; McCaffrey, Joanne; McBride, John W; Cole, Grace; Dunne, Nicholas J; Robson, Tracy; Kissenpfennig, Adrien; Donnelly, Ryan F; McCarthy, Helen O

2017-04-01

HPV subtypes (16, 18) are associated with the development of cervical cancer, with oncoproteins E6 and E7 responsible for pathogenesis. The goal of this study was to evaluate our 'smart system' technology platform for DNA vaccination against cervical cancer. The vaccination platform brings together two main components; a peptide RALA which condenses DNA into cationic nanoparticles (NPs), and a polymeric polyvinylpyrrolidone (PVP) microneedle (MN) patch for cutaneous delivery of the loaded NPs. RALA condensed E6/E7 DNA into NPs not exceeding 100nm in diameter, and afforded the DNA protection from degradation in PVP. Sera from mice vaccinated with MN/RALA-E6/E7 were richer in E6/E7-specific IgGs, displayed a greater T-cell-mediated TC-1 cytotoxicity and contained more IFN-γ than sera from mice that received NPs intramuscularly. More importantly, MN/RALA-E6/E7 delayed TC-1 tumor initiation in a prophylactic model, and slowed tumor growth in a therapeutic model of vaccination, and was more potent than intramuscular vaccination. Copyright © 2016 Elsevier Inc. All rights reserved.

Rapid and repeatable fabrication of high A/R silk fibroin microneedles using thermally-drawn micromolds.

PubMed

Lee, JiYong; Park, Seung Hyun; Seo, Il Ho; Lee, Kang Ju; Ryu, WonHyoung

2015-08-01

Thermal drawing is a versatile rapid prototyping method that can freely form microneedle (MN) structures with ultra-high aspect ratio without relying on any complex and expensive process. However, it is still challenging to repeatedly produce MNs with identical shapes using this thermal drawing due to small fluctuations in processing conditions such as temperatures, drawing speeds, drawing heights, or parallelism in the drawing setup. In addition, thermal drawing is only applicable to thermoplastic materials and most natural biomaterials are incompatible with this method. Thus, we propose use of thermal drawing to fabricate master molds with high aspect ratios and replicate the shape by micromolding. In this work, high A/R MNs with various body profiles were fabricated by thermal drawing and replicated to silk fibroin (SF) MNs multiple times using micromolding. The original MN shape was precisely copied to the SF MNs. Methanol treatment enhanced the mechanical strength of SF MNs up to about 113% more depending on the treatment duration. We also demonstrated that methanol exposure time could effectively control drug release rates from SF MNs. Copyright © 2015 Elsevier B.V. All rights reserved.

Spreading of a Lidocaine Formulation on Microneedle-Treated Skin.

PubMed

Nayak, Atul; Das, Diganta B; Chao, Tzu C; Starov, Victor M

2015-12-01

The spreadability of a liquid drug formulation on skin is an indication of it either remaining stationary or distributing (spreading) as a droplet. Factors determining droplet spreadability of the formulation are spreading area, diameter of the droplet base, viscosity of the liquid, contact angle, volume of droplet on skin and any others. The creation of microcavities from the application of microneedle (MN) has the potential to control droplet spreading, and hence, target specific areas of skin for drug delivery. However, there is little work that demonstrates spreading of liquid drug formulation on MN-treated skin. Below, spreading of a lidocaine hydrogel formulation and lidocaine solution (reference liquid) on porcine skin is investigated over MN-treated skin. Controlled spreadability was achieved with the lidocaine hydrogel on MN-treated skin as compared with lidocaine solution. It was observed that the droplet spreading parameters such as spreading radius, droplet height and dynamic contact angle were slightly lower for the lidocaine hydrogel than the lidocaine solution on skin. Also, the lidocaine hydrogel on MN-treated skin resulted in slower dynamic reduction of droplet height, contact angle and reduced time taken in attaining static advancing droplets because of the MN microcavities. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

Torsional Rigidity of Single Actin Filaments and Actin-Actin Bond Breaking Force under Torsion Measured Directly by in vitro Micromanipulation

NASA Astrophysics Data System (ADS)

Tsuda, Yuri; Yasutake, Hironori; Ishijima, Akihiko; Yanagida, Toshio

1996-11-01

Knowledge of the elastic properties of actin filaments is crucial for considering its role in muscle contraction, cellular motile events, and formation of cell shape. The stiffness of actin filaments in the directions of stretching and bending has been determined. In this study, we have directly determined the torsional rigidity and breaking force of single actin filaments by measuring the rotational Brownian motion and tensile strength using optical tweezers and microneedles, respectively. Rotational angular fluctuations of filaments supplied the torsional rigidity as (8.0 ± 1.2) × 10-26 Nm2. This value is similar to that deduced from the longitudinal rigidity, assuming the actin filament to be a homogeneous rod. The breaking force of the actin-actin bond was measured while twisting a filament through various angles using microneedles. The breaking force decreased greatly under twist, e.g., from 600-320 pN when filaments were turned through 90 degrees, independent of the rotational direction. Our results indicate that an actin filament exhibits comparable flexibility in the rotational and longitudinal directions, but breaks more easily under torsional load.

Combination of microneedle radiofrequency (RF), fractional RF skin resurfacing and multi-source non-ablative skin tightening for minimal-downtime, full-face skin rejuvenation.

PubMed

Kaplan, Haim; Kaplan, Lilach

2016-12-01

In the recent years, there is a growth in demand for radiofrequency (RF)-based procedures to improve skin texture, laxity and contour. The new generation of systems allow non-invasive and fractional resurfacing treatments on one platform. The aim of this study was to evaluate the safety and efficacy of a new treatment protocol using a multisource RF, combining 3 different modalities in each patient: [1] non-ablative RF skin tightening, [2] fractional skin resurfacing, and [3] microneedling RF for non-ablative coagulation and collagen remodelling. 14 subjects were enrolled in this study using EndyMed PRO ™ platform. Each patient had 8 non-ablative treatments and 4 fractional treatments (fractional skin resurfacing and Intensif). The global aesthetic score was used to evaluate improvement. All patients had improvement in skin appearance. About 43% had excellent or very good improvement above 50%, 18% had good improvement between 25 and 50%, and the rest 39% had a mild improvement of < 25%. Downtime was minimal and no adverse effect was reported. Our data show significant improvement of skin texture, skin laxity and wrinkle reduction achieved using RF treatment platform.

The success of microneedle-mediated vaccine delivery into skin

PubMed Central

Marshall, Sarah; Sahm, Laura J.; Moore, Anne C.

2016-01-01

ABSTRACT Microneedles (MNs) are designed to specifically target the outermost, skin barrier layer, the stratum corneum, creating transient pathways for minimally invasive transcutaneous delivery. It is reported that MNs can facilitate delivery without stimulating the pain receptors or damaging blood vessels that lie beneath, thus being perceived as painless and associated with reduced bleeding. This immunocompetence of the skin, coupled with its ease of access, makes this organ an attractive vaccination site. The purpose of this review was to collate primary scientific literature pertaining to MN-mediated in vivo vaccination programmes. A total of 62 original research articles are presented, compiling vaccination strategies in 6 different models (mouse, rat, guinea pig, rabbit, pig, macaque and human). Vaccines tested span a wide range of viral, bacterial and protozoan pathogens and includes 7 of the 13 vaccine-preventable diseases, as defined by the WHO. This review highlights the paucity of available clinical trial data. MN-delivered vaccines have demonstrated safety and immunogenicity in pre-clinical models and boast desirable attributes such as painless administration, thermostability, dose-sparing capacity and the potential for self-administration. These advantages should contribute to enhanced global vaccine access. PMID:27050528

A Microneedle Patch for Measles and Rubella Vaccination Is Immunogenic and Protective in Infant Rhesus Macaques.

PubMed

Joyce, Jessica C; Carroll, Timothy D; Collins, Marcus L; Chen, Min-Hsin; Fritts, Linda; Dutra, Joseph C; Rourke, Tracy L; Goodson, James L; McChesney, Michael B; Prausnitz, Mark R; Rota, Paul A

2018-04-26

New methods to increase measles and rubella (MR) vaccination coverage are needed to achieve global and regional MR elimination goals. Here, we developed microneedle (MN) patches designed to administer MR vaccine by minimally trained personnel, leave no biohazardous sharps waste, remove the need for vaccine reconstitution, and provide thermostability outside the cold chain. This study evaluated the immunogenicity of MN patches delivering MR vaccine to infant rhesus macaques. Protective titers of measles neutralizing antibodies (>120 mIU/mL) were detected in 100% of macaques in the MN group and 75% of macaques in the subcutaneous (SC) injection group. Rubella neutralizing antibody titers were >10 IU/mL for all groups. All macaques in the MN group were protected from challenge with wild-type measles virus, whereas 75% were protected in the SC group. However, vaccination by the MN or SC route was unable to generate protective immune responses to measles in infant macaques pretreated with measles immunoglobulin to simulate maternal antibody. These results show, for the first time, that MR vaccine delivered by MN patch generated protective titers of neutralizing antibodies to both measles and rubella in infant rhesus macaques and afforded complete protection from measles virus challenge.

Preventative Vaccines for Zika Virus Outbreak: Preliminary Evaluation.

PubMed

Kim, Eun; Erdos, Geza; Huang, Shaohua; Kenniston, Thomas; Falo, Louis D; Gambotto, Andrea

2016-11-01

Since it emerged in Brazil in May 2015, the mosquito-borne Zika virus (ZIKV) has raised global concern due to its association with a significant rise in the number of infants born with microcephaly and neurological disorders such as Guillain-Barré syndrome. We developed prototype subunit and adenoviral-based Zika vaccines encoding the extracellular portion of the ZIKV envelope gene (E) fused to the T4 fibritin foldon trimerization domain (Efl). The subunit vaccine was delivered intradermally through carboxymethyl cellulose microneedle array (MNA). The immunogenicity of these two vaccines, named Ad5.ZIKV-Efl and ZIKV-rEfl, was tested in C57BL/6 mice. Prime/boost immunization regimen was associated with induction of a ZIKV-specific antibody response, which provided neutralizing immunity. Moreover, protection was evaluated in seven-day-old pups after virulent ZIKV intraperitoneal challenge. Pups born to mice immunized with Ad5.ZIKV-Efl were all protected against lethal challenge infection without weight loss or neurological signs, while pups born to dams immunized with MNA-ZIKV-rEfl were partially protected (50%). No protection was seen in pups born to phosphate buffered saline-immunized mice. This study illustrates the preliminary efficacy of the E ZIKV antigen vaccination in controlling ZIKV infectivity, providing a promising candidate vaccine and antigen format for the prevention of Zika virus disease. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Custom ceramic microchannel-cooled array for high-power fiber-coupled application

NASA Astrophysics Data System (ADS)

Junghans, Jeremy; Feeler, Ryan; Stephens, Ed

2018-03-01

A low-SWaP (Size, Weight and Power) diode array has been developed for a high-power fiber-coupled application. High efficiency ( 65%) diodes enable high optical powers while minimizing thermal losses. A large amount of waste heat is still generated and must be extracted. Custom ceramic microchannel-coolers (MCCs) are used to dissipate the waste heat. The custom ceramic MCC was designed to accommodate long cavity length diodes and micro-lenses. The coolers provide similar thermal performance as copper MCCs however they are not susceptible to erosion and can be cooled with standard filtered water. The custom ceramic micro-channel cooled array was designed to be a form/fit replacement for an existing copperbased solution. Each array consisted of three-vertically stacked MCCs with 4 mm CL, 976 nm diodes and beamshaping micro-optics. The erosion and corrosion resistance of ceramic array is intended to mitigate the risk of copperbased MCC corrosion failures. Elimination of the water delivery requirements (pH, resistivity and dissolved oxygen control) further reduces the system SWaP while maintaining reliability. The arrays were fabricated and fully characterized. This work discusses the advantages of the ceramic MCC technology and describes the design parameters that were tailored for the fiber-coupled application. Additional configuration options (form/fit, micro-lensing, alternate coolants, etc.) and on-going design improvements are also discussed.

Dissolvable Films of Silk Fibroin for Ultrathin Conformal Bio-integrated Electronics

DTIC Science & Technology

2010-01-01

spin- cast films of polyimide (PI) served as a support for arrays of electrodes designed for passive neural recording. Control devices consisted of...optically transparent, mechanically robust, biocompatible silk fibroin films. Adv. Mater. 20, 3070–3072 (2008). 20. Murphy, A. R., John, P. S. & Kaplan, D...induced colour change on periodically nanopatterned silk films. Opt. Express 17, 21271–21279 (2009). 25. Parker, S. T. et al. Biocompatible silk printed

Dissolvable Films of Silk Fibroin for Ultrathin Conformal Bio-Integrated Electronics

DTIC Science & Technology

2010-06-01

the systems described in the following, ultrathin, spin- cast films of polyimide (PI) served as a support for arrays of electrodes designed for...micropatterning of optically transparent, mechanically robust, biocompatible silk fibroin films. Adv. Mater. 20, 3070–3072 (2008). 20. Murphy, A. R., John, P. S...analysis of induced colour change on periodically nanopatterned silk films. Opt. Express 17, 21271–21279 (2009). 25. Parker, S. T. et al. Biocompatible

Real Time Assessment of Potable Water Quality in Distribution Network based on Low Cost Multi-Sensor Array

NASA Astrophysics Data System (ADS)

Bhardwaj, Jyotirmoy; Gupta, Karunesh K.; Khatri, Punit

2018-03-01

New concepts and techniques are replacing traditional methods of water quality parameters measurement systems. This paper proposed a new way of potable water quality assessment in distribution network using Multi Sensor Array (MSA). Extensive research suggests that following parameters i.e. pH, Dissolved Oxygen (D.O.), Conductivity, Oxygen Reduction Potential (ORP), Temperature and Salinity are most suitable to detect overall quality of potable water. Commonly MSA is not an integrated sensor array on some substrate, but rather comprises a set of individual sensors measuring simultaneously different water parameters all together. Based on research, a MSA has been developed followed by signal conditioning unit and finally, an algorithm for easy user interfacing. A dedicated part of this paper also discusses the platform design and significant results. The Objective of this proposed research is to provide simple, efficient, cost effective and socially acceptable means to detect and analyse water bodies regularly and automatically.

Long-term three-dimensional volumetric assessment of skin tightening using a sharply tapered non-insulated microneedle radiofrequency applicator with novel fractionated pulse mode in asians.

PubMed

Tanaka, Yohei

2015-10-01

Non-insulated microneedle radiofrequency (NIMNRF) is a novel method that allows non-thermal penetration of the epidermis followed by radiofrequency (RF) coagulation at selected depths of the dermis that are surrounded by a zone of non-coagulative volumetric heating. The objective of this study was to investigate subjectively and objectively the efficacy of a single fractional NIMNRF treatment. Twenty Japanese patients underwent full face skin tightening using a sharply tapered NIMNRF applicator with a novel fractionated pulse mode. The system platform (1MHZ) incorporated six independent phase controlled RF generators coupled to RF microneedles that induced skin remodeling via controlled dermal coagulation. Patients received from 500 to 1000 pulses that were 80-110 milliseconds in duration at a power of 10-14 W, and a 1.5-2.5 mm penetration depth. Topical anesthetic cream was applied before the treatment. Monthly three-dimensional (3-D) volumetric assessments were performed for 6 months after treatment. Patients rated their satisfaction using a 5-point scale. During the study patients showed significant skin tightening on the lower two-thirds of the face. Objective assessments with superimposed 3-D color images showed significant median volumetric reduction of 12.1 ml at 6 months post-treatment. Ninety percent of the patients were either "satisfied" or "very satisfied" with the treatment results. The treatments were well tolerated with minimal discomfort. Complications included a slight burning sensation and mild erythema that were minor and transitory; both resolved within 5 hours. Side effects such as post-inflammatory hyperpigmentation, epidermal burns, and scar formation were not observed. The advantages of this NIMNRF treatment for skin tightening are its long-lasting high efficacy as shown through 3-D volumetric assessments. Moreover, NIMNRF produced minimal complications and downtime as well as few side effects. This non-invasive novel fractional NIMNRF approach provides safe and effective treatment of skin tightening in Asian patients. © 2015 Wiley Periodicals, Inc.

PERFORMANCE EVALUATION OF AN AIR COUPLED PHASED ARRAY RADAR FOR NEAR FIELD DETECTION OF STEEL

DTIC Science & Technology

2015-04-24

sulfur dioxide reacts with the hydrated cement, the surface of the concrete starts to dissolve because it does not diffuse into concrete as quickly...Carbon dioxide begins to diffuse into the concrete and reacts with the hydrated cement to produce calcium carbonate. The presence of sulfur ...its design life. The health and state of the concrete roadways and bridge decks that commuters rely on a daily basis can be efficiently examined and

Measuring temporal variability in pore-fluid chemistry to assess gas hydrate stability: development of a continuous pore-fluid array.

PubMed

Lapham, Laura L; Chanton, Jeffrey P; Martens, Christopher S; Higley, Paul D; Jannasch, Hans W; Woolsey, J Robert

2008-10-01

A specialized pore-fluid array (PFA) sampler was designed to collect and store pore fluids to monitor temporal changes of ions and gases in gas hydrate bearing sediments. We tested the hypothesis that pore-fluid chemistry records hydrate formation or decomposition events and reflects local seismic activity. The PFA is a seafloor probe that consists of an interchangeable instrument package that houses OsmoSamplers, long-term pore-fluid samplers, a specialized low-dead volume fluid coupler, and eight sample ports along a 10 m sediment probe shaft. The PFA was deployed at Mississippi Canyon 118, a Gulf of Mexico hydrate site. A 170 day record was acquired from the overlying water and 1.3 m below seafloor (mbsf). Fluids were measured for dissolved chloride, sulfate, and methane concentrations and dissolved inorganic carbon and methane stable carbon and deuterium isotope ratios. Chloride and sulfate did not change significantly over time, suggesting the absence of gas hydrate formation or decomposition events. Over the temporal record, methane concentrations averaged 4 mM at 1.3 mbsf, and methane was thermogenic in origin (delta13C-CH4 = -32.4 +/- 3.4 per thousand). The timing of an anomalous 14 mM methane spike coincided with a nearby earthquake (Mw = 5.8), consistent with the hypothesis that pore-fluid chemistry reflects seismic events.

Remotely adjustable check-valves with an electrochemical release mechanism for implantable biomedical microsystems.

PubMed

Pan, Tingrui; Baldi, Antonio; Ziaie, Babak

2007-06-01

In this paper, we present two remotely adjustable check-valves with an electrochemical release mechanism for implantable biomedical microsystems. These valves allow one to vary the opening pressure set-point and flow resistance over a period of time. The first design consists of a micromachined check-valve array using a SU-8 polymer structural layer deposited on the top of a gold sacrificial layer. The second design is based on a variable length cantilever beam structure with a gold sacrificial layer. The adjustable cantilever-beam structure is fabricated by gold thermo-compression bond of a thin silicon wafer over a glass substrate. In both designs, the evaporated gold can be electrochemically dissolved using a constant DC current via a telemetry link. In the first design the dissolution simply opens up individual outlets, while in the second design, gold anchors are sequentially dissolved hence increasing the effective length of the cantilever beam (reducing the opening pressure). A current density of 35 mA/cm(2) is used to dissolve the gold sacrificial layers. Both gravity and syringe-pump driven flow are used to characterize the valve performance. A multi-stage fluidic performance (e.g. flow resistance and opening pressure) is clearly demonstrated.

Electrowetting-based adaptive vari-focal liquid lens array for 3D display

NASA Astrophysics Data System (ADS)

Won, Yong Hyub

2014-10-01

Electrowetting is a phenomenon that can control the surface tension of liquid when a voltage is applied. This paper introduces the fabrication method of liquid lens array by the electrowetting phenomenon. The fabricated 23 by 23 lens array has 1mm diameter size with 1.6 mm interval distance between adjacent lenses. The diopter of each lens was - 24~27 operated at 0V to 50V. The lens array chamber fabricated by Deep Reactive-Ion Etching (DRIE) is deposited with IZO and parylene C and tantalum oxide. To prevent water penetration and achieve high dielectric constant, parylene C and tantalum oxide (ɛ = 23 ~ 25) are used respectively. Hydrophobic surface which enables the range of contact angle from 60 to 160 degree is coated to maximize the effect of electrowetting causing wide band of dioptric power. Liquid is injected into each lens chamber by two different ways. First way was self water-oil dosing that uses cosolvent and diffusion effect, while the second way was micro-syringe by the hydrophobic surface properties. To complete the whole process of the lens array fabrication, underwater sealing was performed using UV adhesive that does not dissolve in water. The transient time for changing from concave to convex lens was measured <33ms (at frequency of 1kHz AC voltage.). The liquid lens array was tested unprecedentedly for integral imaging to achieve more advanced depth information of 3D image.

Transport generated by mayfly nymphs to breathe

NASA Astrophysics Data System (ADS)

Chabreyrie, Rodolphe; Abdelaziz, Khaled; Balaras, Elias; Kiger, Kenneth

2014-11-01

In order to maintain their metabolism, many species of mayfly nymphs utilize an oscillating array of wing-shaped gills to augment extraction of dissolved oxygen from the surrounding water. As a nymph develops, the kinematics of these gills have been observed to abruptly change from a rowing-like to a flapping-like motion. To better understand the role of this abrupt kinematic change, we study the transport of dissolved oxygen, viewed as a passive scalar surrounding the gills, for an in-silico mayfly nymph. In particular, through a Lagrangian and stochastic dynamical systems approach, we simulate the advection and diffusion of this passive scalar, and reveal the key structures of the transport generated by the gills for both flapping and rowing kinematics. In this talk, we show how the switch from rowing to flapping enables the generation of a better transport skeleton (i.e. breading of Lagrangian Coherent Structures) and how such a transport skeleton influences the oxygen uptake.

Review of applications of microneedling in dermatology

PubMed Central

Iriarte, Christopher; Awosika, Olabola; Rengifo-Pardo, Monica; Ehrlich, Alison

2017-01-01

Microneedling (MN) is a novel therapeutic modality in dermatology. Through physical trauma from needle penetration, MN induces a wound healing cascade with minimal damage to the epidermis. This allows for enhancement in the absorption of mainstay topical therapies across the thick stratum corneum. MN has become increasingly utilized over the last several years as it is a relatively simple procedure that is cost-effective, well tolerated, and offers both cosmetic and therapeutic benefits. The ability to treat localized areas of disease has led to numerous studies gauging its potential in focal diseases of inflammation, dyschromia, and photodamage. This review discusses the principles and evidence behind the expanding applications of MN. It has shown promising results as an adjuvant therapy for enhanced drug delivery in the treatment of atrophic scars, alopecia, actinic keratoses, and disorders of pigmentation such as melasma. The efficacy in treatment of vitiligo remains limited. Overall, the procedure has few adverse sequelae compared to other therapies, is highly efficacious, and is a viable resurfacing option for skin of color. Future research is needed to determine the frequency, interval, and specific device settings that foster optimal results. Additionally, large controlled trials are needed to shed light on the utility of MN as an evidence-based regimen for the treatment of various dermatologic conditions. PMID:28848356

Formulation to target delivery to the ciliary body and choroid via the suprachoroidal space of the eye using microneedles.

PubMed

Kim, Yoo Chun; Oh, Kyung Hee; Edelhauser, Henry F; Prausnitz, Mark R

2015-09-01

In this work, we tested the hypothesis that particles injected into the suprachoroidal space can be localized at the site of injection or broadly distributed throughout the suprachoroidal space by controlling polymeric formulation properties. Single hollow microneedles were inserted into the sclera of New Zealand White rabbits and injected non-biodegradable fluorescently tagged nanoparticles and microparticles suspended in polymeric formulations into the suprachoroidal space of the eye. When formulated in saline, the particles were distributed over 29-42% of the suprachoroidal space immediately after injection. To spread particles over larger areas of the choroidal surface, addition of hyaluronic acid to make moderately non-Newtonian solutions increased particle spread to up to 100% of the suprachoroidal space. To localize particles at the site of injection adjacent to the ciliary body, strongly non-Newtonian polymer solutions localized particles to 8.3-20% of the suprachoroidal space, which exhibited a small increase in area over the course of two months. This study demonstrates targeted particle delivery within the suprachoroidal space using polymer formulations that spread particles over the whole choroidal surface or localized them adjacent to the ciliary body after injection. Copyright © 2015 Elsevier B.V. All rights reserved.

Minimally invasive microneedles for ocular drug delivery.

PubMed

Thakur Singh, Raghu Raj; Tekko, Ismaiel; McAvoy, Kathryn; McMillan, Hannah; Jones, David; Donnelly, Ryan F

2017-04-01

Anterior and posterior segment eye diseases are highly challenging to treat, due to the barrier properties and relative inaccessibility of the ocular tissues. Topical eye drops and systemically delivered treatments result in low bioavailability. Alternatively, direct injection of medication into the ocular tissues is clinically employed to overcome the barrier properties, but injections cause significant tissue damage and are associated with a number of untoward side effects and poor patient compliance. Microneedles (MNs) has been recently introduced as a minimally invasive means for localizing drug formulation within the target ocular tissues with greater precision and accuracy than the hypodermic needles. Areas covered: This review article seeks to provide an overview of a range of challenges that are often faced to achieve efficient ocular drug levels within targeted tissue(s) of the eye. It also describes the problems encountered using conventional hypodermic needle-based ocular injections for anterior and posterior segment drug delivery. It discusses research carried out in the field of MNs, to date. Expert opinion: MNs can aid in localization of drug delivery systems within the selected ocular tissue. And, hold the potential to revolutionize the way drug formulations are administered to the eye. However, the current limitations and challenges of MNs application warrant further research in this field to enable its widespread clinical application.

Fluvastatin as a micropore lifetime enhancer for sustained delivery across microneedle-treated skin.

PubMed

Ghosh, Priyanka; Brogden, Nicole K; Stinchcomb, Audra L

2014-02-01

Microneedles (MNs), a physical skin permeation enhancement technique, facilitate drug delivery across the skin, thus enhancing the number of drugs that can be delivered transdermally in therapeutically relevant concentrations. The micropores created in the skin by MNs reseal because of normal healing processes of the skin, thus limiting the duration of the drug delivery window. Pore lifetime enhancement strategies can increase the effectiveness of MNs as a drug delivery mechanism by prolonging the delivery window. Fluvastatin (FLU), a HMGCoA reductase inhibitor, was used in this study to enhance the pore lifetime by inhibiting the synthesis of cholesterol, a major component of the stratum corneum lipids. The study showed that using FLU as a pretreatment it is possible to enhance the pore lifetime of MN-treated skin and thus allow for sustained drug delivery. The skin recovered within a 30-45-min time period following the removal of occlusion, and there was no significant irritation observed due to the treatment compared to the control sites. Thus, it can be concluded that localized skin treatment with FLU can be used to extend micropore lifetime and deliver drugs for up to 7 days across MN-treated skin. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Diclofenac delays micropore closure following microneedle treatment in human subjects.

PubMed

Brogden, Nicole K; Milewski, Mikolaj; Ghosh, Priyanka; Hardi, Lucia; Crofford, Leslie J; Stinchcomb, Audra L

2012-10-28

Drugs absorbed poorly through the skin are commonly delivered via injection with a hypodermic needle, which is painful and increases the risk of transmitting infectious diseases. Microneedles (MNs) selectively and painlessly permeabilize the outermost skin layer, allowing otherwise skin-impermeable drugs to cross the skin through micron-sized pores and reach therapeutic concentrations. However, rapid healing of the micropores prevents further drug delivery, blunting the clinical utility of this unique transdermal technique. We present the first human study demonstrating that micropore lifetime can be extended following MN treatment. Subjects received one-time MN treatment and daily topical application of diclofenac sodium. Micropore closure was measured with impedance spectroscopy, and area under the admittance-time curve (AUC) was calculated. AUC was significantly higher at MN+diclofenac sodium sites vs. placebo, suggesting slower rates of micropore healing. Colorimetry measurements confirmed the absence of local erythema and irritation. This mechanistic human proof-of-concept study demonstrates that micropore lifetime can be prolonged with simple topical administration of a non-specific cyclooxygenase inhibitor, suggesting the involvement of subclinical inflammation in micropore healing. These results will allow for longer patch wear time with MN-enhanced delivery, thus increasing patient compliance and expanding the transdermal field to a wider variety of clinical conditions. Copyright © 2012 Elsevier B.V. All rights reserved.

Development of in vivo impedance spectroscopy techniques for measurement of micropore formation following microneedle insertion.

PubMed

Brogden, Nicole K; Ghosh, Priyanka; Hardi, Lucia; Crofford, Leslie J; Stinchcomb, Audra L

2013-06-01

Microneedles (MNs) provide a minimally invasive means to enhance skin permeability by creating micron-scale channels (micropores) that provide a drug delivery pathway. Adequate formation of the micropores is critical to the success of this unique drug delivery technique. The objective of the current work was to develop sensitive and reproducible impedance spectroscopy techniques to monitor micropore formation in animal models and human subjects. Hairless guinea pigs, a Yucatan miniature pig, and human volunteers were treated with 100 MN insertions per site following an overnight prehydration period. Repeated measurements were made pre- and post-MN treatment using dry and gel Ag/AgCl electrodes applied with light verses direct pressure to hold the electrode to the skin surface. Impedance measurements dropped significantly post-MN application at all sites (p < 0.05, irrespective of electrode type or gel application), confirming micropore formation. In the Yucatan pig and human subjects, gel electrodes with direct pressure yielded the lowest variability (demonstrated by lower %relative standard deviation), whereas dry electrodes with direct pressure were superior in the guinea pigs. These studies confirm that impedance measurements are suitable for use in both clinical and animal research environments to monitor the formation of new micropores that will allow for drug delivery through the impermeable skin layers. Copyright © 2013 Wiley Periodicals, Inc.

Diclofenac delays micropore closure following microneedle treatment in human subjects

PubMed Central

Brogden, Nicole K.; Milewski, Mikolaj; Ghosh, Priyanka; Hardi, Lucia; Crofford, Leslie J.; Stinchcomb, Audra L.

2013-01-01

Drugs absorbed poorly through the skin are commonly delivered via injection with a hypodermic needle, which is painful and increases the risk of transmitting infectious diseases. Microneedles (MNs) selectively and painlessly permeabilize the outermost skin layer, allowing otherwise skin-impermeable drugs to cross the skin through micron-sized pores and reach therapeutic concentrations. However, rapid healing of the micropores prevents further drug delivery, blunting the clinical utility of this unique transdermal technique. We present the first human study demonstrating that micropore lifetime can be extended following MN treatment. Subjects received one-time MN treatment and daily topical application of diclofenac sodium. Micropore closure was measured with impedance spectroscopy, and area under the admittance–time curve (AUC) was calculated. AUC was significantly higher at MN + diclofenac sodium sites vs. placebo, suggesting slower rates of micropore healing. Colorimetry measurements confirmed the absence of local erythema and irritation. This mechanistic human proof-of-concept study demonstrates that micropore lifetime can be prolonged with simple topical administration of a non-specific cyclooxygenase inhibitor, suggesting the involvement of subclinical inflammation in micropore healing. These results will allow for longer patch wear time with MN-enhanced delivery, thus increasing patient compliance and expanding the transdermal field to a wider variety of clinical conditions. PMID:22929967

Mechanics of a mosquito bite with applications to microneedle design.

PubMed

Ramasubramanian, M K; Barham, O M; Swaminathan, V

2008-12-01

The mechanics of a fascicle insertion into the skin by a mosquito of the type aedes aegypti has been studied experimentally using high-speed video (HSV) imaging, and analytically using a mathematical model. The fascicle is a polymeric microneedle composed of a ductile material, chitin. It has been proposed that the mosquito applies a non-conservative follower force component in addition to the Euler compressive load in order to prevent buckling and penetrate the skin. In addition, the protective sheath surrounding the fascicle (labium) provides lateral support during insertion. The mechanics model presented approximates the fascicle as a slender column supported on an elastic foundation (labium) subjected to non-conservative (Beck) and conservative Euler loads simultaneously at the end. Results show that the lateral support of the fascicle provided by the labium is essential for successful penetration by increasing the critical buckling load by a factor of 5. The non-conservative follower force application increases the buckling load by an additional 20% and may or may not be necessary for successful penetration. Experimental results showing the importance of the labium have been cited to validate the model predictions, in addition to the video observations presented in this work. This understanding may be useful in designing painless needle insertion systems as opposed to miniaturized hypodermic needles.

Clinical study of a retinoic acid-loaded microneedle patch for seborrheic keratosis or senile lentigo.

PubMed

Hirobe, Sachiko; Otsuka, Risa; Iioka, Hiroshi; Quan, Ying-Shu; Kamiyama, Fumio; Asada, Hideo; Okada, Naoki; Nakagawa, Shinsaku

2017-01-01

Pigmented lesions such as of seborrheic keratosis and senile lentigo, which are commonly seen on skin of people>50years of age, are considered unattractive and disfiguring because of their negative psychological impact. Drug therapy using all-trans retinoic acid (ATRA) is an attractive option for self-treatment at home. We have developed an ATRA-loaded microneedle patch (ATRA-MN) and confirmed the pharmacological effects of ATRA-MN application in mice. Here, we describe a clinical study to evaluate the safety and efficacy of ATRA-MN in subjects with seborrheic keratosis or senile lentigo. ATRA-MN was applied to the lesion site of each subject for 6h once per week for 4weeks. The skin irritation reaction was scored to assess adverse reactions and blood tests were performed to evaluate the presence of systemic adverse reactions. To assess the treatment effect using ATRA-MN, the desquamation and whitening ability of the investigational skin was observed. Desquamation of the stratum corneum was observed following four ATRA-MN applications at 1-week intervals, but ATRA-MN applications did not induce severe local or systemic adverse effects. These results showed that ATRA-MN treatment is promising as a safe and effective therapy for seborrheic keratosis and senile lentigo. Copyright © 2016 Elsevier Inc. All rights reserved.

Assessment of treatment efficacy and sebosuppressive effect of fractional radiofrequency microneedle on acne vulgaris.

PubMed

Lee, Kyung Real; Lee, Eo Gin; Lee, Hee Jung; Yoon, Moon Soo

2013-12-01

A minimally invasive fractional radiofrequency microneedle (FRM) device has been used in skin rejuvenation and acne scars, and a recent pilot study demonstrated the positive therapeutic effect on acne. We evaluated the efficacy of FRM device for acne vulgaris in Asians and conducted objective measurement to assess its effect on sebum production. Twenty Korean patients with acne vulgaris received a single full-face FRM treatment. Outcome assessments included standardized photography, physician's global assessment, patient's satisfaction scores, acne lesion count, and objective measurements of casual sebum level (CSL) and sebum excretion rate (SER). They were evaluated at baseline and 2, 4, 8 weeks after the treatment. After a single FRM treatment, the CSL and the SER showed 30-60% and 70-80% reduction, respectively, at week 2 (P < 0.01), and remained below the baseline level until week 8. Physician's global improvement scores for acne severity and acne lesion count also revealed clinical improvement with maximum efficacy at week 2, but returned to the baseline in most patients by week 8. Patients' satisfaction scores (0-4) were above 2 on average, and adverse effects were minimal. This prospective study demonstrated the sebosuppressive effect from a single FRM treatment, but its therapeutic efficacy in acne requires further evaluation. © 2013 Wiley Periodicals, Inc.

Spontaneous oscillation of tension and sarcomere length in skeletal myofibrils. Microscopic measurement and analysis.

PubMed

Anazawa, T; Yasuda, K; Ishiwata, S

1992-05-01

We have devised a simple method for measuring tension development of single myofibrils by micromanipulation with a pair of glass micro-needles. The tension was estimated from the deflection of a flexible needle under an inverted phase-contrast microscope equipped with an image processor, so that the tension development is always accompanied by the shortening of the myofibril (auxotonic condition) in the present setup. The advantage of this method is that the measurement of tension (1/30 s for time resolution and about 0.05 micrograms for accuracy of tension measurement; 0.05 microns as a spatial resolution for displacement of the micro-needle) and the observation of sarcomere structure are possible at the same time, and the technique to hold myofibrils, even single myofibrils, is very simple. This method has been applied to study the tension development of glycerinated skeletal myofibrils under the condition where spontaneous oscillation of sarcomeres is induced, i.e., the coexistence of MgATP, MgADP and inorganic phosphate without free Ca2+. Under this condition, we found that the tension of myofibrils spontaneously oscillates accompanied by the oscillation of sarcomere length with a main period of a few seconds; the period was lengthened and shortened with stretch and release of myofibrils. A possible mechanism of the oscillation is discussed.

Microneedle-based drug delivery systems: Microfabrication, drug delivery, and safety

PubMed Central

Donnelly, Ryan F.; Raj Singh, Thakur Raghu; Woolfson, A. David

2010-01-01

Many promising therapeutic agents are limited by their inability to reach the systemic circulation, due to the excellent barrier properties of biological membranes, such as the stratum corneum (SC) of the skin or the sclera/cornea of the eye and others. The outermost layer of the skin, the SC, is the principal barrier to topically-applied medications. The intact SC thus provides the main barrier to exogenous substances, including drugs. Only drugs with very specific physicochemical properties (molecular weight < 500 Da, adequate lipophilicity, and low melting point) can be successfully administered transdermally. Transdermal delivery of hydrophilic drugs and macromolecular agents of interest, including peptides, DNA, and small interfering RNA is problematic. Therefore, facilitation of drug penetration through the SC may involve by-pass or reversible disruption of SC molecular architecture. Microneedles (MNs), when used to puncture skin, will by-pass the SC and create transient aqueous transport pathways of micron dimensions and enhance the transdermal permeability. These micropores are orders of magnitude larger than molecular dimensions, and, therefore, should readily permit the transport of hydrophilic macromolecules. Various strategies have been employed by many research groups and pharmaceutical companies worldwide, for the fabrication of MNs. This review details various types of MNs, fabrication methods and, importantly, investigations of clinical safety of MN. PMID:20297904

Effect of lipophilicity on microneedle-mediated iontophoretic transdermal delivery across human skin in vitro.

PubMed

Pawar, Kasturi R; Smith, Forrest; Kolli, Chandra Sekhar; Babu, R Jayachandra

2013-10-01

The effect of lipophilicity of drug on the microneedle (MN)-mediated iontophoretic delivery across dermatomed human skin was studied. Beta blockers with similar pKa but varied log P values were selected as model drugs in this study. Iontophoresis (ITP) or MNs, when used independently, increased the transdermal flux of beta blockers as compared with passive delivery (PD). ITP across the MN-treated skin (MN + ITP) increased the permeation rate of all beta blockers as compared with PD (p < 0.001). The enhancement ratios (ER) for hydrophilic molecules (atenolol and sotalol) were 71- and 78-fold higher for ITP + MN as compared with PD. However, for lipophilic molecule such as propranolol, there was 10-fold increase in the ER as compared with PD. These observations were further substantiated by the skin retention data; an inverse relationship between the skin retention and the hydrophilicity of the drug was observed. The results in the present study point out that the lipophilicity of the molecule plays a significant role on the electrically assisted transdermal delivery of drugs across the microporated skin. Using the combination of ITP + MN, hydrophilic drugs (atenolol and sotalol) were delivered at a much higher rate as compared with lipophilic molecules (propranolol and acebutolol). © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.

Habitat heterogeneity and associated microbial community structure in a small-scale floodplain hyporheic flow path.

PubMed

Lowell, Jennifer L; Gordon, Nathan; Engstrom, Dale; Stanford, Jack A; Holben, William E; Gannon, James E

2009-10-01

The Nyack floodplain is located on the Middle Fork of the Flathead River, an unregulated, pristine, fifth-order stream in Montana, USA, bordering Glacier National Park. The hyporheic zone is a nutritionally heterogeneous floodplain component harboring a diverse array of microbial assemblages essential in fluvial biogeochemical cycling, riverine ecosystem productivity, and trophic interactions. Despite these functions, microbial community structure in pristine hyporheic systems is not well characterized. The current study was designed to assess whether physical habitat heterogeneity within the hyporheic zone of the Nyack floodplain was sufficient to drive bacterial beta diversity between three different hyporheic flow path locations. Habitat heterogeneity was assessed by measuring soluble reactive phosphorous, nitrate, dissolved organic carbon, dissolved oxygen, and soluble total nitrogen levels seasonally at surface water infiltration, advection, and exfiltration zones. Significant spatial differences were detected in dissolved oxygen and nitrate levels, and seasonal differences were detected in dissolved oxygen, nitrate, and dissolved organic carbon levels. Denaturing gradient gel electrophoresis (DGGE) and cell counts indicated that bacterial diversity increased with abundance, and DGGE fingerprints covaried with nitrate levels where water infiltrated the hyporheic zone. The ribosomal gene phylogeny revealed that hyporheic habitat heterogeneity was sufficient to drive beta diversity between bacterial assemblages. Phylogenetic (P) tests detected sequence disparity between the flow path locations. Small distinct lineages of Firmicutes, Actinomycetes, Planctomycetes, and Acidobacteria defined the infiltration zone and alpha- and beta-proteobacterial lineages delineated the exfiltration and advection zone communities. These data suggest that spatial habitat heterogeneity drives hyporheic microbial community development and that attempts to understand functional differences between bacteria inhabiting nutritionally heterogeneous hyporheic environments might begin by focusing on the biology of these taxa.

Polymeric nanoparticles-based topical delivery systems for the treatment of dermatological diseases

PubMed Central

Zhang, Zheng; Tsai, Pei-Chin; Ramezanli, Tannaz; Michniak-Kohn, Bozena B.

2013-01-01

Human skin not only functions as a permeation barrier (mainly due to the stratum corneum layer), but also provides a unique delivery pathway for therapeutic and other active agents. These compounds penetrate via intercellular, intracellular and transappendageal routes, resulting in topical delivery (into skin strata) and transdermal delivery (to subcutaneous tissues and into the systemic circulation). Passive and active permeation enhancement methods have been widely applied to increase the cutaneous penetration. The pathology, pathogenesis and topical treatment approaches of dermatological diseases, such as psoriasis, contact dermatitis, and skin cancer, are then discussed. Recent literature has demonstrated that nanoparticles-based topical delivery systems can be successful in treating these skin conditions. The studies are reviewed starting with the nanoparticles based on natural polymers specially chitosan, followed by those made of synthetic, degradable (aliphatic polyesters) and non-degradable (polyarylates) polymers; emphasis is given to nanospheres made of polymers derived from naturally occurring metabolites, the tyrosine-derived nanospheres (TyroSpheres™). In summary, the nanoparticles-based topical delivery systems combine the advantages of both the nano-sized drug carriers and the topical approach, and are promising for the treatment of skin diseases. For the perspectives, the penetration of ultra-small nanoparticles (size smaller than 40 nm) into skin strata, the targeted delivery of the encapsulated drugs to hair follicle stem cells, and the combination of nanoparticles and microneedle array technologies for special applications such as vaccine delivery are discussed. PMID:23386536

Patient-controlled analgesia: therapeutic interventions using transdermal electro-activated and electro-modulated drug delivery.

PubMed

Indermun, Sunaina; Choonara, Yahya E; Kumar, Pradeep; Du Toit, Lisa C; Modi, Girish; Luttge, Regina; Pillay, Viness

2014-02-01

Chronic pain poses a major concern to modern medicine and is frequently undertreated, causing suffering and disability. Patient-controlled analgesia, although successful, does have limitations. Transdermal delivery is the pivot to which analgesic research in drug delivery has centralized, especially with the confines of needle phobias and associated pain related to traditional injections, and the existing limitations associated with oral drug delivery. Highlighted within is the possibility of further developing transdermal drug delivery for chronic pain treatment using iontophoresis-based microneedle array patches. A concerted effort was made to review critically all available therapies designed for the treatment of chronic pain. The drug delivery systems developed for this purpose and nondrug routes are elaborated on, in a systematic manner. Recent developments and future goals in transdermal delivery as a means to overcome the individual limitations of the aforementioned delivery routes are represented as well. The approval of patch-like devices that contain both the microelectronic-processing mechanism and the active medicament in a small portable device is still awaited by the pharmaceutical industry. This anticipated platform may provide transdermal electro-activated and electro-modulated drug delivery systems a feasible attempt in chronic pain treatment. Iontophoresis has been proven an effective mode used to administer ionized drugs in physiotherapeutic, diagnostic, and dermatological applications and may be an encouraging probability for the development of devices and aids in the treatment of chronic pain. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.

Flattened-Top Domical Water Drops Formed through Self-Organization of Hydrophobin Membranes: A Structural and Mechanistic Study Using Atomic Force Microscopy.

PubMed

Yamasaki, Ryota; Takatsuji, Yoshiyuki; Asakawa, Hitoshi; Fukuma, Takeshi; Haruyama, Tetsuya

2016-01-26

The Trichoderma reesei hydrophobin, HFBI, is a unique structural protein. This protein forms membranes by self-organization at air/water or water/solid interfaces. When HFBI forms a membrane at an air/water interface, the top of the water droplet is flattened. The mechanism underlying this phenomenon has not been explored. In this study, this unique phenomenon has been investigated. Self-organized HFBI membranes form a hexagonal structured membrane on the surface of water droplets; the structure was confirmed by atomic force microscopy (AFM) measurement. Assembled hexagons can form a planar sheet or a tube. Self-organized HFBI membranes on water droplets form a sheet with an array of hexagonal structures or a honeycomb structure. This membrane, with its arrayed hexagonal structures, has very high buckling strength. We hypothesized that the high buckling strength is the reason that water droplets containing HFBI form flattened domes. To test this hypothesis, the strength of the self-organized HFBI membranes was analyzed using AFM. The buckling strength of HFBI membranes was measured to be 66.9 mN/m. In contrast, the surface tension of water droplets containing dissolved HFBI is 42 mN/m. Thus, the buckling strength of a self-organized HFBI membrane is higher than the surface tension of water containing dissolved HFBI. This mechanistic study clarifies why the water droplets formed by self-organized HFBI membranes have a flattened top.

Characterising the material properties at the interface between skin and a skin vaccination microprojection device.

PubMed

Crichton, Michael L; Archer-Jones, Cameron; Meliga, Stefano; Edwards, Grant; Martin, Darren; Huang, Han; Kendall, Mark A F

2016-05-01

The rapid emergence of micro-devices for biomedical applications over the past two decades has introduced new challenges for the materials used in the devices. Devices like microneedles and the Nanopatch, require sufficient strength to puncture skin often with sharp-slender micro-scale profiles, while maintaining mechanical integrity. For these technologies we sought to address two important questions: 1) On the scale at which the device operates, what forces are required to puncture the skin? And 2) What loads can the projections/microneedles withstand prior to failure. First, we used custom fabricated nanoindentation micro-probes to puncture skin at the micrometre scale, and show that puncture forces are ∼0.25-1.75mN for fresh mouse skin, in agreement with finite element simulations for our device. Then, we used two methods to perform strength tests of Nanopatch projections with varied aspect ratios. The first method used a nanoindenter to apply a force directly on the top or on the side of individual silicon projections (110μm in length, 10μm base radius), to measure the force of fracture. Our second method used an Instron to fracture full rows of projections and characterise a range of projection designs (with the method verified against previous nanoindentation experiments). Finally, we used Cryo-Scanning Electron Microscopy to visualise projections in situ in the skin to confirm the behaviour we quantified, qualitatively. Micro-device development has proliferated in the past decade, including devices that interact with tissues for biomedical outcomes. The field of microneedles for vaccine delivery to skin has opened new material challenges both in understanding tissue material properties and device material. In this work we characterise both the biomaterial properties of skin and the material properties of our microprojection vaccine delivery device. This study directly measures the micro-scale puncture properties of skin, whilst demonstrating clearly how these relate to device design. This will be of strong interest to those in the field of biomedical microdevices. This includes work in the field of wearable and semi-implantable devices, which will require clear understanding of tissue behaviour and material characterisation. Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Chemical and spectroscopic characterization of dissolved humic substances in a mangrove-fringed estuary in the eastern coast of Hainan Island, China

NASA Astrophysics Data System (ADS)

Zhang, Yaoling; Du, Jinzhou; Peng, Bo; Zhang, Fenfen; Zhao, Xin; Zhang, Jing

2013-03-01

Mangrove-derived dissolved organic matter (DOM) has an important effect on estuarine and coastal area on a large scale. In order to improve the understanding of origin, composition, and fate of DOM in mangrove-fringed estuarine and coastal areas, dissolved humic substances (DHS) were isolated from one mangrove pore-water sample and one near-shore seawater sample downstream the mangrove pore-water site in the eastern coast of Hainan Island, South China. Fulvic acids, humic acids and XAD-4 fractions were obtained from the two water samples by using a two-column array of XAD-8 and XAD-4 resins. Chemical and spectroscopic methods were used to analyze the features of these DHS. Compared to the mangrove pore-water DHS, the near-shore seawater DHS were found rich in 13C with lower C/N ratios and more aliphatic compounds and carbohydrates, but less aromatic structures and carboxyl groups. As for the three fractions of the two DHS, XAD-4 fractions contain more aliphatics, carbohydrates, carboxyl groups, and enrich in 13C with respect to both fulvic and humic acids. Photo-oxidation transformation and contribution from marine-derived DOM were considered as the main reasons resulted in the difference in compositional features for these DHS in this study.

Enhanced photocatalytic activity of hydrogenated and vanadium doped TiO2 nanotube arrays grown by anodization of sputtered Ti layers

NASA Astrophysics Data System (ADS)

Motola, Martin; Satrapinskyy, Leonid; Čaplovicová, Mária; Roch, Tomáš; Gregor, Maroš; Grančič, Branislav; Greguš, Ján; Čaplovič, Ľubomír; Plesch, Gustav

2018-03-01

TiO2 nanotube (TiNT) arrays were grown on silicon substrate via electrochemical anodization of titanium films sputtered by magnetron. To improve the photocatalytic activity of arrays annealed in air (o-TiNT), doping of o-TiNT with vanadium was performed (o-V/TiNT). These non-doped and doped TiNT arrays were also hydrogenated in H2/Ar atmosphere to r-TiNT and r-V/TiNT samples, respectively. Investigation of composition and morphology by X-ray diffraction (XRD), electron microscopy (SEM and TEM) and X-ray photoelectron spectroscopy (XPS) showed the presence of well-ordered arrays of anatase nanotubes with average diameter and length of 100 nm and 1.3 μm, respectively. In both oxidized and reduced V-doped samples, vanadium is partly dissolved in the structure of anatase and partly deposited in form of oxide on the nanotube surface. Vanadium-doped and reduced samples exhibited higher rates in the photodegradation of organic dyes (compared to non-modified o-TiNT sample) and this is caused by limitation of electron-hole recombination rates and by shift of the energy gap into visible region. The photocatalytic activity was measured under UV, sunlight and visible irradiation, and the corresponding efficiency increased in the order (o-TiNT) < (r-TiNT) < (o-V/TiNT) < (r-V/TiNT). Under visible light, only r-TiNT and r-V/TiNT showed significant photocatalytic activity.

Intravitreal, Subretinal, and Suprachoroidal Injections: Evolution of Microneedles for Drug Delivery.

PubMed

Hartman, Rachel R; Kompella, Uday B

Even though the very thought of an injection into the eye may be frightening, an estimated 6 million intravitreal (IVT) injections were made in the USA during 2016. With the introduction of new therapeutic agents, this number is expected to increase. In addition, drug products that are injectable in ocular compartments other than the vitreous humor are expected to enter the back of the eye market in the not so distant future. Besides the IVT route, some of the most actively investigated routes of invasive administration to the eye include periocular, subretinal, and suprachoroidal (SC) routes. While clinical efficacy is the driving force behind new injectable drug product development for the eye, safety is also being improved with time. In the case of IVT injections, the procedural guidelines have evolved over the years to improve patient comfort and reduce injection-related injury and infection. Similar advances are anticipated for other routes of administration of injectable products to the eye. In addition to procedural improvements, the design of needles, particularly those with smaller diameters, length, and controlled bevel angles are expected to improve overall safety and acceptance of injected ophthalmic drug products. A key development in this area is the introduction of microneedles of a length less than a millimeter that can target the SC space. In the future, needles with smaller diameters and lengths, potentially approaching nanodimensions, are expected to revolutionize ophthalmic disease management.

Healing kinetics of microneedle-formed pores in PLGA films.

PubMed

Mazzara, J M; Balagna, M A; Thouless, M D; Schwendeman, S P

2013-10-28

The spontaneous healing of aqueous pores in poly(D,L-lactic-co-glycolic acid) (PLGA) drug delivery systems has been identified to play a key role in terminating the burst release of large molecules, and to provide a means for novel aqueous-based microencapsulation. To examine healing of PLGA, pores were created of defined size and depth on the surface of thin PLGA films by stamping with blunt-tip microneedles. Pore dimensions on the micron-scale were relevant to surface pores of common PLGA microspheres and could be easily monitored by light microscopy. Most pores healed reproducibly at temperatures above the glass-transition temperature (T(g)) of the films, with healing times decreasing sharply with increasing temperature according to Williams-Landel-Ferry (WLF) behavior. It is suggested that healing is driven by high surface tension in the films and occurs through viscoelastic creep. Hydrated films healed at lower temperatures than dry films, consistent with a drop in Tg upon polymer hydration. Larger pores took longer to heal than smaller ones, while pores larger than 20 μm did not heal before significant polymer degradation occurred. Films of a less hydrophobic PLGA showed slower healing kinetics, attributed to a weaker surface tension driving force. Deeper pores showed signs of in-plane stress from spin-coating, and either ruptured or only partially healed when incubated wet and dry, respectively. © 2013.

Bioremediation of chlorpyrifos contaminated soil by two phase bioslurry reactor: Processes evaluation and optimization by Taguchi's design of experimental (DOE) methodology.

PubMed

Pant, Apourv; Rai, J P N

2018-04-15

Two phase bioreactor was constructed, designed and developed to evaluate the chlorpyrifos remediation. Six biotic and abiotic factors (substrate-loading rate, slurry phase pH, slurry phase dissolved oxygen (DO), soil water ratio, temperature and soil micro flora load) were evaluated by design of experimental (DOE) methodology employing Taguchi's orthogonal array (OA). The selected six factors were considered at two levels L-8 array (2^7, 15 experiments) in the experimental design. The optimum operating conditions obtained from the methodology showed enhanced chlorpyrifos degradation from 283.86µg/g to 955.364µg/g by overall 70.34% of enhancement. In the present study, with the help of few well defined experimental parameters a mathematical model was constructed to understand the complex bioremediation process and optimize the approximate parameters upto great accuracy. Copyright © 2017 Elsevier Inc. All rights reserved.

Field emitter arrays and displays produced by ion tracking lithography

NASA Astrophysics Data System (ADS)

Felter, T. E.; Musket, R. G.; Bernhardt, A. F.

2005-12-01

When ions of sufficient electronic energy loss traverse a dielectric film or foil, they alter the chemical bonding along their nominally straight path within the material. A suitable etchant can quickly dissolve these so-called latent tracks leaving holes of small diameter (∼10 nm) but long length - several microns. Continuing the etching process gradually increases the diameter reproducibly and uniformly. The trackable medium can be applied as a uniform film onto large substrates. The small, monodisperse holes produced by this track etching can be used in conjunction with additional thin film processing to create functional structures attached to the substrate. For example, Lawrence Livermore National Laboratory and Candescent Technologies Corporation (CTC) co-developed a process to make arrays of gated field emitters (∼100 nm diameter electron guns) for CTC's Thin CRTTM displays, which have been fabricated to diagonal dimensions >13 in. Additional technological applications of ion tracking lithography will be briefly covered.

Selective labeling of retinal ganglion cells with calcium indicators by retrograde loading in vitro

PubMed Central

Behrend, Matthew R.; Ahuja, Ashish K.; Humayun, Mark S.; Weiland, James D.; Chow, Robert H.

2012-01-01

Here we present a retrograde loading technique that makes it possible for the first time to rapidly load a calcium indicator in the majority of retinal ganglion cells (RGCs) in salamander retina, and then to observe physiological activity of these dye-loaded cells. Dextran-conjugated calcium indicator, dissolved in water, was applied to the optic nerve stump. Following dye loading, the isolated retina was mounted on a microelectrode array to demonstrate that electrical activity and calcium activity were preserved, as the retina responded to electrical stimuli. PMID:19428523

Structurally Integrated Photoluminescent Chemical and Biological Sensors: An Organic Light-Emitting Diode-Based Platform

NASA Astrophysics Data System (ADS)

Shinar, J.; Shinar, R.

The chapter describes the development, advantages, challenges, and potential of an emerging, compact photoluminescence-based sensing platform for chemical and biological analytes, including multiple analytes. In this platform, the excitation source is an array of organic light-emitting device (OLED) pixels that is structurally integrated with the sensing component. Steps towards advanced integration with additionally a thin-film-based photodetector are also described. The performance of the OLED-based sensing platform is examined for gas-phase and dissolved oxygen, glucose, lactate, ethanol, hydrazine, and anthrax lethal factor.

Recent developments in OLED-based chemical and biological sensors

NASA Astrophysics Data System (ADS)

Shinar, Joseph; Zhou, Zhaoqun; Cai, Yuankun; Shinar, Ruth

2007-09-01

Recent developments in the structurally integrated OLED-based platform of luminescent chemical and biological sensors are reviewed. In this platform, an array of OLED pixels, which is structurally integrated with the sensing elements, is used as the photoluminescence (PL) excitation source. The structural integration is achieved by fabricating the OLED array and the sensing element on opposite sides of a common glass substrate or on two glass substrates that are attached back-to-back. As it does not require optical fibers, lens, or mirrors, it results in a uniquely simple, low-cost, and potentially rugged geometry. The recent developments on this platform include the following: (1) Enhancing the performance of gas-phase and dissolved oxygen sensors. This is achieved by (a) incorporating high-dielectric TiO II nanoparticles in the oxygen-sensitive Pt and Pd octaethylporphyrin (PtOEP and PdOEP, respectively)- doped polystyrene (PS) sensor films, and (b) embedding the oxygen-sensitive dyes in a matrix of polymer blends such as PS:polydimethylsiloxane (PDMS). (2) Developing sensor arrays for simultaneous detection of multiple serum analytes, including oxygen, glucose, lactate, and alcohol. The sensing element for each analyte consists of a PtOEP-doped PS oxygen sensor, and a solution containing the oxidase enzyme specific to the analyte. Each sensing element is coupled to two individually addressable OLED pixels and a Si photodiode photodetector (PD). (3) Enhancing the integration of the platform, whereby a PD array is also structurally integrated with the OLED array and sensing elements. This enhanced integration is achieved by fabricating an array of amorphous or nanocrystalline Si-based PDs, followed by fabrication of the OLED pixels in the gaps between these Si PDs.

Fabrication of high quality cDNA microarray using a small amount of cDNA.

PubMed

Park, Chan Hee; Jeong, Ha Jin; Jung, Jae Jun; Lee, Gui Yeon; Kim, Sang-Chul; Kim, Tae Soo; Yang, Sang Hwa; Chung, Hyun Cheol; Rha, Sun Young

2004-05-01

DNA microarray technology has become an essential part of biological research. It enables the genome-scale analysis of gene expression in various types of model systems. Manufacturing high quality cDNA microarrays of microdeposition type depends on some key factors including a printing device, spotting pins, glass slides, spotting solution, and humidity during spotting. UsingEthe Microgrid II TAS model printing device, this study defined the optimal conditions for producing high density, high quality cDNA microarrays with the least amount of cDNA product. It was observed that aminosilane-modified slides were superior to other types of surface modified-slides. A humidity of 30+/-3% in a closed environment and the overnight drying of the spotted slides gave the best conditions for arraying. In addition, the cDNA dissolved in 30% DMSO gave the optimal conditions for spotting compared to the 1X ArrayIt, 3X SSC and 50% DMSO. Lastly, cDNA in the concentration range of 100-300 ng/ micro l was determined to be best for arraying and post-processing. Currently, the printing system in this study yields reproducible 9000 spots with a spot size 150 mm diameter, and a 200 nm spot spacing.

Laser-induced capillary leakage for blood biomarker detection and vaccine delivery via the skin.

PubMed

Wu, Jeffrey H; Li, Bo; Wu, Mei X

2016-07-01

Circulation system is the center for coordination and communication of all organs in our body. Examination of any change in its analytes or delivery of therapeutic drugs into the system consists of important medical practice in today's medicine. Two recent studies prove that brief illumination of skin with a low powered laser, at wavelengths preferentially absorbed by hemoglobin, increases the amount of circulating biomarkers in the epidermis and upper dermis by more than 1,000-fold. When probe-coated microneedle arrays are applied into laser-treated skin, plasma blood biomarkers can be reliably, accurately, and sufficiently quantified in 15∼30 min assays, with a maximal detection in one hr in a manner independent of penetration depth or a molecular mass of the biomarker. Moreover, the laser treatment permits a high efficient delivery of radiation-attenuated malarial sporozoites (RAS) into the circulation, leading to robust immunity against malaria infections, whereas similar immunization at sham-treated skin elicits poor immune responses. Thus this technology can potentially instruct designs of small, portable devices for onsite, in mobile clinics, or at home for point-of-care diagnosis and drug/vaccine delivery via the skin. Laser-induced capillary leakage (a) to induce extravasation of circualing molecules only (b) or facilitate entry of attenuated malaria sporozoites into the capillary (c). Skin illumination with a laser preferably absorbed by hemoglobin causes dilation of the capillary beneath the skin. The extravasated molecules can be sufficiently measured in the skin or guide sporozoites to enter the vessel. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Evaluation of a Novel Glucose Area Under the Curve (AUC) Monitoring System: Comparison with the AUC by Continuous Glucose Monitoring

PubMed Central

Maegawa, Hiroshi; Morino, Katsutaro; Nishio, Yoshihiko; Sato, Toshiyuki; Okada, Seiki; Kikkawa, Yasuo; Watanabe, Toshihiro; Nakajima, Hiromu; Kashiwagi, Atsunori

2016-01-01

Background Management of postprandial hyperglycemia is a key aspect in diabetes treatment. We developed a novel system to measure glucose area under the curve (AUC) using minimally invasive interstitial fluid extraction technology (MIET) for simple monitoring of postprandial glucose excursions. In this study, we evaluated the relationship between our system and continuous glucose monitoring (CGM) by comparing glucose AUC obtained using MIET with that obtained using CGM for a long duration. Methods Twenty diabetic inpatients wearing a CGM system were enrolled. For MIET measurement, a plastic microneedle array was applied to the skin as pretreatment, and hydrogels were placed on the pretreated area to collect interstitial fluid. Hydrogels were replaced every 2 or 4 hours and AUC was predicted on the basis of glucose and sodium ion levels. Results AUC predicted by MIET correlated well with that measured by CGM (r=0.93). Good performances of both consecutive 2- and 4-hour measurements were observed (measurement error: 11.7%±10.2% for 2 hours and 11.1%±7.9% for 4 hours), indicating the possibility of repetitive measurements up to 8 hours. The influence of neither glucose fluctuation nor average glucose level over the measurement accuracy was observed through 8 hours. Conclusion Our system showed good relationship with AUC values from CGM up to 8 hours, indicating that single pretreatment can cover a large portion of glucose excursion in a day. These results indicated possibility of our system to contribute to convenient monitoring of glucose excursions for a long duration. PMID:27535643

Evaluation of a Novel Glucose Area Under the Curve (AUC) Monitoring System: Comparison with the AUC by Continuous Glucose Monitoring.

PubMed

Ugi, Satoshi; Maegawa, Hiroshi; Morino, Katsutaro; Nishio, Yoshihiko; Sato, Toshiyuki; Okada, Seiki; Kikkawa, Yasuo; Watanabe, Toshihiro; Nakajima, Hiromu; Kashiwagi, Atsunori

2016-08-01

Management of postprandial hyperglycemia is a key aspect in diabetes treatment. We developed a novel system to measure glucose area under the curve (AUC) using minimally invasive interstitial fluid extraction technology (MIET) for simple monitoring of postprandial glucose excursions. In this study, we evaluated the relationship between our system and continuous glucose monitoring (CGM) by comparing glucose AUC obtained using MIET with that obtained using CGM for a long duration. Twenty diabetic inpatients wearing a CGM system were enrolled. For MIET measurement, a plastic microneedle array was applied to the skin as pretreatment, and hydrogels were placed on the pretreated area to collect interstitial fluid. Hydrogels were replaced every 2 or 4 hours and AUC was predicted on the basis of glucose and sodium ion levels. AUC predicted by MIET correlated well with that measured by CGM (r=0.93). Good performances of both consecutive 2- and 4-hour measurements were observed (measurement error: 11.7%±10.2% for 2 hours and 11.1%±7.9% for 4 hours), indicating the possibility of repetitive measurements up to 8 hours. The influence of neither glucose fluctuation nor average glucose level over the measurement accuracy was observed through 8 hours. Our system showed good relationship with AUC values from CGM up to 8 hours, indicating that single pretreatment can cover a large portion of glucose excursion in a day. These results indicated possibility of our system to contribute to convenient monitoring of glucose excursions for a long duration.

An array of highly flexible electrodes with a tailored configuration locked by gelatin during implantation-initial evaluation in cortex cerebri of awake rats.

PubMed

Agorelius, Johan; Tsanakalis, Fotios; Friberg, Annika; Thorbergsson, Palmi T; Pettersson, Lina M E; Schouenborg, Jens

2015-01-01

A major challenge in the field of neural interfaces is to overcome the problem of poor stability of neuronal recordings, which impedes long-term studies of individual neurons in the brain. Conceivably, unstable recordings reflect relative movements between electrode and tissue. To address this challenge, we have developed a new ultra-flexible electrode array and evaluated its performance in awake non-restrained animals. An array of eight separated gold leads (4 × 10 μm), individually flexible in 3D, were cut from a gold sheet using laser milling and insulated with Parylene C. To provide structural support during implantation into rat cortex, the electrode array was embedded in a hard gelatin based material, which dissolves after implantation. Recordings were made during 3 weeks. At termination, the animals were perfused with fixative and frozen to prevent dislocation of the implanted electrodes. A thick slice of brain tissue, with the electrode array still in situ, was made transparent using methyl salicylate to evaluate the conformation of the implanted electrode array. Median noise levels and signal/noise remained relatively stable during the 3 week observation period; 4.3-5.9 μV and 2.8-4.2, respectively. The spike amplitudes were often quite stable within recording sessions and for 15% of recordings where single-units were identified, the highest-SNR unit had an amplitude higher than 150 μV. In addition, high correlations (>0.96) between unit waveforms recorded at different time points were obtained for 58% of the electrode sites. The structure of the electrode array was well preserved 3 weeks after implantation. A new implantable multichannel neural interface, comprising electrodes individually flexible in 3D that retain its architecture and functionality after implantation has been developed. Since the new neural interface design is adaptable, it offers a versatile tool to explore the function of various brain structures.

Microneedle-mediated transdermal bacteriophage delivery

PubMed Central

Ryan, Elizabeth; Garland, Martin J.; Singh, Thakur Raghu Raj; Bambury, Eoin; O’Dea, John; Migalska, Katarzyna; Gorman, Sean P.; McCarthy, Helen O.; Gilmore, Brendan F.; Donnelly, Ryan F.

2012-01-01

Interest in bacteriophages as therapeutic agents has recently been reawakened. Parenteral delivery is the most routinely-employed method of administration. However, injection of phages has numerous disadvantages, such as the requirement of a health professional for administration and the possibility of cross-contamination. Transdermal delivery offers one potential means of overcoming many of these problems. The present study utilized a novel poly (carbonate) (PC) hollow microneedle (MN) device for the transdermal delivery of Escherichia coli-specific T4 bacteriophages both in vitro and in vivo. MN successfully achieved bacteriophage delivery in vitro across dermatomed and full thickness skin. A concentration of 2.67 × 106 PFU/ml (plaque forming units per ml) was detected in the receiver compartment when delivered across dermatomed skin and 4.0 × 103 PFU/ml was detected in the receiver compartment when delivered across full thickness skin. An in vivo study resulted in 4.13 × 103 PFU/ml being detected in blood 30 min following initial MN-mediated phage administration. Clearance occurred rapidly, with phages being completely cleared from the systemic circulation within 24 h, which was expected in the absence of infection. We have shown here that MN-mediated delivery allows successful systemic phage absorption. Accordingly, bacteriophage-based therapeutics may now have an alternative route for systemic delivery. Once fully-investigated, this could lead to more widespread investigation of these interesting therapeutic viruses. PMID:22750416

Development of electrical conductivity measurement technology for key plant physiological information using microneedle sensor

NASA Astrophysics Data System (ADS)

Jeon, Eunyong; Choi, Seungyul; Yeo, Kyung-Hwan; Park, Kyoung Sub; Rathod, Mitesh L.; Lee, Junghoon

2017-08-01

Impedance measurement is a widely used technique for monitoring ion species in various applications. In plant cultivation, the impedance system is used to measure the electrical conductivity (EC) of nutrient solutions. Recent research has shown that the quality and quantity of horticultural crops, e.g. tomato, can be optimized by controlling the salinity of nutrient solutions. However, understanding the detailed response of a plant to a nutrient solution is not possible until the fruit is fully grown or by sacrificing the stem. To overcome this issue, horticultural crop cultivation requires real-time monitoring of the EC inside the stem. Using this data, the growth model of a plant could be constructed, and the response of the plant to external environment determined. In this paper, we propose an implantable microneedle device equipped with a micro-patterned impedance measurement system for direct measurement of the EC inside the tomato stem. The fabrication process includes silicon-based steps such as microscale deposition, photolithography, and a deep etching process. Further, microscale fabrication enables all functional elements to fulfill the area budget and be very accurate with minimal plant invasion. A two-electrode geometry is used to match the measurement condition of the tomato stem. Real-time measurement of local sap condition inside the plant in which real-time data for tomato sap EC is obtained after calibration at various concentrations of standard solution demonstrate the efficacy of the proposed device.

Demi-embryo production from hatching of zona-drilled bovine and rabbit blastocysts.

PubMed

Skrzyszowska, M; Smorag, Z; Katska, L

1997-09-01

It is known that the pregnancy rate resulting after transfer of bisected embryos is lower than after transfer of whole embryos. The main reason is the reduced cell number in the demi-embryo which is less than 1 2 of that in the intact embryo, since a number of blastomeres is damaged as a result of the procedure used in conventional embryo splitting. The aim of our experiment was to develop a non-invasive procedure which would limit cell losses during microsurgery. The experiment was carried out on bovine IVM-IVF embryos at middle, late and expanded blastocyst stage and rabbit embryos at late blastocyst stage cultured in vitro from in vivo produced zygotes. The zona pellucida of these embryos was drilled on the line between the inner cell mass and the trophoblast using a glass microneedle (

Microneedling combined with platelet-rich plasma or trichloroacetic acid peeling for management of acne scarring: A split-face clinical and histologic comparison.

PubMed

El-Domyati, Moetaz; Abdel-Wahab, Hossam; Hossam, Aliaa

2018-02-01

Minimally invasive procedures provide effective, safe, relatively long-lasting, and natural results without large damage to the skin. A combination treatment is considered an approach that includes at least 2 different and unrelated modalities. This study aims to evaluate the use and effectiveness of some combined minimally invasive procedures for management of acne scarring. Twenty-four volunteers with postacne atrophic scars were randomly divided into 3 equal groups according to performed procedure on each side of the face (microneedling by dermaroller alone or combined with platelet-rich plasma [PRP] or trichloroacetic acid [TCA] 15% peeling) and received 6 bi-weekly sessions of treatment. Photography and punch biopsies were taken before and after 3 months of treatment for clinical, histological, and histometrical evaluation. Combined treatment of dermaroller and PRP or dermaroller and TCA 15% showed significant improvement when compared with dermaroller alone (P = .015 and .011 respectively). Epidermal thickness showed statistically significant increase in studied groups, mainly after dermaroller and TCA 15%. Moreover, the 3 studied groups showed more organized collagen bundles and newly formed collagen formation and markedly decreased abnormal elastic fibers. Based on the clinical, histometrical, and histochemical assessment, inspite that most volunteers showed significant improvement after treatment, however, the combined use of dermaroller and TCA 15% was more effective in postacne atrophic scars than the use of dermaroller and PRP or dermaroller only. © 2017 Wiley Periodicals, Inc.

Porous polymer coatings on metal microneedles for enhanced drug delivery

NASA Astrophysics Data System (ADS)

Ullah, Asad; Kim, Chul Min; Kim, Gyu Man

2018-04-01

We present a simple method to coat microneedles (MNs) uniformly with a porous polymer (PLGA) that can deliver drugs at high rates. Stainless steel (SS) MNs of high mechanical strength were coated with a thin porous polymer layer to enhance their delivery rates. Additionally, to improve the interfacial adhesion between the polymer and MNs, the MN surface was modified by plasma treatment followed by dip coating with polyethyleneimine, a polymer with repeating amine units. The average failure load (the minimum force sufficient for detaching the polymer layer from the surface of SS) recorded for the modified surface coating was 25 N, whereas it was 2.2 N for the non-modified surface. Calcein dye was successfully delivered into porcine skin to a depth of 750 µm by the porous polymer-coated MNs, demonstrating that the developed MNs can pierce skin easily without deformation of MNs; additional skin penetration tests confirmed this finding. For visual comparison, rhodamine B dye was delivered using porous-coated and non-coated MNs in gelatin gel which showed that delivery with porous-coated MNs penetrate deeper when compared with non-coated MNs. Finally, lidocaine and rhodamine B dye were delivered in phosphate-buffered saline (PBS) medium by porous polymer-coated and non-coated MNs. For rhodamine B, drug delivery with the porous-coated MNs was five times higher than that with the non-coated MNs, whereas 25 times more lidocaine was delivered by the porous-coated MNs compared with the non-coated MNs.

An experimental study of microneedle-assisted microparticle delivery.

PubMed

Zhang, Dongwei; Das, Diganta B; Rielly, Chris D

2013-10-01

A set of well-defined experiments has been carried out to explore whether microneedles (MNs) can enhance the penetration depths of microparticles moving at high velocity such as those expected in gene guns for delivery of gene-loaded microparticles into target tissues. These experiments are based on applying solid MNs that are used to reduce the effect of mechanical barrier function of the target so as to allow delivery of microparticles at less imposed pressure as compared with most typical gene guns. Further, a low-cost material, namely, biomedical-grade stainless steel microparticle with size ranging between 1 and 20 μm, has been used in this study. The microparticles are compressed and bound in the form of a cylindrical pellet and mounted on a ground slide, which are then accelerated together by compressed air through a barrel. When the ground slide reaches the end of the barrel, the pellet is separated from the ground slide and is broken down into particle form by a mesh that is placed at the end of the barrel. Subsequently, these particles penetrate into the target. This paper investigates the implications of velocity of the pellet along with various other important factors that affect the particle delivery into the target. Our results suggest that the particle passage increases with an increase in pressure, mesh pore size, and decreases with increase in polyvinylpyrrolidone concentration. Most importantly, it is shown that MNs increase the penetration depths of the particles. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.

An HPLC-DAD and LC-MS study of condensation oscillations with S(+)-ketoprofen dissolved in acetonitrile.

PubMed

Sajewicz, Mieczysław; Gontarska, Monika; Kronenbach, Dorota; Berry, Etienne; Kowalska, Teresa

2012-03-01

In our earlier studies, a spontaneous chiral conversion of the selected low-molecular-weight carboxylic acids (i.e., amino acids, hydroxy acids, and profen drugs) dissolved in aqueous ethanol medium, running in vitro was described. Then it became clear that this spontaneous chiral conversion is accompanied by the spontaneous condensation of the discussed compounds. With several acids, it was established that this condensation is also oscillatory in nature. The theoretical models were developed aiming to give a rough explanation of the observed non-linear processes. In this paper, the results of these studies on the dynamics of condensation with S(+)-ketoprofen, a very popular profen drug, when stored for certain amount of time dissolved in a non-aqueous medium (i.e., acetonitrile) is presented. These investigations were carried out with the aid of two independent high-performance liquid chromatographic systems with the diode array detection and of a third high-performance liquid chromatographic system equipped with mass spectrometric detection. In one cycle of chromatographic measurements, it was possible to monitor condensation of S(+)-ketoprofen in 25-min intervals for 30 h, thus obtaining kinetic information on the progress of this process. Mass spectrometric detection confirmed the presence of new species in the stored solution with molecular weights much higher than that of S(+)-ketoprofen, which can be attributed to the condensation products. The obtained data show that condensation of S(+)-ketoprofen dissolved in acetonitrile progresses in a rapid manner, and that the observed oscillatory concentration changes with S(+)-ketoprofen and with the main condensation product characterize with an irregularity and shallow amplitudes. A theoretical model was referenced that jointly describes the oscillatory chiral conversion and the oscillatory condensation with the low-molecular-weight chiral carboxylic acids.

Distribution of Particles, Small Molecules and Polymeric Formulation Excipients in the Suprachoroidal Space after Microneedle Injection

PubMed Central

Chiang, Bryce; Venugopal, Nitin; Edelhauser, Henry F.; Prausnitz, Mark R.

2016-01-01

The purpose of this work was to determine the effect of injection volume, formulation composition, and time on circumferential spread of particles, small molecules and polymeric formulation excipients in the suprachoroidal space (SCS) after microneedle injection into New Zealand White rabbit eyes ex vivo and in vivo. Microneedle injections of 25–150 μL Hank’s Balanced Salt Solution (HBSS) containing 0.2 μm red-fluorescent particles and a model small molecule (fluorescein) were performed in rabbit eyes ex vivo, and visualized via flat mount. Particles with diameters of 0.02 – 2 μm were co-injected into SCS in vivo with fluorescein or a polymeric formulation excipient: fluorescein isothiocyanate (FITC)-labeled Discovisc or FITC-labeled carboxymethyl cellulose (CMC). Fluorescent fundus images were acquired over time to determine area of particle, fluorescein and polymeric formulation excipient spread, as well as their co-localization. We found that fluorescein covered a significantly larger area than co-injected particles when suspended in HBSS, and that this difference was present from 3 min post-injection onwards. We further showed that there was no difference in initial area covered by FITC-Discovisc and particles; the transport time (i.e., the time until the FITC-Discovisc and particle area began dissociating) was 2 d. There was also no difference in initial area covered by FITC-CMC and particles; the transport time in FITC-CMC was 4 d. We also found that particle size (20 nm – 2 μm) had no effect on spreading area when delivered in HBSS or Discovisc. We conclude that (i) the area of particle spread in SCS during injection generally increased with increasing injection volume, was unaffected by particle size and was significantly less than the area of fluorescein spread, (ii) particles suspended in low-viscosity HBSS formulation were entrapped in the SCS after injection, whereas fluorescein was not and (iii) particles co-injected with viscous polymeric formulation excipients co-localized near the site of injection in the SCS, continued to co-localize while spreading over larger areas for 2 – 4 days, and then no longer co-localized as the polymeric formulation excipients were cleared within 1 – 3 weeks and the particles remained largely in place. These data suggest that particles encounter greater barriers to flow in SCS compared to molecules and that co-localization of particles and polymeric formulation excipients allow spreading over larger areas of the SCS until the particles and excipients dissociate. PMID:27742547

Distribution of particles, small molecules and polymeric formulation excipients in the suprachoroidal space after microneedle injection.

PubMed

Chiang, Bryce; Venugopal, Nitin; Edelhauser, Henry F; Prausnitz, Mark R

2016-12-01

The purpose of this work was to determine the effect of injection volume, formulation composition, and time on circumferential spread of particles, small molecules, and polymeric formulation excipients in the suprachoroidal space (SCS) after microneedle injection into New Zealand White rabbit eyes ex vivo and in vivo. Microneedle injections of 25-150 μL Hank's Balanced Salt Solution (HBSS) containing 0.2 μm red-fluorescent particles and a model small molecule (fluorescein) were performed in rabbit eyes ex vivo, and visualized via flat mount. Particles with diameters of 0.02-2 μm were co-injected into SCS in vivo with fluorescein or a polymeric formulation excipient: fluorescein isothiocyanate (FITC)-labeled Discovisc or FITC-labeled carboxymethyl cellulose (CMC). Fluorescent fundus images were acquired over time to determine area of particle, fluorescein, and polymeric formulation excipient spread, as well as their co-localization. We found that fluorescein covered a significantly larger area than co-injected particles when suspended in HBSS, and that this difference was present from 3 min post-injection onwards. We further showed that there was no difference in initial area covered by FITC-Discovisc and particles; the transport time (i.e., the time until the FITC-Discovisc and particle area began dissociating) was 2 d. There was also no difference in initial area covered by FITC-CMC and particles; the transport time in FITC-CMC was 4 d. We also found that particle size (20 nm-2 μm) had no effect on spreading area when delivered in HBSS or Discovisc. We conclude that (i) the area of particle spread in SCS during injection generally increased with increasing injection volume, was unaffected by particle size, and was significantly less than the area of fluorescein spread, (ii) particles suspended in low-viscosity HBSS formulation were entrapped in the SCS after injection, whereas fluorescein was not and (iii) particles co-injected with viscous polymeric formulation excipients co-localized near the site of injection in the SCS, continued to co-localize while spreading over larger areas for 2-4 days, and then no longer co-localized as the polymeric formulation excipients were cleared within 1-3 weeks and the particles remained largely in place. These data suggest that particles encounter greater barriers to flow in SCS compared to molecules and that co-localization of particles and polymeric formulation excipients allows spreading over larger areas of the SCS until the particles and excipients dissociate. Copyright © 2016 Elsevier Ltd. All rights reserved.

Analysis of the Maillard reaction in human hair using Fourier transform infrared spectroscopic imaging and a focal-plane array detector.

PubMed

Jung, In-Keun; Park, Sang-Chul; Bin, Sung-Ah; Roh, Young Sup; Lee, John Hwan; Kim, Boo-Min

2016-03-01

The Maillard reaction has been well researched and used in the food industry and the fields of environmental science and organic chemistry. Here, we induced the Maillard reaction inside human hair and analyzed its effects by using Fourier transform infrared spectroscopy with a focal-plane array (FTIR-FPA) detector. We used arginine (A), glycine (G), and D-xylose (X) to generate the Maillard reaction by dissolving them in purified water and heating it to 150 °C. This label-free process generated a complex compound (named AGX after its ingredients) with a monomer structure, which was determined by using nuclear magnetic resonance (NMR) and FTIR-FPA. This compound was stable in hair and substantially increased its tensile strength. To our knowledge, we are the first to report the formation of this monomer in human hair, and our study provides insights into a new method that could be used to improve the condition of damaged or aging hair.

Interview with faz chowdhury.

PubMed

Chowdhury, Faz

2014-06-01

Faz Chowdhury is the Chief Executive Officer of Nemaura Pharma (Loughborough, UK), a pharmaceutical drug-delivery company developing patented formulation technologies alongside transdermal systems. Having originally trained as a pharmaceutical scientist, Dr Chowdhury received his PhD in Nanomedicine from the University of Oxford (Oxford, UK). With recognized expertise in the pharmaceutical industry and the holder of more than 15 patents on drug-delivery systems, Dr Chowdhury discussed the challenges faced in microneedle-based drug delivery, an area widely expected to revolutionize the transdermal field over the coming years. Interview conducted by James Potticary, Commissioning Editor.

Assay Methods for 238U, 232Th, and 210Pb in Lead and Calibration of 210Bi Bremsstrahlung Emission from Lead

DOE Office of Scientific and Technical Information (OSTI.GOV)

Orrell, John L.; Aalseth, Craig E.; Arnquist, Isaac J.

2016-02-13

Assay methods for measuring 238U, 232Th, and 210Pb concentrations in refined lead are presented. The 238U and 232Th concentrations are assayed via inductively coupled plasma mass spectrometry (ICP-MS) after anion exchange column separation on dissolved lead samples. The 210Pb concentration is inferred through α-spectroscopy of a daughter isotope, 210Po, after chemical precipitation separation on dissolved lead samples. Subsequent to the 210Po α-spectroscopy assay, a method for evaluating 210Pb concentrations in solid lead samples was developed via measurement of bremsstrahlung radiation from β-decay of a daughter isotope, 210Bi, by employing a 14-crystal array of high purity germanium (HPGe) detectors. Ten sourcesmore » of refined lead were assayed. The 238U concentrations were <34 microBq/kg and the 232Th concentrations ranged <0.6 – 15 microBq/kg, as determined by the ICP-MS assay method. The 210Pb concentrations ranged from ~0.1 – 75 Bq/kg, as inferred by the 210Po α-spectroscopy assay method.« less

Biogeochemical cycling and phyto- and bacterioplankton communities in a large and shallow tropical lagoon (Términos Lagoon, Mexico) under 2009-2010 El Niño Modoki drought conditions

NASA Astrophysics Data System (ADS)

Conan, Pascal; Pujo-Pay, Mireille; Agab, Marina; Calva-Benítez, Laura; Chifflet, Sandrine; Douillet, Pascal; Dussud, Claire; Fichez, Renaud; Grenz, Christian; Gutierrez Mendieta, Francisco; Origel-Moreno, Montserrat; Rodríguez-Blanco, Arturo; Sauret, Caroline; Severin, Tatiana; Tedetti, Marc; Torres Alvarado, Rocío; Ghiglione, Jean-François

2017-03-01

The 2009-2010 period was marked by an episode of intense drought known as the El Niño Modoki event. Sampling of the Términos Lagoon (Mexico) was carried out in November 2009 in order to understand the influence of these particular environmental conditions on organic matter fluxes within the lagoon's pelagic ecosystem and, more specifically, on the relationship between phyto- and bacterioplankton communities. The measurements presented here concern biogeochemical parameters (nutrients, dissolved and particulate organic matter [POM], and dissolved polycyclic aromatic hydrocarbons [PAHs]), phytoplankton (biomass and photosynthesis), and bacteria (diversity and abundance, including PAH degradation bacteria and ectoenzymatic activities). During the studied period, the water column of the Términos Lagoon functioned globally as a sink and, more precisely, as a nitrogen assimilator. This was due to the high production of particulate and dissolved organic matter (DOM), even though exportation of autochthonous matter to the Gulf of Mexico was weak. We found that bottom-up control accounted for a large portion of the variability of phytoplankton productivity. Nitrogen and phosphorus stoichiometry mostly accounted for the heterogeneity in phytoplankton and free-living prokaryote distribution in the lagoon. In the eastern part, we found a clear decoupling between areas enriched in dissolved inorganic nitrogen near the Puerto Real coastal inlet and areas enriched in phosphate (PO4) near the Candelaria estuary. Such a decoupling limited the potential for primary production, resulting in an accumulation of dissolved organic carbon and nitrogen (DOC and DON, respectively) near the river mouths. In the western part of the lagoon, maximal phytoplankton development resulted from bacterial activity transforming particulate organic phosphorus (PP) and dissolved organic phosphorus (DOP) to available PO4 and the coupling between Palizada River inputs of nitrate (NO3) and PP. The Chumpan River contributed only marginally to PO4 inputs due to its very low contribution to overall river inputs. The highest dissolved total PAH concentrations were measured in the El Carmen Inlet, suggesting that the anthropogenic pollution of the zone is probably related to the oil-platform exploitation activities in the shallow waters of the southern of the Gulf of Mexico. We also found that a complex array of biogeochemical and phytoplanktonic parameters were the driving force behind the geographical distribution of bacterial community structure and activities. Finally, we showed that nutrients brought by the Palizada River supported an abundant bacterial community of PAH degraders, which are of significance in this important oil-production zone.

Characterization of aquatic dissolved organic matter by asymmetrical flow field-flow fractionation coupled to UV-Visible diode array and excitation emission matrix fluorescence.

PubMed

Guéguen, Céline; Cuss, Chad W

2011-07-08

Flow field-flow fractionation (FlFFF) with on-line UV/Visible diode array detector (DAD) and excitation emission matrix (EEM) fluorescence detector has been developed for the characterization of optical properties of aquatic dissolved organic matter (DOM) collected in the Otonabee River (Ontario, Canada) and Athabasca River (Alberta, Canada). The molecular weight (MW) distribution of DOM was estimated using a series of organic macromolecules ranging from 479 to 66,000 Da. Both the number-average (M(n)) and weight-average (M(w)) molecular weights of Suwannee River fulvic acid (SRFA) and Suwannee River humic acid (SRHA) determined using these macromolecular standards were comparable to those obtained using polystyrenesulfonate (PSS) standards, suggesting that organic macromolecules can be used to estimate MW of natural organic colloids. The MW of eight river DOM samples determined by this method was found to have an M(n) range of 0.8-1.1 kDa, which agrees with available literature estimates. The FlFFF-DAD-EEM system provided insight into the MW components of river DOM including the optical properties by on-line absorbance and fluorescence measurement. A red-shift in emission and excitation wavelength maxima associated with lower spectral slope ratios (S(R)=S₂₇₅₋₂₉₅:S₃₅₀₋₄₀₀) was related to higher MW DOM. However, DOM of different origins at similar MW also showed significant difference in optical properties. A difference of 47 and 40 nm in excitation and emission peak C maxima was found. This supports the hypothesis that river DOM is not uniform in size and optical composition. Copyright © 2010 Elsevier B.V. All rights reserved.

Characterisation of dissolved organic matter in stormwater using high-performance size exclusion chromatography.

PubMed

Huang, Huiping; Chow, Christopher W K; Jin, Bo

2016-04-01

Understanding the complexity of dissolved organic matter (DOM) in stormwater has drawn a lot of interest, since DOM from stormwater causes not only environmental impacts, but also worsens downstream aquatic quality associated with water supply and treatability. This study introduced and employed high-performance size exclusion chromatography (HPSEC) coupled with an ultraviolet-visible (UV-vis) diode array detector to assess changes in stormwater-associated DOM characteristics. Stormwater DOM was also analysed in relation to storm event characteristics, water quality and spectroscopic analysis. Statistical tools were used to determine the correlations within DOM and water quality measurements. Results showed that dissolved organic carbon (DOC) and UV absorbance at 254 nm (UV254) as conventional DOM parameters were found to be correlated well to the changes in stormwater quality during each of the three storm events studied. Both detector wavelengths (210 and 254 nm) and their ratio (A210/A254) were found to provide additional information on the physiochemical properties of stormwater-associated DOM. This study indicated that A210/A254 is an important parameter which could be used to estimate the DOM proportions of functional groups and conjugated carbon species. This study provided also an understanding of stormwater quality constituents through assessing variability and sensitivity for various parameters, and the additional information of rainfall characteristics on runoff quality data for a better understanding of parameter correlations and influences. Copyright © 2015. Published by Elsevier B.V.

Lagrangian approach to understanding the origin of the gill-kinematics switch in mayfly nymphs.

PubMed

Chabreyrie, R; Balaras, E; Abdelaziz, K; Kiger, K

2014-12-01

The mayfly nymph breathes under water through an oscillating array of plate-shaped tracheal gills. As the nymph grows, the kinematics of these gills change abruptly from rowing to flapping. The classical fluid dynamics approach to consider the mayfly nymph as a pumping device fails in giving clear reasons for this switch. In order to shed some light on this switch between the two distinct kinematics, we analyze the problem under a Lagrangian viewpoint. We consider that a good Lagrangian transport that effectively distributes and stirs water and dissolved oxygen between and around the gills is the main goal of the gill motion. Using this Lagrangian approach, we are able to provide possible reasons behind the observed switch from rowing to flapping. More precisely, we conduct a series of in silico mayfly nymph experiments, where body shape, as well as gill shapes, structures, and kinematics are matched to those from in vivo. In this paper, we show both qualitatively and quantitatively how the change of kinematics enables better attraction, confinement, and stirring of water charged of dissolved oxygen inside the gills area. We reveal the attracting barriers to transport, i.e., attracting Lagrangian coherent structures, that form the transport skeleton between and around the gills. In addition, we quantify how well the fluid particles are stirred inside the gills area, which by extension leads us to conclude that it will increase the proneness of molecules of dissolved oxygen to be close enough to the gills for extraction.

One-Step Formation of WO3-Loaded TiO2 Nanotubes Composite Film for High Photocatalytic Performance

PubMed Central

Lee, Wai Hong; Lai, Chin Wei; Abd Hamid, Sharifah Bee

2015-01-01

High aspect ratio of WO3-loaded TiO2 nanotube arrays have been successfully synthesized using the electrochemical anodization method in an ethylene glycol electrolyte containing 0.5 wt% ammonium fluoride in a range of applied voltage of 10–40 V for 30 min. The novelty of this research works in the one-step formation of WO3-loaded TiO2 nanotube arrays composite film by using tungsten as the cathode material instead of the conventionally used platinum electrode. As compared with platinum, tungsten metal has lower stability, forming dissolved ions (W6+) in the electrolyte. The W6+ ions then move towards the titanium foil and form a coherent deposit on titanium foil. By controlling the oxidation rate and chemical dissolution rate of TiO2 during the electrochemical anodization, the nanotubular structure of TiO2 film could be achieved. In the present study, nanotube arrays were characterized using FESEM, EDAX, XRD, as well as Raman spectroscopy. Based on the results obtained, nanotube arrays with average pore diameter of up to 74 nm and length of 1.6 µm were produced. EDAX confirmed the presence of tungsten element within the nanotube arrays which varied in content from 1.06 at% to 3.29 at%. The photocatalytic activity of the nanotube arrays was then investigated using methyl orange degradation under TUV 96W UV-B Germicidal light irradiation. The nanotube with the highest aspect ratio, geometric surface area factor and at% of tungsten exhibited the highest photocatalytic activity due to more photo-induced electron-hole pairs generated by the larger surface area and because WO3 improves charge separation, reduces charge carrier recombination and increases charge carrier lifetime via accumulation of electrons and holes in the two different metal oxide semiconductor components.

Fractionated microneedle radiofrequency for treatment of primary axillary hyperhidrosis: A sham control study.

PubMed

Fatemi Naeini, Farahnaz; Abtahi-Naeini, Bahareh; Pourazizi, Mohsen; Nilforoushzadeh, Mohammad Ali; Mirmohammadkhani, Majid

2015-11-01

Primary axillary hyperhidrosis (PAH) creates social stress in patients. Although there are several options for treating PAH, only surgical modalities have conferred a permanent solution. This study evaluated the clinical effectiveness of fractionated microneedle radiofrequency (FMR) treatment for PAH. This study is based on a single-blind, sham control comparative design. In all, 25 patients with severe PAH underwent three sessions of FMR at 3-week intervals. One side was treated with FMR while the other was sham controlled. Efficacy was evaluated using the hyperhidrosis disease severity scale (HDSS), sweating intensity visual analogue scale (VAS) and patient satisfaction at baseline, 3 weeks after each session and at 3 months after the last. Skin biopsies were obtained from two enrolled patients. The HDSS and VAS demonstrated significant improvement after treatment on the treated side in comparison with the control side. The mean ± SD of the HDSS after 21 weeks were 1.87 ± 0.61 and 3.38 ± 0.49 (P < 0.001) for the treated and the controlled side, respectively. The follow-up evaluation revealed that 79% of the patients showed a 1 or 2-score decrease in HDSS. In total, 80% of patients reported more than 50% satisfaction at the end of the study. Histopathological findings showed a decrease of the number of the sweat glands in the treated side, confirming the above findings. Treatment of PAH with FMR as a non-invasive modality can be a safe option with positive therapeutic effects on HDSS without any long-lasting side effects. © 2014 The Australasian College of Dermatologists.

Comparison of fractional microneedling radiofrequency and bipolar radiofrequency on acne and acne scar and investigation of mechanism: comparative randomized controlled clinical trial.

PubMed

Min, Seonguk; Park, Seon Yong; Yoon, Ji Young; Suh, Dae Hun

2015-12-01

Fractional microneedling radiofrequency (FMR) is one of the promising methods in acne treatment. Moreover, bipolar radiofrequency (BR) generates heat thereby which induces neocollagenosis. FMR may have the potential to be a safe and effective treatment for the patients both with acne and acne scar. This study was performed to compare the efficacy and safety of FMR and BR in acne and acne scar treatment. Furthermore, mechanism of the FMR treatment was investigated through skin tissues obtained from subjects. Twenty subjects with mild-to-moderate acne and acne scars were treated in a split-face manner with FMR and BR. Two sessions of treatment was done 4 weeks apart in a total 12-week prospective single-blind, randomized clinical trial. Clinical assessment and sebum measurement were carried out for the evaluation of efficacy and safety. Skin tissues were acquired for investigation of molecular changes. FMR was more effective for acne scar especially in icepick and boxcar scar compared to BR. Both inflammatory and non-inflammatory acne lesions decreased by 80 and 65 % in the FMR-treated side at the final visit of 12 weeks, respectively. FMR treatment resulted in significant reduction of sebum excretion. Both treatments showed no severe adverse effects other than erythema. The FMR showed superior efficacy in acne and acne scar compared with BR. Increased expression of TGFβ and collagen I and decreased expression of NF-κB, IL-8 are suggested to involve in the improvement of acne scar and acne lesion by FMR.

Principles of the Kenzan Method for Robotic Cell Spheroid-Based Three-Dimensional Bioprinting^.

PubMed

Moldovan, Nicanor I; Hibino, Narutoshi; Nakayama, Koichi

2017-06-01

Bioprinting is a technology with the prospect to change the way many diseases are treated, by replacing the damaged tissues with live de novo created biosimilar constructs. However, after more than a decade of incubation and many proofs of concept, the field is still in its infancy. The current stagnation is the consequence of its early success: the first bioprinters, and most of those that followed, were modified versions of the three-dimensional printers used in additive manufacturing, redesigned for layer-by-layer dispersion of biomaterials. In all variants (inkjet, microextrusion, or laser assisted), this approach is material ("scaffold") dependent and energy intensive, making it hardly compatible with some of the intended biological applications. Instead, the future of bioprinting may benefit from the use of gentler scaffold-free bioassembling methods. A substantial body of evidence has accumulated, indicating this is possible by use of preformed cell spheroids, which have been assembled in cartilage, bone, and cardiac muscle-like constructs. However, a commercial instrument capable to directly and precisely "print" spheroids has not been available until the invention of the microneedles-based ("Kenzan") spheroid assembling and the launching in Japan of a bioprinter based on this method. This robotic platform laces spheroids into predesigned contiguous structures with micron-level precision, using stainless steel microneedles ("kenzans") as temporary support. These constructs are further cultivated until the spheroids fuse into cellular aggregates and synthesize their own extracellular matrix, thus attaining the needed structural organization and robustness. This novel technology opens wide opportunities for bioengineering of tissues and organs.

Development of portable health monitoring system for automatic self-blood glucose measurement

NASA Astrophysics Data System (ADS)

Kim, Huijun; Mizuno, Yoshihumi; Nakamachi, Eiji; Morita, Yusuke

2010-02-01

In this study, a new HMS (Health Monitoring System) device is developed for diabetic patient. This device mainly consists of I) 3D blood vessel searching unit and II) automatic blood glucose measurement (ABGM) unit. This device has features such as 1)3D blood vessel location search 2) laptop type, 3) puncturing a blood vessel by using a minimally invasive micro-needle, 4) very little blood sampling (10μl), and 5) automatic blood extraction and blood glucose measurement. In this study, ABGM unit is described in detail. It employs a syringe type's blood extraction mechanism because of its high accuracy. And it consists of the syringe component and the driving component. The syringe component consists of a syringe itself, a piston, a magnet, a ratchet and a micro-needle whose inner diameter is about 80μm. And the syringe component is disposable. The driving component consists of body parts, a linear stepping motor, a glucose enzyme sensor and a slider for accurate positioning control. The driving component has the all-in-one mechanism with a glucose enzyme sensor for compact size and stable blood transfer. On designing, required thrust force to drive the slider is designed to be greater than the value of the blood extraction force. Further, only one linear stepping motor is employed for blood extraction and transportation processes. The experimental result showed more than 80% of volume ratio under the piston speed 2.4mm/s. Further, the blood glucose was measured successfully by using the prototype unit. Finally, the availability of our ABGM unit was confirmed.

Workshop report: Nucleic acid delivery devices for HIV vaccines: Workshop proceedings, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA, May 21, 2015.

PubMed

Weniger, Bruce G; Anglin, Ian E; Tong, Tina; Pensiero, Michael; Pullen, Jeffrey K

2018-01-25

On May 21st, 2015, the U.S. National Institute of Allergy and Infectious Diseases (NIAID) convened a workshop on delivery devices for nucleic acid (NA) as vaccines in order to review the landscape of past and future technologies for administering NA (e.g., DNA, RNA, etc.) as antigen into target tissues of animal models and humans. Its focus was on current and future applications for preventing and treating human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS) disease, among other infectious-disease priorities. Meeting participants presented the results and experience of representative clinical trials of NA vaccines using a variety of alternative delivery devices, as well as a broader group of methods studied in animal models and at bench top, to improve upon the performance and/or avoid the drawbacks of conventional needle-syringe (N-S) delivery. The subjects described and discussed included (1) delivery targeted into oral, cutaneous/intradermal, nasal, upper and lower respiratory, and intramuscular tissues; (2) devices and techniques for jet injection, solid, hollow, and dissolving microneedles, patches for topical passive diffusion or iontophoresis, electroporation, thermal microporation, nasal sprayers, aerosol upper-respiratory and pulmonary inhalation, stratum-corneum ablation by ultrasound, chemicals, and mechanical abrasion, and kinetic/ballistic delivery; (3) antigens, adjuvants, and carriers such as DNA, messenger RNA, synthesized plasmids, chemokines, wet and dry aerosols, and pollen-grain and microparticle vectors; and (4) the clinical experience and humoral, cellular, and cytokine immune responses observed for many of these target tissues, technologies, constructs, and carriers. This report summarizes the presentations and discussions from the workshop (https://web.archive.org/web/20160228112310/https://www.blsmeetings.net/NucleicAcidDeliveryDevices/), which was webcast live in its entirety and archived online (http://videocast.nih.gov/summary.asp?live=16059). Copyright © 2018.

Galvanic Couple Current and Potential Distribution between a Mg Electrode and 2024-T351 under Droplets Analyzed by Microelectrode Arrays

DTIC Science & Technology

2015-11-04

cathodically to – 1.5 V vs. SCE in aearated NaCl solution dissolves at a rate as high as 4 mA/cm2. However, the same alloy was shown to avoid significant...MgRP coating could be utilized in place of the Mg electrode. It is well known that the wettability of the surface of aluminum and its oxides is high ...aluminum alloys , such as precipitation age hardened 2024-T351, and has performed well in field studies.1–13 The MgRP is designed to be applied to an

A computer program for calculating relative-transmissivity input arrays to aid model calibration

USGS Publications Warehouse

Weiss, Emanuel

1982-01-01

A program is documented that calculates a transmissivity distribution for input to a digital ground-water flow model. Factors that are taken into account in the calculation are: aquifer thickness, ground-water viscosity and its dependence on temperature and dissolved solids, and permeability and its dependence on overburden pressure. Other factors affecting ground-water flow are indicated. With small changes in the program code, leakance also could be calculated. The purpose of these calculations is to provide a physical basis for efficient calibration, and to extend rational transmissivity trends into areas where model calibration is insensitive to transmissivity values.

Comparison of Glucose Area Under the Curve Measured Using Minimally Invasive Interstitial Fluid Extraction Technology with Continuous Glucose Monitoring System in Diabetic Patients

PubMed Central

Uemura, Mei; Suzuki, Toshinari; Yasuma, Taro; Sato, Toshiyuki; Morimoto, Aya; Hosoya, Samiko; Suminaka, Chihiro; Nakajima, Hiromu; Gabazza, Esteban C.; Takei, Yoshiyuki

2017-01-01

Background Continuous glucose monitoring (CGM) is reported to be a useful technique, but difficult or inconvenient for some patients and institutions. We are developing a glucose area under the curve (AUC) monitoring system without blood sampling using a minimally invasive interstitial fluid extraction technology (MIET). Here we evaluated the accuracy of interstitial fluid glucose (IG) AUC measured by MIET in patients with diabetes for an extended time interval and the potency of detecting hyperglycemia using CGM data as a reference. Methods Thirty-eight inpatients with diabetes undergoing CGM were enrolled. MIET comprised a pretreatment step using a plastic microneedle array and glucose accumulation step with a hydrogel patch, which was placed on two sites from 9:00 AM to 5:00 PM or from 10:00 PM to 6:00 AM. IG AUC was calculated by accumulated glucose extracted by hydrogel patches using sodium ion as standard. Results A significant correlation was observed between the predicted AUC by MIET and CGM in daytime (r=0.76) and nighttime (r=0.82). The optimal cutoff for the IG AUC value of MIET to predict hyperglycemia over 200 mg/dL measured by CGM for 8 hours was 1,067.3 mg·hr/dL with 88.2% sensitivity and 81.5% specificity. Conclusion We showed that 8-hour IG AUC levels using MIET were valuable in estimating the blood glucose AUC without blood sampling. The results also supported the concept of using this technique for evaluating glucose excursion and for screening hyperglycemia during 8 hours in patients with diabetes at any time of day. PMID:28868824

Comparison of Glucose Area Under the Curve Measured Using Minimally Invasive Interstitial Fluid Extraction Technology with Continuous Glucose Monitoring System in Diabetic Patients.

PubMed

Uemura, Mei; Yano, Yutaka; Suzuki, Toshinari; Yasuma, Taro; Sato, Toshiyuki; Morimoto, Aya; Hosoya, Samiko; Suminaka, Chihiro; Nakajima, Hiromu; Gabazza, Esteban C; Takei, Yoshiyuki

2017-08-01

Continuous glucose monitoring (CGM) is reported to be a useful technique, but difficult or inconvenient for some patients and institutions. We are developing a glucose area under the curve (AUC) monitoring system without blood sampling using a minimally invasive interstitial fluid extraction technology (MIET). Here we evaluated the accuracy of interstitial fluid glucose (IG) AUC measured by MIET in patients with diabetes for an extended time interval and the potency of detecting hyperglycemia using CGM data as a reference. Thirty-eight inpatients with diabetes undergoing CGM were enrolled. MIET comprised a pretreatment step using a plastic microneedle array and glucose accumulation step with a hydrogel patch, which was placed on two sites from 9:00 AM to 5:00 PM or from 10:00 PM to 6:00 AM. IG AUC was calculated by accumulated glucose extracted by hydrogel patches using sodium ion as standard. A significant correlation was observed between the predicted AUC by MIET and CGM in daytime (r=0.76) and nighttime (r=0.82). The optimal cutoff for the IG AUC value of MIET to predict hyperglycemia over 200 mg/dL measured by CGM for 8 hours was 1,067.3 mg·hr/dL with 88.2% sensitivity and 81.5% specificity. We showed that 8-hour IG AUC levels using MIET were valuable in estimating the blood glucose AUC without blood sampling. The results also supported the concept of using this technique for evaluating glucose excursion and for screening hyperglycemia during 8 hours in patients with diabetes at any time of day. Copyright © 2017 Korean Diabetes Association

Evaluation of a minimally invasive system for measuring glucose area under the curve during oral glucose tolerance tests: usefulness of sweat monitoring for precise measurement.

PubMed

Sakaguchi, Kazuhiko; Hirota, Yushi; Hashimoto, Naoko; Ogawa, Wataru; Hamaguchi, Tomoya; Matsuo, Toshihiro; Miyagawa, Jun-ichiro; Namba, Mitsuyoshi; Sato, Toshiyuki; Okada, Seiki; Tomita, Koji; Matsuhisa, Munehide; Kaneto, Hideaki; Kosugi, Keisuke; Maegawa, Hiroshi; Nakajima, Hiromu; Kashiwagi, Atsunori

2013-05-01

We developed a system for measuring glucose area under the curve (AUC) using minimally invasive interstitial fluid extraction technology (MIET). Sweat contamination during interstitial fluid glucose (IG) extraction affects the accuracy of glucose AUC measurement, because this technology uses extracted sodium ion levels as an internal standard. Therefore, we developed a sweat monitoring patch to reduce this effect and investigated its efficacy in volunteers undergoing oral glucose tolerance tests (OGTTs). Fifty diabetes mellitus inpatients and 10 healthy subjects undergoing the 75 g OGTT were included. Two sites on the forearm were pretreated with microneedle arrays, then hydrogels for interstitial fluid extraction were placed on the treated sites. Simultaneously, hydrogels for sweat monitoring were placed on untreated sites near the treated sites. Plasma glucose (PG) levels were measured every 30 min for 2 h to calculate reference AUC values. Using MIET, IG AUC was calculated from extracted glucose and sodium ion levels after attachment of the hydrogel for 2 h. Good correlation between IG AUC measurements using MIET and reference AUCs measured using PG levels was confirmed over a wide AUC range (202-610 mg/h/dl) after correction for the sweat-induced error detected by the hydrogel patches on the nonpretreated skin. Strong correlation between IG AUC and peak glucose levels indicates that glucose spikes can be easily detected by this system. We confirmed the effectiveness of a sweat monitoring patch for precise AUC measurement using MIET. This novel, easy-to-use system has potential for glucose excursion evaluation in daily clinical practice. © 2013 Diabetes Technology Society.

A minimally invasive system for glucose area under the curve measurement using interstitial fluid extraction technology: evaluation of the accuracy and usefulness with oral glucose tolerance tests in subjects with and without diabetes.

PubMed

Sakaguchi, Kazuhiko; Hirota, Yushi; Hashimoto, Naoko; Ogawa, Wataru; Sato, Toshiyuki; Okada, Seiki; Hagino, Kei; Asakura, Yoshihiro; Kikkawa, Yasuo; Kojima, Junko; Maekawa, Yasunori; Nakajima, Hiromu

2012-06-01

Recent studies have highlighted the importance of managing postprandial hyperglycemia, but adequate monitoring of postprandial glucose remains difficult because of wide variations in levels. We have therefore developed a minimally invasive system to monitor postprandial glucose area under the curve (AUC). This system involves no blood sampling and uses interstitial fluid glucose (IG) AUC (IG-AUC) as a surrogate marker of postprandial glucose. This study aimed to evaluate the usefulness of this system by comparing data with the findings of oral glucose tolerance tests (OGTTs) in subjects with and without diabetes. The glucose AUC monitoring system was validated by OGTTs in 37 subjects with and 10 subjects without diabetes. A plastic microneedle array was stamped on the forearm to extract IG. A hydrogel patch was then placed on the pretreated area to accumulate IG. Glucose and sodium ion concentrations in the hydrogel were measured to calculate IG-AUC at 2-h postload glucose. Plasma glucose (PG) levels were measured every 30 min to calculate reference PG-AUC. IG-AUC correlated strongly with reference PG-AUC (r=0.93) over a wide range. The level of correlation between IG-AUC and maximum PG level was also high (r=0.86). The painless nature of the technique was confirmed by the response of patients to questionnaires. The glucose AUC monitoring system using IG provided good estimates of reference PG-AUC and maximum PG level during OGTTs in subjects with and without diabetes. This system provides easy-to-use monitoring of glucose AUC, which is a good indicator of postprandial glucose.

Evaluation of a Minimally Invasive System for Measuring Glucose Area under the Curve during Oral Glucose Tolerance Tests: Usefulness of Sweat Monitoring for Precise Measurement

PubMed Central

Sakaguchi, Kazuhiko; Hirota, Yushi; Hashimoto, Naoko; Ogawa, Wataru; Hamaguchi, Tomoya; Toshihiro, Matsuo; Miyagawa, Jun-ichiro; Namba, Mitsuyoshi; Sato, Toshiyuki; Okada, Seiki; Tomita, Koji; Matsuhisa, Munehide; Kaneto, Hideaki; Kosugi, Keisuke; Maegawa, Hiroshi; Nakajima, Hiromu; Kashiwagi, Atsunori

2013-01-01

Aims: We developed a system for measuring glucose area under the curve (AUC) using minimally invasive interstitial fluid extraction technology (MIET). Sweat contamination during interstitial fluid glucose (IG) extraction affects the accuracy of glucose AUC measurement, because this technology uses extracted sodium ion levels as an internal standard. Therefore, we developed a sweat monitoring patch to reduce this effect and investigated its efficacy in volunteers undergoing oral glucose tolerance tests (OGTTs). Materials and Methods: Fifty diabetes mellitus inpatients and 10 healthy subjects undergoing the 75 g OGTT were included. Two sites on the forearm were pretreated with microneedle arrays, then hydrogels for interstitial fluid extraction were placed on the treated sites. Simultaneously, hydrogels for sweat monitoring were placed on untreated sites near the treated sites. Plasma glucose (PG) levels were measured every 30 min for 2 h to calculate reference AUC values. Using MIET, IG AUC was calculated from extracted glucose and sodium ion levels after attachment of the hydrogel for 2 h. Results: Good correlation between IG AUC measurements using MIET and reference AUCs measured using PG levels was confirmed over a wide AUC range (202–610 mg/h/dl) after correction for the sweat-induced error detected by the hydrogel patches on the nonpretreated skin. Strong correlation between IG AUC and peak glucose levels indicates that glucose spikes can be easily detected by this system. Conclusion: We confirmed the effectiveness of a sweat monitoring patch for precise AUC measurement using MIET. This novel, easy-to-use system has potential for glucose excursion evaluation in daily clinical practice. PMID:23759401

Lipid Bilayer Vesicles with Numbers of Membrane-Linking Pores

NASA Astrophysics Data System (ADS)

Ken-ichirou Akashi,; Hidetake Miyata,

2010-06-01

We report that phospholipid membranes spontaneously formed in aqueous medium giant unilamellar vesicles (GUVs) possessing many membranous wormhole-like structures (membrane-linking pores, MLPs). By phase contract microscopy and confocal fluorescence microscopy, the structures of the MLPs, consisting of lipid bilayer, were resolvable, and a variety of vesicular shapes having many MLPs (a high genus topology) were found. These vesicles were stable but easily deformed by micromanipulation with a microneedle. We also observed the size reduction of the MLPs with the increase in membrane tension, which was qualitatively consistent with a prediction from a simple dynamical model.

Variability of Remote Sensing Spectral Indices in Boreal Lake Basins

NASA Astrophysics Data System (ADS)

Hakala, T.; Pölönen, I.; Honkavaara, E.; Näsi, R.; Hakala, T.; Lindfors, A.

2018-05-01

Remotely sensed hyperspectral data has widely been used to determine water quality parameters in oceanic waters. However in freshwater basins the dependence between the hyperspectral data and the parameters is more complicated. In this work some ideas are presented concerning the study of this dependence. The data used in this study were collected from the lake Hiidenvesi in southern Finland. The hyperspectral data consists of reflectances in 36 bands in the wavelength area 508…878 nm and the separately measured water quality parameters are turbidity, blue-green algae, chlorophyll, pH and dissolved oxygen. Hyperspectral data was used as bare band reflectances, but also in the form of two simple spectral indices: ratio A / B and difference A - B, where A and B go through all the bands. The correlations of the indices with the parameters were presented visually as 1- or 2-dimensional arrays. To examine the significance on the results of different variables, the data was classified in two different ways: the natural basins and the values of the water quality parameters. It was noticed that the variability of the correlation arrays was particularly strong among different basins in both the magnitude of correlation and the best performing indices. Further studies are needed to clarify which features of the basins are of most importance in predicting the shapes of the correlation arrays.

Transitions in low Re pumping by oscillating plate arrays of mayfly nymphs

NASA Astrophysics Data System (ADS)

Kiger, Ken; Sensenig, Andrew; Shultz, Jeffrey

2008-11-01

Mayfly nymphs are aquatic insects which alter behavior and metabolism to accommodate changes in ambient dissolved oxygen. Many species can generate a ventilation current to compensate for low oxygen levels by beating two linear arrays of plate-like gills that line the lateral edge of the abdomen. The oscillation Reynolds number associated with the gill motion changes with animal size, varying over a span of Re = 2 to 50 depending on age and species. Thus mayflies provide a novel system model for studying ontological changes in pumping mechanisms associated with transitions from a viscous- to inertia-dominated flow. Observation of the detailed 3-D kinematics of the gill motion of the species Centroptilum triangulifer reveal that the mayfly makes a marked transition in stroke motion when Re>5, with a corresponding shift in mean flow from the ventral to the dorsal direction. Results of the time-resolved flow within the inter-gill space shows that for Re>12 the plate motion generates a complex array of bound and shed vortices, which interact to produce an intermittent dorsally directed jet. For the Re<5, distinct bound vortices are still observed, but increased diffusive effects creates vortices which simultaneously envelope several gills, forcing a new flow pattern to emerge. Details of the flow mechanism and its implications will be discussed. This work is supported by NSF under grant CBET-0730907.

Novel device-based acne treatments: comparison of a 1450-nm diode laser and microneedling radiofrequency on mild-to-moderate acne vulgaris and seborrhoea in Korean patients through a 20-week prospective, randomized, split-face study.

PubMed

Kwon, H H; Park, H Y; Choi, S C; Bae, Y; Jung, J Y; Park, G-H

2018-04-01

While device-based acne treatments are widely applied for patients not tolerating conventional medications, related controlled studies have been still limited. Recently, non-ablative 1450-nm diode laser (DL) and fractional microneedling radiofrequency (FMR) have been effectively used for acne, in addition to well-recognized dermal remodelling effects. To compare the clinical course of acne treatment between DL and FMR. Twenty-five Korean patients with mild-to-moderate facial acne completed treatments with DL and FMR through a 20-week, randomized split-face study. One randomly assigned half side of each patient's face received DL and the other side by FMR. Treatments were scheduled to receive three consecutive sessions at 4-week intervals. Objective assessments including revised Leeds grades, lesion counts, sebum output measurements, and patients' subjective satisfaction were investigated. Both DL and FMR demonstrated steady improvement of acne and seborrhoea during treatment sessions. While results between two devices were similar during treatment sessions, FMR was superior to DL in the 12-week follow-up. Patients' subjective assessments for seborrhoea improvement were similar between two devices, while those for acne, skin texture, and acne scars were more satisfactory for FMR. For safety profile, no significant difference was observed between two regimens, while mild postinflammatory hyperpigmentation was observed only in DL side. Both DL and FMR demonstrated efficacies for acne and seborrhoea, with reasonable safety profile. FMR was more effective than DL for the long-term maintenance, and subjective assessments for texture and scar improvements. Therefore, a few sessions of these devices would be a viable option for acne treatments. © 2017 European Academy of Dermatology and Venereology.

Towards Robot-Assisted Retinal Vein Cannulation: A Motorized Force-Sensing Microneedle Integrated with a Handheld Micromanipulator †

PubMed Central

Gonenc, Berk; Chae, Jeremy; Gehlbach, Peter; Taylor, Russell H.; Iordachita, Iulian

2017-01-01

Retinal vein cannulation is a technically demanding surgical procedure where therapeutic agents are injected into the retinal veins to treat occlusions. The clinical feasibility of this approach has been largely limited by the technical challenges associated with performing the procedure. Among the challenges to successful vein cannulation are identifying the moment of venous puncture, achieving cannulation of the micro-vessel, and maintaining cannulation throughout drug delivery. Recent advances in medical robotics and sensing of tool-tissue interaction forces have the potential to address each of these challenges as well as to prevent tissue trauma, minimize complications, diminish surgeon effort, and ultimately promote successful retinal vein cannulation. In this paper, we develop an assistive system combining a handheld micromanipulator, called “Micron”, with a force-sensing microneedle. Using this system, we examine two distinct methods of precisely detecting the instant of venous puncture. This is based on measured tool-tissue interaction forces and also the tracked position of the needle tip. In addition to the existing tremor canceling function of Micron, a new control method is implemented to actively compensate unintended movements of the operator, and to keep the cannulation device securely inside the vein following cannulation. To demonstrate the capabilities and performance of our uniquely upgraded system, we present a multi-user artificial phantom study with subjects from three different surgical skill levels. Results show that our puncture detection algorithm, when combined with the active positive holding feature enables sustained cannulation which is most evident in smaller veins. Notable is that the active holding function significantly attenuates tool motion in the vein, thereby reduces the trauma during cannulation. PMID:28946634

Evaluation of Intradermal and Subcutaneous Infusion Set Performance Under 24-Hour Basal and Bolus Conditions

PubMed Central

McVey, Elaine; Keith, Steven; Herr, Joshua K.; Sutter, Diane; Pettis, Ronald J.

2015-01-01

Background: This study sought to assess the function and delivery reliability of intradermal (ID) infusion sets used with commercial insulin pumps. Method: Healthy subjects (n = 43) were randomized to either ID or subcutaneous (SC) arms, and received basal/bolus placebo delivery for 24 hours. Subjects received 4 of 8 infusion set combinations (ID: microneedle design A or B, with 2 pump brands [Animas or MiniMed]; SC: Teflon Quickset or steel Rapid-D, Animas pump only, with or without overtaping) and were evaluated for pump occlusion alarms, fluid leakage, pain, and tissue tolerability. A novel algorithm was developed to determine flow consistency based on fluid pressure, and the duration and occurrence rate for periods of unalarmed but interrupted flow (“silent occlusions’”) were compared. Results: ID delivery was successfully maintained over the 24-hour infusion period. The number of silent occlusions was lower for ID microneedle cannula design B than A (P < .01) and lower for Rapid-D SC device compared to Quick-set (P = .03). There was no significant difference in the number of occlusion alarms between the ID and SC devices with the Animas pump. However, the pumps tested with ID devices had significantly different alarm rates (MiniMed 29.5%, Animas 0%, P < .001). Leakage and tissue tolerability were comparable across devices. Conclusion: The ID infusion set reliably delivered diluent for an extended 24-hour period in healthy subjects and was well tolerated. Silent occlusion flow interruptions could be detected in both ID and SC infusion sets using a proprietary algorithm. This algorithm is a promising method for quantitatively evaluating infusion set flow performance. PMID:26319228

Rapid Changes in Water Properties on a Shallow Reef in the Chesapeake Bay due to a Wind Driven Internal Seiche

NASA Astrophysics Data System (ADS)

Kilbourne, B.

2016-12-01

The Chesapeake Bay Interpretive Buoy System has collected oceanographic and meteorological observations in Chesapeake Bay from 2007 to the present. The relatively long and well resolved time series of wind, current, and salinity data provided by this array creates an opportunity to better understand the many finescale circulation pathways in Chesapeake Bay. The mean vertical structure of Chesapeake Bay is approximated by a three layer system: a well-mixed surface boundary layer from 1 to 8 m depth, a stratified transition layer from 8 to 15 m depth, and a well-mixed bottom boundary layer from 15 m to the bottom (typically < 30 m). The conditions in the surface and bottom boundary layers can be strikingly different with the bottom layer being saltier, lower in pH, and lower in dissolved oxygen than the surface layer. The Gooses Reef station of this array is located on `Gooses Reef', a shallow bar just 10 m in depth, dividing the Choptank River basin from the main channel of the Chesapeake Bay. This shallow bar provides habitat for oysters, a keystone species in the Chesapeake Bay, and is both commercially and ecologically critical to the region. These shallow habitats are threatened when anoxic (< 0.5 mg l-1 O2) conditions exist in the upper 10 m of the water column. The Gooses Reef station is unique in the array due to the addition of a bottom mounted sensor package; data from August 2012 show rapid changes in the salinity (11 to 17 PSU), dissolved oxygen (6 to 0.05 mg l-1) , and pH (8.3 to 7.7) at the bottom. Investigations of wind and current data before these rapid changes show along channel wind stress oscillations near the M2 tidal frequency. Current profiles from the buoy ADCP show low-frequency along-channel baroclinic oscillations. Observed currents appear to be an internal seiche, forced by resonance between the along-channel wind and diurnal tide. At the Gooses Reef bar, this internal seiche forced the bottom boundary layer up and over the bar, causing the sudden shift in water properties. These observations highlight the strong physical controls on local water conditions in the Chesapeake Bay and similar estuaries.

NASA Tech Briefs, September 2009

NASA Technical Reports Server (NTRS)

2009-01-01

opics covered include: Filtering Water by Use of Ultrasonically Vibrated Nanotubes; Computer Code for Nanostructure Simulation; Functionalizing CNTs for Making Epoxy/CNT Composites; Improvements in Production of Single-Walled Carbon Nanotubes; Progress Toward Sequestering Carbon Nanotubes in PmPV; Two-Stage Variable Sample-Rate Conversion System; Estimating Transmitted-Signal Phase Variations for Uplink Array Antennas; Board Saver for Use with Developmental FPGAs; Circuit for Driving Piezoelectric Transducers; Digital Synchronizer without Metastability; Compact, Low-Overhead, MIL-STD-1553B Controller; Parallel-Processing CMOS Circuitry for M-QAM and 8PSK TCM; Differential InP HEMT MMIC Amplifiers Embedded in Waveguides; Improved Aerogel Vacuum Thermal Insulation; Fluoroester Co-Solvents for Low-Temperature Li+ Cells; Using Volcanic Ash to Remove Dissolved Uranium and Lead; High-Efficiency Artificial Photosynthesis Using a Novel Alkaline Membrane Cell; Silicon Wafer-Scale Substrate for Microshutters and Detector Arrays; Micro-Horn Arrays for Ultrasonic Impedance Matching; Improved Controller for a Three-Axis Piezoelectric Stage; Nano-Pervaporation Membrane with Heat Exchanger Generates Medical-Grade Water; Micro-Organ Devices; Nonlinear Thermal Compensators for WGM Resonators; Dynamic Self-Locking of an OEO Containing a VCSEL; Internal Water Vapor Photoacoustic Calibration; Mid-Infrared Reflectance Imaging of Thermal-Barrier Coatings; Improving the Visible and Infrared Contrast Ratio of Microshutter Arrays; Improved Scanners for Microscopic Hyperspectral Imaging; Rate-Compatible LDPC Codes with Linear Minimum Distance; PrimeSupplier Cross-Program Impact Analysis and Supplier Stability Indicator Simulation Model; Integrated Planning for Telepresence With Time Delays; Minimizing Input-to-Output Latency in Virtual Environment; Battery Cell Voltage Sensing and Balancing Using Addressable Transformers; Gaussian and Lognormal Models of Hurricane Gust Factors; Simulation of Attitude and Trajectory Dynamics and Control of Multiple Spacecraft; Integrated Modeling of Spacecraft Touch-and-Go Sampling; Spacecraft Station-Keeping Trajectory and Mission Design Tools; Efficient Model-Based Diagnosis Engine; and DSN Simulator.

Advancements in ocular drug delivery.

PubMed

Weiner, Alan L; Gilger, Brian C

2010-11-01

This review covers both noninvasive and invasive ophthalmic drug delivery systems that can have application to therapy of veterinary ophthalmic diseases. Noninvasive approaches include gel technologies, permeation enhancement via pro-drug development, solubilization agents and nanoparticle technologies, iontophoresis, microneedles, drug-eluting contact lenses and eye misters, and microdroplets. More invasive systems include both eroding implants and noneroding technologies that encompass diffusion based systems, active pumps, intraocular lenses, suprachoroidal drug delivery, and episcleral reservoirs. In addition to addressing the physiologic challenges of achieving the necessary duration of delivery, tissue targeting and patient compliance, the commercial development factors of biocompatibility, sterilization, manufacturability and long-term stability will be discussed. © 2010 American College of Veterinary Ophthalmologists.

Intradermal Inactivated Poliovirus Vaccine: A Preclinical Dose-Finding Study

PubMed Central

Kouiavskaia, Diana; Mirochnitchenko, Olga; Dragunsky, Eugenia; Kochba, Efrat; Levin, Yotam; Troy, Stephanie; Chumakov, Konstantin

2015-01-01

Intradermal delivery of vaccines has been shown to result in dose sparing. We tested the ability of fractional doses of inactivated poliovirus vaccine (IPV) delivered intradermally to induce levels of serum poliovirus-neutralizing antibodies similar to immunization through the intramuscular route. Immunogenicity of fractional doses of IPV was studied by comparing intramuscular and intradermal immunization of Wistar rats using NanoPass MicronJet600 microneedles. Intradermal delivery of partial vaccine doses induced antibodies at titers comparable to those after immunization with full human dose delivered intramuscularly. The results suggest that intradermal delivery of IPV may lead to dose-sparing effect and reduction of the vaccination cost. PMID:25391313

Cross-shelf transport into nearshore waters due to shoaling internal tides in San Pedro Bay, CA

USGS Publications Warehouse

Noble, Marlene A.; Burt Jones,; Peter Hamilton,; Xu, Jingping; George Robertson,; Rosenfeld, Leslie; John Largier,

2009-01-01

In the summer of 2001, a coastal ocean measurement program in the southeastern portion of San Pedro Bay, CA, was designed and carried out. One aim of the program was to determine the strength and effectiveness of local cross-shelf transport processes. A particular objective was to assess the ability of semidiurnal internal tidal currents to move suspended material a net distance across the shelf. Hence, a dense array of moorings was deployed across the shelf to monitor the transport patterns associated with fluctuations in currents, temperature and salinity. An associated hydrographic program periodically monitored synoptic changes in the spatial patterns of temperature, salinity, nutrients and bacteria. This set of measurements show that a series of energetic internal tides can, but do not always, transport subthermocline water, dissolved and suspended material from the middle of the shelf into the surfzone. Effective cross-shelf transport occurs only when (1) internal tides at the shelf break are strong and (2) subtidal currents flow strongly downcoast. The subtidal downcoast flow causes isotherms to tilt upward toward the coast, which allows energetic, nonlinear internal tidal currents to carry subthermocline waters into the surfzone. During these events, which may last for several days, the transported water remains in the surfzone until the internal tidal current pulses and/or the downcoast subtidal currents disappear. This nonlinear internal tide cross-shelf transport process was capable of carrying water and the associated suspended or dissolved material from the mid-shelf into the surfzone, but there were no observation of transport from the shelf break into the surfzone. Dissolved nutrients and suspended particulates (such as phytoplankton) transported from the mid-shelf into the nearshore region by nonlinear internal tides may contribute to nearshore algal blooms, including harmful algal blooms that occur off local beaches.

Chemically and geographically distinct solid-phase iron pools in the Southern Ocean.

PubMed

von der Heyden, B P; Roychoudhury, A N; Mtshali, T N; Tyliszczak, T; Myneni, S C B

2012-11-30

Iron is a limiting nutrient in many parts of the oceans, including the unproductive regions of the Southern Ocean. Although the dominant fraction of the marine iron pool occurs in the form of solid-phase particles, its chemical speciation and mineralogy are challenging to characterize on a regional scale. We describe a diverse array of iron particles, ranging from 20 to 700 nanometers in diameter, in the waters of the Southern Ocean euphotic zone. Distinct variations in the oxidation state and composition of these iron particles exist between the coasts of South Africa and Antarctica, with different iron pools occurring in different frontal zones. These speciation variations can result in solubility differences that may affect the production of bioavailable dissolved iron.

Patterning of oxide-hardened gold black by photolithography and metal lift-off

NASA Astrophysics Data System (ADS)

Panjwani, Deep; Yesiltas, Mehmet; Nath, Janardan; Maukonen, D. E.; Rezadad, Imen; Smith, Evan M.; Peale, R. E.; Hirschmugl, Carol; Sedlmair, Julia; Wehlitz, Ralf; Unger, Miriam; Boreman, Glenn

2014-01-01

A method to pattern infrared-absorbing gold black by conventional photolithography and lift-off is described. A photo-resist pattern is developed on a substrate by standard photolithography. Gold black is deposited over the whole by thermal evaporation in an inert gas at ˜1 Torr. SiO2 is then deposited as a protection layer by electron beam evaporation. Lift-off proceeds by dissolving the photoresist in acetone. The resulting sub-millimeter size gold black patterns that remain on the substrate retain high infrared absorption out to ˜5 μm wavelength and exhibit good mechanical stability. This technique allows selective application of gold black coatings to the pixels of thermal infrared imaging array detectors.

Identification of geometrical isomers and comparison of different isomeric samples of astaxanthin.

PubMed

Qiu, Dan; Wu, Yue-Chan; Zhu, Wen-Li; Yin, Hong; Yi, Long-Tao

2012-09-01

A high-performance liquid chromatographic (HPLC) analysis system for isomeric astaxanthin was developed. The separation system consisted of a C(30) column and an elution system of methanol/MTBE/water/dichloromethane (77:13:8:2, v/v/v/v). Using the combination of HPLC diode array detector and HPLC atmospheric pressure chemical ionization mass spectrometry, 11 geometrical isomers and 4 epoxides of astaxanthin were successfully identified. Referred to crystal, only isomerization with different degrees was found for solvent dissolving and iodine catalysis, while melting of astaxanthin caused isomerization, slight oxidation, and more noticeable polymerization confirmed by gel permeation chromatography. Chemical changes in isomeric samples all caused a decrease in UV content. The vibrational spectra (infrared and Raman) showed that epoxide was the only new functional group generated for melting. Changes of several key bands and formations of new bands were found in iodine catalysis and melting samples because of isomerization. Practical Application:  Eleven geometrical isomers and 4 epoxides, which were normally generated for solvent dissolving, iodine catalysis, and melting of astaxanthin, have been identified by C(30) -HPLC-MS technology. Furthermore, different samples were measured by gel permeation chromatography, UV, infrared, and Raman, based on the analysis of messages, the effect of each processing was well understood. © 2012 Institute of Food Technologists®

Dissolved organic carbon in coral-reef lagoons, by high temperature catalytic oxidation and UV spectrometry

NASA Astrophysics Data System (ADS)

Pagès, Jean; Torréton, Jean-Pascal; Sempéré, Richard

1997-06-01

Two surveys were carried out on ten atolls in the Tuamotu archipelago (French Polynesia, Pacific Ocean). In vitro UV (250-400 nm) spectra of water samples gave absorption at 254 nm, A 254, and spectrum slope, S ⋆ (computed from In A λ versus λ).These two descriptors are negatively correlated, and data points are arrayed along a hyperbola spanned between an oceanic pole (high S ⋆, low A 254) and a confined pole (low 5 ⋆, high A 254). Dissolved organic carbon (DOC) concentrations, [C], as assessed by HTCO, exhibit a narrow range (0.7-1.0 mg C.L -1 for most lagoons) contrasting with the wide diversity of optical characteristics. [C] and A 254 are positively correlated, with a significant intercept (0.5 mg C.L -1) representing non-chromophoric DOC. Carbon-specific absorption, ɛ 254 increases (from 0.4 to 1.3 m 2.g -1) with increasing [C], mainly according to the literature) owing to increased average molecular weight (MW) of the chromophoric DOC fraction, which also lowers S ⋆. Our optical data thus illustrate a gradient of confinement (or residence time) that corresponds to a continuum in DOC nature, especially in MW and hence in bioavailability. Optical methods are confirmed as quick and effective means of assessing DOM distribution.

Sustained in situ measurements of dissolved oxygen, methane and water transport processes in the benthic boundary layer at MC118, northern Gulf of Mexico

NASA Astrophysics Data System (ADS)

Martens, Christopher S.; Mendlovitz, Howard P.; Seim, Harvey; Lapham, Laura; D'Emidio, Marco

2016-07-01

Within months of the BP Macondo Wellhead blowout, elevated methane concentrations within the water column revealed a significant retention of light hydrocarbons in deep waters plus corresponding dissolved oxygen (DO) deficits. However, chemical plume tracking efforts were hindered by a lack of in situ monitoring capabilities. Here, we describe results from in situ time-series, lander-based investigations of physical and biogeochemical processes controlling dissolved oxygen, and methane at Mississippi Canyon lease block 118 ( 18 km from the oil spill) conducted shortly after the blowout through April 2012. Multiple sensor arrays plus open-cylinder flux chambers (;chimneys;) deployed from a benthic lander collected oxygen, methane, pressure, and current speed and direction data within one meter of the seafloor. The ROVARD lander system was deployed for an initial 21-day test experiment (9/13/2010-10/04/2010) at 882 m depth before a longer 160-day deployment (10/24/2011-4/01/2012) at 884 m depth. Temporal variability in current directions and velocities and water temperatures revealed strong influences of bathymetrically steered currents and overlying along-shelf flows on local and regional water transport processes. DO concentrations and temperature were inversely correlated as a result of water mass mixing processes. Flux chamber measurements during the 160-day deployment revealed total oxygen utilization (TOU) averaging 11.6 mmol/m2 day. Chimney DO concentrations measured during the 21-day deployment exhibited quasi-daily variations apparently resulting from an interaction between near inertial waves and the steep topography of an elevated scarp immediately adjacent to the 21-day deployment site that modulated currents at the top of the chimney. Variability in dissolved methane concentrations suggested significant temporal variability in gas release from nearby hydrocarbon seeps and/or delivery by local water transport processes. Free-vehicle (lander) monitoring over time scales of months to years utilizing in situ sensors can provide an understanding of processes controlling water transport, respiration and the fate and impacts of accidental and natural gas and oil releases.

The suprachoroidal pathway: a new drug delivery route to the back of the eye.

PubMed

Rai, Uma Do J P; Young, Simon A; Thrimawithana, Thilini R; Abdelkader, Hamdy; Alani, Adam W G; Pierscionek, Barbara; Alany, Raid G

2015-04-01

The development of safe and convenient drug delivery strategies for treatment of posterior segment eye diseases is challenging. Although intravitreal injection has wide acceptance amongst clinicians, its use is associated with serious side-effects. Recently, the suprachoroidal space (SCS) has attracted the attention of ophthalmologists and pharmaceutical formulators as a potential site for drug administration and delivery to the posterior segment of the eye. This review highlights the major constraints of drug delivery to the posterior eye segment, key anatomical and physiological features of the SCS and drug delivery applications of this route with emphasis on microneedles along with future perspectives. Copyright © 2014 Elsevier Ltd. All rights reserved.

Flexible MEMS: A novel technology to fabricate flexible sensors and electronics

NASA Astrophysics Data System (ADS)

Tu, Hongen

This dissertation presents the design and fabrication techniques used to fabricate flexible MEMS (Micro Electro Mechanical Systems) devices. MEMS devices and CMOS(Complementary Metal-Oxide-Semiconductor) circuits are traditionally fabricated on rigid substrates with inorganic semiconductor materials such as Silicon. However, it is highly desirable that functional elements like sensors, actuators or micro fluidic components to be fabricated on flexible substrates for a wide variety of applications. Due to the fact that flexible substrate is temperature sensitive, typically only low temperature materials, such as polymers, metals, and organic semiconductor materials, can be directly fabricated on flexible substrates. A novel technology based on XeF2(xenon difluoride) isotropic silicon etching and parylene conformal coating, which is able to monolithically incorporate high temperature materials and fluidic channels, was developed at Wayne State University. The technology was first implemented in the development of out-of-plane parylene microneedle arrays that can be individually addressed by integrated flexible micro-channels. These devices enable the delivery of chemicals with controlled temporal and spatial patterns and allow us to study neurotransmitter-based retinal prosthesis. The technology was further explored by adopting the conventional SOI-CMOS processes. High performance and high density CMOS circuits can be first fabricated on SOI wafers, and then be integrated into flexible substrates. Flexible p-channel MOSFETs (Metal-Oxide-Semiconductor Field-Effect-Transistors) were successfully integrated and tested. Integration of pressure sensors and flow sensors based on single crystal silicon has also been demonstrated. A novel smart yarn technology that enables the invisible integration of sensors and electronics into fabrics has been developed. The most significant advantage of this technology is its post-MEMS and post-CMOS compatibility. Various high-performance MEMS devices and electronics can be integrated into flexible substrates. The potential of our technology is enormous. Many wearable and implantable devices can be developed based on this technology.

Efficacy of functional microarray of microneedles combined with topical tranexamic acid for melasma

PubMed Central

Xu, Yang; Ma, Renyan; Juliandri, Juliandri; Wang, Xiaoyan; Xu, Bai; Wang, Daguang; Lu, Yan; Zhou, Bingrong; Luo, Dan

2017-01-01

Abstract To evaluate the efficacy of a functional microarray of microneedles (MNs) plus topical tranexamic acid (TA) for melasma in middle-aged women in China. Thirty female subjects with melasma were enrolled in this study. The left or right side of the face was chosen randomly to be pretreated with a functional microarray of MNs, followed by topical 0.5% TA solution once per week for 12 weeks. The other half-face was the control, treated with a sham device plus topical 0.5% TA solution. At baseline and at weeks 4, 8, and 12 of treatment, clinical (photographic) evaluations and parameters determined by Visia were recorded. At baseline and week 12, patient satisfaction scores and the biophysical parameters measured by Mexameter were also recorded. Side effects were evaluated at baseline and at the end of the 12 weeks. In total, 28 women (93.3%) completed the study. The brown spots’ scores measured by Visia were significantly lower on the combined therapy side than on the control side at 12 weeks after starting treatment; there was no significant difference between sides at 4 or 8 weeks. After 12 weeks, melanin index (MI) decreased significantly in both 2 groups, and the MI was significantly less on the combined side at week 12. Transepidermal water loss, roughness, skin hydration, skin elasticity, and erythema index showed no significant differences between 2 sides at baseline, 4, 8, and 12 weeks after treatment. Physicians’ evaluations of photographs showed better results at week 12 with combined therapy: >25% improvement was observed in the MNs plus TA side in 25 patients, and in the TA side in only 10 patients. Subjective satisfaction scores on both sides increased significantly. The participants were more satisfied with the results of the combined therapy side than the control side. No obvious adverse reactions were observed throughout the study. Combined therapy with a functional microarray of MNs and topical TA solution is a promising treatment for melasma. PMID:28489798

Efficacy of fractionated microneedle radiofrequency with and without adding subcision for the treatment of atrophic facial acne scars: A randomized split-face clinical study.

PubMed

Faghihi, Gita; Poostiyan, Nazila; Asilian, Ali; Abtahi-Naeini, Bahareh; Shahbazi, Masoom; Iraji, Fariba; Fatemi Naeini, Farahnaz; Nilforoushzadeh, Mohammad Ali

2017-06-01

There is no gold standard treatment for facial acne scars, and overall, little literature exists about the combination therapy for treatment of acne scar. The aim of this study was to evaluate the efficacy of fractionated microneedle radiofrequency (FMR) vs FMR combined with subcision for the treatment of atrophic acne scars. This was a randomized, split-face clinical study of 25 patients with II-IV Fitzpatrick skin types with moderate to severe facial atrophic acne scars. Initially, standard subcision by Nokor needle was performed on one side. Two weeks after subcision, FMR treatment was performed on both cheeks of each participant. Second and third FMR treatment sessions were performed within 4-week intervals. Two-blinded dermatologists performed clinical assessments using a quartile grading scale, and patients were also asked to judge their satisfaction using a visual analog scale (VAS) scoring system. The age of the patients varied from 24 to 40 years (mean: 30.08±4.94 years). Only nine patients (36%) were males. Clinical assessment by two-blinded dermatologists showed statistically significant improvement in the combination (FMR+subcision) group (P=.009). Patient satisfaction was statistically significantly better in the combination group (P=.001). A darkening of skin phototype was associated with a decrease in patient's satisfaction VAS score (P=.07). The combination of subcision and FMR is a safe and effective modality for mixed type acne scars. Additional randomized clinical study with long-term follow-up is necessary for further evaluation of FMR in combination with other procedures. The full trial protocol can be accessed in: http://www.irct.ir/searchresult.php?keyword=%20%20IRCT2016103130597N1&id=30597&number=1&field=a&prt=1&total=1&m=1. The clinical trial registration number is IRCT2016103130597N1. © 2017 Wiley Periodicals, Inc.

Polydopamine-Coated TiO2 Nanotubes for Selective Photocatalytic Oxidation of Benzyl Alcohol to Benzaldehyde Under Visible Light.

PubMed

Tripathy, Jyotsna; Loget, Gabriel; Altomare, Marco; Schmuki, Patrik

2016-05-01

TiO2 nanotube arrays grown by anodization were coated with thin layers of polydopamine as visible light sensitizer. The PDA-coated TiO2 scaffolds were used as photocatalyst for selective oxidation of benzyl alcohol under monochromatic irradiation at 473 nm. Benzaldehyde was selectively formed and no by-products could be detected. A maximized reaction yield was obtained in O2-saturated acetonitrile. A mechanism is proposed that implies firstly the charge carrier generation in polydopamine as a consequence of visible light absorption. Secondly, photo-promoted electrons are injected in TiO2 conduction band, and subsequently transferred to dissolved O2 to form O*2- radicals. These radicals react with benzyl alcohol and lead to its selective dehydrogenation oxidation towards benzaldehyde.

NFLUX: a test of vertical nitrogen flux by diel migrant biota

NASA Astrophysics Data System (ADS)

Longhurst, A. R.; Bedo, A.; Harrison, W. G.; Head, E. J. H.; Horne, E. P.; Irwin, B.; Morales, C.

1989-11-01

At a station (NFLUX), occupied for 10 days in the northern Sargasso Sea, we assembled data to test the hypothesis that diel migrant biota in the open ocean induce a downward flux of dissolved inorganic nitrogen that is significant in relation to the passive flux under gravity of particulate organic nitrogen at the base on the photic zone. We founf taht NH 4+ excretion rates by day at depths below the photic zone were approximately 8% of particulate nitrogen flux obtained by a sediment trap array at the same depth. This figure is in the lower part of the range of values calculated previously for 10 published station data sets; we attribute this to the quite high rate of passive flux relative to primary production at the NFLUX station.

Liquid chromatography-mass spectrometry identification of anthocyanins of isla oca (Oxalis tuberosa, Mol.) tubers.

PubMed

Alcalde-Eon, Cristina; Saavedra, Gloria; de Pascual-Teresa, Sonia; Rivas-Gonzalo, Julián C

2004-10-29

High-performance liquid chromatography (HPLC)-diode array detection (DAD)-mass spectrometry (MS) techniques have been successfully employed in the identification of the anthocyanins of the coloured tubers of isla oca (Oxalis tuberosa), the second most cultivated tuber in the Andean region. Tubers underwent a pre-treatment step in order to inhibit enzymatic reactions and to obtain a stable powder or "concentrate". This concentrate was dissolved, purified and then analysed. Eight different compounds were found. The major peaks were malvidin glucosides (malvidin 3-O-glucoside and 3,5-O-diglucoside). The rest of the peaks were 3,5-O-diglucosides of petunidin and peonidin, and 3-O-glucosides of delphinidin, petunidin and peonidin. Only malvidin 3-O-acetylglucoside-5-O-glucoside was found as an acylated anthocyanin.

Tensile stress stimulates microtubule outgrowth in living cells

NASA Technical Reports Server (NTRS)

Kaverina, Irina; Krylyshkina, Olga; Beningo, Karen; Anderson, Kurt; Wang, Yu-Li; Small, J. Victor

2002-01-01

Cell motility is driven by the sum of asymmetric traction forces exerted on the substrate through adhesion foci that interface with the actin cytoskeleton. Establishment of this asymmetry involves microtubules, which exert a destabilising effect on adhesion foci via targeting events. Here, we demonstrate the existence of a mechano-sensing mechanism that signals microtubule polymerisation and guidance of the microtubules towards adhesion sites under increased stress. Stress was applied either by manipulating the body of cells moving on glass with a microneedle or by stretching a flexible substrate that cells were migrating on. We propose a model for this mechano-sensing phenomenon whereby microtubule polymerisation is stimulated and guided through the interaction of a microtubule tip complex with actin filaments under tension.

Transdermal Drug Delivery: Innovative Pharmaceutical Developments Based on Disruption of the Barrier Properties of the stratum corneum

PubMed Central

Zaid Alkilani, Ahlam; McCrudden, Maelíosa T.C.; Donnelly, Ryan F.

2015-01-01

The skin offers an accessible and convenient site for the administration of medications. To this end, the field of transdermal drug delivery, aimed at developing safe and efficacious means of delivering medications across the skin, has in the past and continues to garner much time and investment with the continuous advancement of new and innovative approaches. This review details the progress and current status of the transdermal drug delivery field and describes numerous pharmaceutical developments which have been employed to overcome limitations associated with skin delivery systems. Advantages and disadvantages of the various approaches are detailed, commercially marketed products are highlighted and particular attention is paid to the emerging field of microneedle technologies. PMID:26506371

Micro-scale Devices for Transdermal Drug Delivery

PubMed Central

Arora, Anubhav; Prausnitz, Mark; Mitragotri, Samir

2009-01-01

Skin makes an excellent site for drug and vaccine delivery due to easy accessibility, immuno-surveillance functions, avoidance of macromolecular degradation in the gastrointestinal tract and possibility of self-administration. However, macromolecular drug delivery across the skin is primarily accomplished using hypodermic needles, which have several disadvantages including accidental needle-sticks, pain and needle phobia. These limitations have led to extensive research and development of alternative methods for drug and vaccine delivery across the skin. This review focuses on the recent trends and developments in this field of micro-scale devices for transdermal macromolecular delivery. These include liquid jet injectors, powder injectors, microneedles and thermal microablation. The historical perspective, mechanisms of action, important design parameters, applications and challenges are discussed for each method. PMID:18805472

Transdermal drug delivery: from micro to nano

NASA Astrophysics Data System (ADS)

Pegoraro, Carla; MacNeil, Sheila; Battaglia, Giuseppe

2012-03-01

Delivery across skin offers many advantages compared to oral or intravenous routes of drug administration. Skin however is highly impermeable to most molecules on the basis of size, hydrophilicity, lipophilicity and charge. For this reason it is often necessary to temporarily alter the barrier properties of skin for effective administration. This can be done by applying chemical enhancers, which alter the lipid structure of the top layer of skin (the stratum corneum, SC), by applying external forces such as electric currents and ultrasounds, by bypassing the stratum corneum via minimally invasive microneedles or by using nano-delivery vehicles that can cross and deliver their payload to the deeper layers of skin. Here we present a critical summary of the latest technologies used to increase transdermal delivery.

In vivo MRI Using Laser Polarized Noble Gases.

NASA Astrophysics Data System (ADS)

Cates, G. D.

1996-03-01

A new technique for magnetic resonance imaging (MRI) will be reviewed in which the noble gas nuclei ^3He and ^129Xe are used as the source of signal instead of the protons in water, as is the case in conventional MRI. The noble gas nuclei are polarized by spin exchange with laser optically pumped alkali-metal vapor. The noble gas, which under appropriate conditions can exhibit spin relaxation times of hours to days, can be inhaled, making it possible to obtain images of the gas space of the lungs of unprecedented resolution. In the case of ^129Xe, substantial quantities of gas dissolves into the blood, opening up the prospect of imaging other parts of the body such as the heart and the brain. Recent results will be reviewed, including lung images of both guinea pigs and humans from a Duke/Princeton collaboration, and spectroscopic measurements of ^129Xe that is dissolved in mouse blood, from the Stony Brook group. Other results will be reviewed as available. Attention will be given to the issues involved in producing large quantities of polarized noble gas for imaging, including a discussion of the use of high power diode laser arrays, a technology that has helped this new MRI technique grow quickly to be of potential clinical value. Finally, future prospects for the diagnosis of disease will be discussed.

High-performance liquid chromatography ultraviolet-photodiode array detection method for aflatoxin B1 in cattle feed supplements

PubMed Central

Mochamad, Lazuardi; Hermanto, Bambang

2017-01-01

Aim: The objective of the current study is to determine the concentration of aflatoxin B1 using high-performance liquid chromatography (HPLC) with a photodiode array (PDA) detector. Materials and Methods: Aflatoxin B1 certified reference grade from Trilogy Analytical Laboratory dissolved acetonitrile (ACN) at 10 µg/mL was using standard assessment. HPLC instruments such as ultraviolet-PDA detector used a Shimadzu LC-6AD pump with DGU-20A5 degasser, communication module-20A, and PDA detector SPD-M20A with FRC-10A fraction collector. The HPLC was set isocratic method at 354 nm with a reverse-phase ODS C18 column (LiChrospher® 100 RP-18; diameter, 5 µm) under a 20°C controlled column chamber. Rheodyne® sample loops were performed in 20 µL capacities. The mobile phase was performed at fraction 63:26:11 H2O: methanol:ACN at pH 6.8. A total of 1 kg of feed contained 10% bread crumbs and 30% concentrated, 40% forage, and 20% soybean dregs were using commercials samples. Samples were extracted by ACN and separated with solid phase extraction ODS 1 mL than elution with mobile phase to collect at drying samples performed. The samples were ready to use after added 1 mL mobile phase than injected into the system of HPLC. Results: We found that the retention time of aflatoxin B1 was approximately 10.858 min. Linearity of 0.01-0.08 µg/mL aflatoxin B1 dissolved in mobile phase was obtained at R2=0.9. These results demonstrate that these methods can be used to analyze aflatoxin B1 and gain 89-99% recovery. The limit of detection of this assay was obtained at 3.5 × 10−6 µg/mL. Conclusion: This method was easy to apply and suitable to analyzing at small concentrations of aflatoxin B1 in formulated product of feed cattle. PMID:28919686

Ionic Liquid Microstrips Impregnated with Magnetic Nanostirrers for Sensitive Gas Sensors.

PubMed

Gondosiswanto, Richard; Hibbert, D Brynn; Fang, Yu; Zhao, Chuan

2017-12-13

Ionic liquids (IL) have been regarded as promising electrolytes as substitutes for volatile aqueous or organic solvents for electrochemical gas sensors. However, ILs are viscous, and the slow diffusion of gas molecules leads to poor sensitivity and sluggish response times. Herein, we describe a strategy using an array of microstrips of IL containing magnetic nanoparticles as nanostirrers for enhanced mass transport and gas sensing. Magnetic CoFe 2 O 4 nanoparticles are synthesized and dispersed in a hydrophobic IL [BMP][Ntf 2 ]. First, the convection effect of the IL dispersion was studied using the reversible redox couple ferrocene/ferrocenium ion. In a rotating magnetic field, steady-state currents for oxidation of dissolved ferrocene are three to five times greater than that in an unstirred solution. Then, the IL dispersion is micropatterned onto a gold electrode using microcontact printing. A self-assembled monolayer was printed onto a gold surface creating 70 μm wide hydrophobic lines with a 30 μm gap between them. Upon applying the IL dispersion into the gap, a 30 μm wide array of microstrips was successfully fabricated. The system is demonstrated as an oxygen sensor in the range of volume fraction of O 2 of 50-500 ppm giving a linear calibration with a sensitivity of 1.94 nA cm -2 ppm -1 .

Remediation of an aquifer polluted with dissolved tetrachloroethylene by an array of wells filled with activated carbon.

PubMed

Bortone, I; Di Nardo, A; Di Natale, M; Erto, A; Musmarra, D; Santonastaso, G F

2013-09-15

In this work, an array of deep passive wells filled with activated carbon, namely a Discontinuous Permeable Adsorptive Barrier (PAB-D), has been proposed for the remediation of an aquifer contaminated by tetrachloroethylene (PCE). The dynamics of the aquifer in the particular PAB-D configuration chosen, including the contaminant transport in the aquifer and the adsorption onto the barrier material, has been accurately performed by means of a computer code which allows describing all the phenomena occurring in the aquifer, simultaneously. A PAB-D design procedure is presented and the main dimensions of the barrier (number and position of passive wells) have been evaluated. Numerical simulations have been carried out over a long time span to follow the contaminant plume and to assess the effectiveness of the remediation method proposed. The model results show that this PAB-D design allows for a complete remediation of the aquifer under a natural hydraulic gradient, the PCE concentrations flowing out of the barrier being always lower than the corresponding Italian regulation limit. Finally, the results have been compared with those obtained for the design of a more traditional continuous barrier (PAB-C) for the same remediation process. Copyright © 2013 Elsevier B.V. All rights reserved.

Influence of fracture anisotropy on ground water ages and chemistry, Valley and Ridge province, Pennsylvania

USGS Publications Warehouse

Burton, W.C.; Plummer, Niel; Busenberg, E.; Lindsey, B.D.; Gburek, W.J.

2002-01-01

Model ground water ages based on chlorofluorocarbons (CFCs) and tritium/helium-3 (3H/3He) data were obtained from two arrays of nested piezometers located on the north limb of an anticline in fractured sedimentary rocks in the Valley and Ridge geologic province of Pennsylvania. The fracture geometry of the gently east plunging fold is very regular and consists predominately of south dipping to subhorizontal to north dipping bedding-plane parting and east striking, steeply dipping axial-plane spaced cleavage. In the area of the piezometer arrays, which trend north-south on the north limb of the fold, north dipping bedding-plane parting is a more dominant fracture set than is steeply south dipping axial-plane cleavage. The dating of ground water from the piezometer arrays reveals that ground water traveling along paths parallel to the dip direction of bedding-plane parting has younger 3H/3He and CFC model ages, or a greater component of young water, than does ground water traveling along paths opposite to the dip direction. In predominantly unmixed samples there is a strong positive correlation between age of the young fraction of water and dissolved sodium concentration. The travel times inferred from the model ages are significantly longer than those previously calculated by a ground water flow model, which assumed isotropically fractured layers parallel to topography. A revised model factors in the directional anisotropy to produce longer travel times. Ground water travel times in the watershed therefore appear to be more influenced by anisotropic fracture geometry than previously realized. This could have significant implications for ground water models in other areas underlain by similarly tilted or folded sedimentary rock, such as elsewhere in the Valley and Ridge or the early Mesozoic basins.

Overcoming ocular drug delivery barriers through the use of physical forces.

PubMed

Huang, Di; Chen, Ying-Shan; Rupenthal, Ilva D

2018-02-15

Overcoming the physiological barriers in the eye remains a key obstacle in the field of ocular drug delivery. While ocular barriers naturally have a protective function, they also limit drug entry into the eye. Various pharmaceutical strategies, such as novel formulations and physical force-based techniques, have been investigated to weaken these barriers and transport therapeutic agents effectively to both the anterior and the posterior segments of the eye. This review summarizes and discusses the recent research progress in the field of ocular drug delivery with a focus on the application of physical methods, including electrical fields, sonophoresis, and microneedles, which can enhance penetration efficiency by transiently disrupting the ocular barriers in a minimally or non-invasive manner. Copyright © 2017 Elsevier B.V. All rights reserved.

Episcleral, intrascleral, and suprachoroidal routes of ocular drug delivery - recent research advances and patents.

PubMed

Gilger, Brian C; Mandal, Abhirup; Shah, Sujay; Mitra, Ashim K

2014-01-01

Subconjunctival/episcleral, intrascleral, and suprachoroidal routes of drug delivery for treatment of posterior segment eye diseases have become more feasible and popular in the past few years. These routes have the advantage of bypassing the main barriers to topical drug penetration, the ocular surface epithelium, the conjunctivallymphatics, and in the case of deep intrascleral and suprachoroidial delivery, the sclera barrier. Many ocular drug delivery application devices, drug delivery methods, and therapeutics that have been developed for intravitreal use can also be used subconjunctivally, intrasclerally, and in the suprachoroidal space. Alternatively, site-specific devices, such microneedles, and therapeutics, such as hydrogel matrices, have been developed to enhance ocular drug delivery. This manuscript will review the recent research advances and patents on episcleral, intrascleral, and suprachoroidal routes of ocular drug delivery.

Recent insights into cutaneous immunization: How to vaccinate via the skin.

PubMed

Engelke, Laura; Winter, Gerhard; Hook, Sarah; Engert, Julia

2015-09-08

Technologies and strategies for cutaneous vaccination have been evolving significantly during the past decades. Today, there is evidence for increased efficacy of cutaneously delivered vaccines allowing for dose reduction and providing a minimally invasive alternative to traditional vaccination. Considerable progress has been made within the field of well-established cutaneous vaccination strategies: Jet and powder injection technologies, microneedles, microporation technologies, electroporation, sonoporation, and also transdermal and transfollicular vaccine delivery. Due to recent advances, the use of cutaneous vaccination can be expanded from prophylactic vaccination for infectious diseases into therapeutic vaccination for both infectious and non-infectious chronic conditions. This review will provide an insight into immunological processes occurring in the skin and introduce the key innovations of cutaneous vaccination technologies. Copyright © 2015 Elsevier Ltd. All rights reserved.

Admittance Control for Robot Assisted Retinal Vein Micro-Cannulation under Human-Robot Collaborative Mode.

PubMed

Zhang, He; Gonenc, Berk; Iordachita, Iulian

2017-10-01

Retinal vein occlusion is one of the most common retinovascular diseases. Retinal vein cannulation is a potentially effective treatment method for this condition that currently lies, however, at the limits of human capabilities. In this work, the aim is to use robotic systems and advanced instrumentation to alleviate these challenges, and assist the procedure via a human-robot collaborative mode based on our earlier work on the Steady-Hand Eye Robot and force-sensing instruments. An admittance control method is employed to stabilize the cannula relative to the vein and maintain it inside the lumen during the injection process. A pre-stress strategy is used to prevent the tip of microneedle from getting out of vein in in prolonged infusions, and the performance is verified through simulations.

Devices for overcoming biological barriers: the use of physical forces to disrupt the barriers.

PubMed

Mitragotri, Samir

2013-01-01

Overcoming biological barriers including skin, mucosal membranes, blood brain barrier as well as cell and nuclear membrane constitutes a key hurdle in the field of drug delivery. While these barriers serve the natural protective function in the body, they limit delivery of drugs into the body. A variety of methods have been developed to overcome these barriers including formulations, targeting peptides and device-based technologies. This review focuses on the use of physical methods including acoustic devices, electric devices, high-pressure devices, microneedles and optical devices for disrupting various barriers in the body including skin and other membranes. A summary of the working principles of these devices and their ability to enhance drug delivery is presented. Copyright © 2012. Published by Elsevier B.V.

CADDIS Volume 2. Sources, Stressors and Responses: Dissolved Oxygen

EPA Pesticide Factsheets

Introduction to the dissolved oxygen module, when to list dissolved oxygen as a candidate cause, ways to measure dissolved oxygen, simple and detailed conceptual model diagrams for dissolved oxygen, references for the dissolved oxygen module.

CADDIS Volume 2. Sources, Stressors and Responses: Dissolved Oxygen - Simple Conceptual Diagram

EPA Pesticide Factsheets

Introduction to the dissolved oxygen module, when to list dissolved oxygen as a candidate cause, ways to measure dissolved oxygen, simple and detailed conceptual model diagrams for dissolved oxygen, references for the dissolved oxygen module.

CADDIS Volume 2. Sources, Stressors and Responses: Dissolved Oxygen - Detailed Conceptual Diagram

EPA Pesticide Factsheets

Introduction to the dissolved oxygen module, when to list dissolved oxygen as a candidate cause, ways to measure dissolved oxygen, simple and detailed conceptual model diagrams for dissolved oxygen, references for the dissolved oxygen module.

An overview of dissolved organic carbon in groundwater and implications for drinking water safety

NASA Astrophysics Data System (ADS)

Regan, S.; Hynds, P.; Flynn, R.

2017-06-01

Dissolved organic carbon (DOC) is composed of a diverse array of compounds, predominantly humic substances, and is a near ubiquitous component of natural groundwater, notwithstanding climatic extremes such as arid and hyper-arid settings. Despite being a frequently measured parameter of groundwater quality, the complexity of DOC composition and reaction behaviour means that links between concentration and human health risk are difficult to quantify and few examples are reported in the literature. Measured concentrations from natural/unpolluted groundwater are typically below 4 mg C/l, whilst concentrations above these levels generally indicate anthropogenic influences and/or contamination issues and can potentially compromise water safety. Treatment processes are effective at reducing DOC concentrations, but refractory humic substance reaction with chlorine during the disinfection process produces suspected carcinogenic disinfectant by-products (DBPs). However, despite engineered artificial recharge systems being commonly used to remove DOC from recycled treated wastewaters, little research has been conducted on the presence of DBPs in potable groundwater systems. In recent years, the capacity to measure the influence of organic matter on colloidal contaminants and its influence on the mobility of pathogenic microorganisms has aided understanding of transport processes in aquifers. Additionally, advances in polymerase chain reaction techniques used for the detection, identification, and quantification of waterborne pathogens, provide a method to confidently investigate the behaviour of DOC and its effect on contaminant transfer in aquifers. This paper provides a summary of DOC occurrence in groundwater bodies and associated issues capable of indirectly affecting human health.

Atmospheric nitrogen deposition in south-east Scotland: Quantification of the organic nitrogen fraction in wet, dry and bulk deposition

NASA Astrophysics Data System (ADS)

González Benítez, Juan M.; Cape, J. Neil; Heal, Mathew R.; van Dijk, Netty; Díez, Alberto Vidal

Water soluble organic nitrogen (WSON) compounds are ubiquitous in precipitation and in the planetary boundary layer, and therefore are a potential source of bioavailable reactive nitrogen. This paper examines weekly rain data over a period of 22 months from June 2005 to March 2007 collected in 2 types of rain collector (bulk deposition and "dry + wet" deposition) located in a semi-rural area 15 km southwest of Edinburgh, UK (N55°51'44″, W3°12'19″). Bulk deposition collectors are denoted in this paper as "standard rain gauges", and they are the design used in the UK national network for monitoring precipitation composition. "Dry + wet" deposition collectors are flushing rain gauges and they are equipped with a rain detector (conductivity array), a spray nozzle, a 2-way valve and two independent bottles to collect funnel washings (dry deposition) and true wet deposition. On average, for the 27 weekly samples with 3 valid replicates for the 2 types of collectors, dissolved organic nitrogen (DON) represented 23% of the total dissolved nitrogen (TDN) in bulk deposition. Dry deposition of particles and gas on the funnel surface, rather than rain, contributed over half of all N-containing species (inorganic and organic). Some discrepancies were found between bulk rain gauges and flushing rain gauges, for deposition of both TDN and DON, suggesting biological conversion and loss of inorganic N in the flushing samplers.

Germanium and indium

USGS Publications Warehouse

Shanks, W.C. Pat; Kimball, Bryn E.; Tolcin, Amy C.; Guberman, David E.; Schulz, Klaus J.; DeYoung,, John H.; Seal, Robert R.; Bradley, Dwight C.

2017-12-19

Germanium and indium are two important elements used in electronics devices, flat-panel display screens, light-emitting diodes, night vision devices, optical fiber, optical lens systems, and solar power arrays. Germanium and indium are treated together in this chapter because they have similar technological uses and because both are recovered as byproducts, mainly from copper and zinc sulfides.The world’s total production of germanium in 2011 was estimated to be 118 metric tons. This total comprised germanium recovered from zinc concentrates, from fly ash residues from coal burning, and from recycled material. Worldwide, primary germanium was recovered in Canada from zinc concentrates shipped from the United States; in China from zinc residues and coal from multiple sources in China and elsewhere; in Finland from zinc concentrates from the Democratic Republic of the Congo; and in Russia from coal.World production of indium metal was estimated to be about 723 metric tons in 2011; more than one-half of the total was produced in China. Other leading producers included Belgium, Canada, Japan, and the Republic of Korea. These five countries accounted for nearly 95 percent of primary indium production.Deposit types that contain significant amounts of germanium include volcanogenic massive sulfide (VMS) deposits, sedimentary exhalative (SEDEX) deposits, Mississippi Valley-type (MVT) lead-zinc deposits (including Irish-type zinc-lead deposits), Kipushi-type zinc-lead-copper replacement bodies in carbonate rocks, and coal deposits.More than one-half of the byproduct indium in the world is produced in southern China from VMS and SEDEX deposits, and much of the remainder is produced from zinc concentrates from MVT deposits. The Laochang deposit in Yunnan Province, China, and the VMS deposits of the Murchison greenstone belt in Limpopo Province, South Africa, provide excellent examples of indium-enriched deposits. The SEDEX deposits at Bainiuchang, China (located in southeastern Yunnan Province), and the Dabaoshan SEDEX deposit (located in the Nanling region of China) contain indium-enriched sphalerite. Another major potential source of indium occurs in the polymetallic tin-tungsten belt in the Eastern Cordillera of the Andes Mountains of Bolivia. Deposits there occur as dense arrays of narrow, elongate, indium-enriched tin oxide-polymetallic sulfide veins in volcanic rocks and porphyry stocks.Information about the behavior of germanium and indium in the environment is limited. In surface weathering environments, germanium and indium may dissolve from host minerals and form complexes with chloride, fluoride, hydroxide, organic matter, phosphate, or sulfate compounds. The tendency for germanium and indium to be dissolved and transported largely depends upon the pH and temperature of the weathering solutions. Because both elements are commonly concentrated in sulfide minerals, they can be expected to be relatively mobile in acid mine drainage where oxidative dissolution of sulfide minerals releases metals and sulfuric acid, resulting in acidic pH values that allow higher concentrations of metals to be dissolved into solution.

Situ treatment of contaminated groundwater

DOEpatents

McNab, Jr., Walt W.; Ruiz, Roberto; Pico, Tristan M.

2001-01-01

A system for treating dissolved halogenated organic compounds in groundwater that relies upon electrolytically-generated hydrogen to chemically reduce the halogenated compounds in the presence of a suitable catalyst. A direct current is placed across at least a pair, or an array, of electrodes which are housed within groundwater wells so that hydrogen is generated at the cathode and oxygen at the anode. A pump is located within the well housing in which the cathode(s) is(are) located and draws in groundwater where it is hydrogenated via electrolysis, passes through a well-bore treatment unit, and then transported to the anode well(s) for reinjection into the ground. The well-bore treatment involves a permeable cylinder located in the well bore and containing a packed bed of catalyst material that facilitates the reductive dehalogenation of the halogenated organic compounds by hydrogen into environmentally benign species such as ethane and methane. Also, electro-osmatic transport of contaminants toward the cathode also contributes to contaminant mass removal. The only above ground equipment required are the transfer pipes and a direct circuit power supply for the electrodes. The electrode wells in an array may be used in pairs or one anode well may be used with a plurality of cathode wells. The DC current flow between electrode wells may be periodically reversed which controls the formation of mineral deposits in the alkaline cathode well-bore water, as well as to help rejuvenate the catalysis.

Wirelessly powered and remotely controlled valve-array for highly multiplexed analytical assay automation on a centrifugal microfluidic platform.

PubMed

Torres Delgado, Saraí M; Kinahan, David J; Nirupa Julius, Lourdes Albina; Mallette, Adam; Ardila, David Sáenz; Mishra, Rohit; Miyazaki, Celina M; Korvink, Jan G; Ducrée, Jens; Mager, Dario

2018-06-30

In this paper we present a wirelessly powered array of 128 centrifugo-pneumatic valves that can be thermally actuated on demand during spinning. The valves can either be triggered by a predefined protocol, wireless signal transmission via Bluetooth, or in response to a sensor monitoring a parameter like the temperature, or homogeneity of the dispersion. Upon activation of a resistive heater, a low-melting membrane (Parafilm™) is removed to vent an entrapped gas pocket, thus letting the incoming liquid wet an intermediate dissolvable film and thereby open the valve. The proposed system allows up to 12 heaters to be activated in parallel, with a response time below 3 s, potentially resulting in 128 actuated valves in under 30 s. We demonstrate, with three examples of common and standard procedures, how the proposed technology could become a powerful tool for implementing diagnostic assays on Lab-on-a-Disc. First, we implement wireless actuation of 64 valves during rotation in a freely programmable sequence, or upon user input in real time. Then, we show a closed-loop centrifugal flow control sequence for which the state of mixing of reagents, evaluated from stroboscopically recorded images, triggers the opening of the valves. In our last experiment, valving and closed-loop control are used to facilitate centrifugal processing of whole blood. Copyright © 2018 Elsevier B.V. All rights reserved.

Systematic assessment of microneedle injection into the mouse cornea

PubMed Central

2012-01-01

Background Corneal intrastromal injection is an important mode of gene-vector application to subepithelial layers. In a mouse model, this procedure is substantially complicated by the reduced corneal dimensions. Furthermore, it may be difficult to estimate the corneal area reached by the volume of a single injection. This study aimed to investigate intrastromal injections into the mouse cornea using different microneedles and to quantify the effect of injecting varying volumes. A reproducible injection technique is described. Methods Forty eyes of 20 129 Sv/J mice were tested. India ink was intrastromally injected using 30° beveled 33 G needles, tri-surface 25° beveled 35 G needles, or hand-pulled and 25° beveled glass needles. Each eye received a single injection of a volume of 1 or 2 μL. Corneoscleral buttons were fixed and flat mounted for computer-assisted quantification of the affected corneal area. Histological assessment was performed to investigate the intrastromal location of the injected dye. Results A mean corneal area of 5.0 ±1.4 mm2 (mean ± SD) and 7.7 ±1.4 mm2 was covered by intrastromal injections of 1 and 2 μL, respectively. The mean percentage of total corneal area reached ranged from 39% to 53% for 1 μL injections, and from 65% to 81% for 2 μL injections. Injections using the 33 G needles tended to provide the highest distribution area. Perforation rates were 8% for 30° beveled 33 G needles and 44% for tri-surface beveled 35 G needles. No perforation was observed with glass needle; however, intrastromal breakage of needle tips was noted in 25% of these cases. Conclusions Intracorneal injection using a 30° beveled 33 G needle was safe and effective. The use of tri-surface beveled 35 G needles substantially increased the number of corneal perforations. Glass needles may break inside the corneal stroma. Injections of 1 μL and 2 μL resulted in an overall mean of 49% and 73% respectively of total corneal area involved. PMID:22716296

Lidocaine permeation from a lidocaine NaCMC/gel microgel formulation in microneedle-pierced skin: vertical (depth averaged) and horizontal permeation profiles.

PubMed

Nayak, Atul; Short, Liam; Das, Diganta B

2015-08-01

Common local anaesthetics such as lidocaine are administered by the hypodermic parenteral route but it causes pain or anxiety to patients. Alternatively, an ointment formulation may be applied which involves a slow drug diffusion process. In addressing these two issues, this paper aims to understand the significance of the 'poke and patch' microneedle (MN) treatment on skin in conjunction to the lidocaine permeation, and in particular, the vertical (depth averaged) and horizontal (e.g. lateral) permeation profiles of the drug in the skin. The instantaneous pharmacokinetics of lidocaine in skin was determined by a skin denaturation technique coupled with Franz diffusion cell measurements of the drug pharmacokinetics. All pharmacokinetic profiles were performed periodically on porcine skin. Three MN insertion forces of 3.9, 7.9 and 15.7 N were applied on the MN to pierce the skin. For the smaller force (3.9 N), post MN-treated skin seems to provide an 'optimum' percutaneous delivery rate. A 10.2-fold increase in lidocaine permeation was observed for a MN insertion force of 3.9 N at 0.25 h and similarly, a 5.4-fold increase in permeation occurred at 0.5 h compared to passive diffusional delivery. It is shown that lidocaine permeates horizontally beyond the area of the MN-treated skin for the smaller MN insertion forces, namely, 3.9 and 7.9 N from 0.25 to 0.75 h, respectively. The lateral diffusion/permeation of lidocaine for larger MN-treated force (namely, 15.7 N in this work) seems to be insignificant at all recorded timings. The MN insertion force of 15.7 N resulted in lidocaine concentrations slightly greater than control (passive diffusion) but significantly less than 3.9 and 7.9 N impact force treatments on skin. We believe this likelihood is due to the skin compression effect that inhibits diffusion until the skin had time to relax at which point lidocaine levels increase.

Systematic assessment of microneedle injection into the mouse cornea.

PubMed

Matthaei, Mario; Meng, Huan; Bhutto, Imran; Xu, Qingguo; Boelke, Edwin; Hanes, Justin; Jun, Albert S

2012-06-20

Corneal intrastromal injection is an important mode of gene-vector application to subepithelial layers. In a mouse model, this procedure is substantially complicated by the reduced corneal dimensions. Furthermore, it may be difficult to estimate the corneal area reached by the volume of a single injection. This study aimed to investigate intrastromal injections into the mouse cornea using different microneedles and to quantify the effect of injecting varying volumes. A reproducible injection technique is described. Forty eyes of 20 129 Sv/J mice were tested. India ink was intrastromally injected using 30° beveled 33 G needles, tri-surface 25° beveled 35 G needles, or hand-pulled and 25° beveled glass needles. Each eye received a single injection of a volume of 1 or 2 μL. Corneoscleral buttons were fixed and flat mounted for computer-assisted quantification of the affected corneal area. Histological assessment was performed to investigate the intrastromal location of the injected dye. A mean corneal area of 5.0 ± 1.4 mm(2) (mean ± SD) and 7.7 ± 1.4 mm(2) was covered by intrastromal injections of 1 and 2 μL, respectively. The mean percentage of total corneal area reached ranged from 39% to 53% for 1 μL injections, and from 65% to 81% for 2 μL injections. Injections using the 33 G needles tended to provide the highest distribution area. Perforation rates were 8% for 30° beveled 33 G needles and 44% for tri-surface beveled 35 G needles. No perforation was observed with glass needle; however, intrastromal breakage of needle tips was noted in 25% of these cases. Intracorneal injection using a 30° beveled 33 G needle was safe and effective. The use of tri-surface beveled 35 G needles substantially increased the number of corneal perforations. Glass needles may break inside the corneal stroma. Injections of 1 μL and 2 μL resulted in an overall mean of 49% and 73% respectively of total corneal area involved.

Potential Cost-Effectiveness of an Influenza Vaccination Program Offering Microneedle Patch for Vaccine Delivery in Children.

PubMed

Wong, Carlos; Jiang, Minghuan; You, Joyce H S

2016-01-01

The influenza vaccine coverage rate of children is low in Hong Kong. Microneedle patches (MNPs) is a technology under development for painless delivery of vaccines. This study aimed to examine the potential clinical outcomes and direct medical costs of an influenza program offering MNP vaccine to children who have declined intramuscular (IM) vaccine in Hong Kong. A decision model was designed to compare potential outcomes between IM vaccine program and a program offering MNP vaccine to those declined IM vaccine (IM/MNP program) in a hypothetical cohort of children over one-year time horizon. The model outcomes included direct medical cost, influenza infection rate, mortality rate, and quality-adjusted life-years (QALYs) loss. Model inputs were retrieved from published literature. Sensitivity analyses were performed to examine the robustness of model results. In base-case analysis, IM/MNP program was more costly per child (USD19.13 versus USD13.69; USD1 = HKD7.8) with lower influenza infection rate (98.9 versus 124.8 per 1,000 children), hospitalization rate (0.83 versus 1.05 per 1,000 children) and influenza-related mortality rate (0.00042 versus 0.00052 per 1,000 children) when compared to IM program. The incremental cost per QALY saved (ICER) of IM/MNP program versus IM program was 27,200 USD/QALY. Using gross domestic product (GDP) per capita of Hong Kong (USD40,594) as threshold of willingness-to-pay (WTP) per QALY, one-way sensitivity analysis found ICER of IM/MNP to exceed WTP when duration of illness in outpatient setting was <5.7 days or cost per MNP vaccine was >1.39-time of IM vaccine cost. In 10,000 Monte Carlo simulations, IM/MNP program was the preferred option in 57.28% and 91.68% of the time, using 1x and 3x GDP per capita as WTP threshold, respectively. Acceptance of IM/MNP program as the preferred program was subject to the WTP threshold, duration of illness in outpatient settings, and cost of MNP vaccine.

Efficacy of functional microarray of microneedles combined with topical tranexamic acid for melasma: A randomized, self-controlled, split-face study.

PubMed

Xu, Yang; Ma, Renyan; Juliandri, Juliandri; Wang, Xiaoyan; Xu, Bai; Wang, Daguang; Lu, Yan; Zhou, Bingrong; Luo, Dan

2017-05-01

To evaluate the efficacy of a functional microarray of microneedles (MNs) plus topical tranexamic acid (TA) for melasma in middle-aged women in China.Thirty female subjects with melasma were enrolled in this study. The left or right side of the face was chosen randomly to be pretreated with a functional microarray of MNs, followed by topical 0.5% TA solution once per week for 12 weeks. The other half-face was the control, treated with a sham device plus topical 0.5% TA solution. At baseline and at weeks 4, 8, and 12 of treatment, clinical (photographic) evaluations and parameters determined by Visia were recorded. At baseline and week 12, patient satisfaction scores and the biophysical parameters measured by Mexameter were also recorded. Side effects were evaluated at baseline and at the end of the 12 weeks.In total, 28 women (93.3%) completed the study. The brown spots' scores measured by Visia were significantly lower on the combined therapy side than on the control side at 12 weeks after starting treatment; there was no significant difference between sides at 4 or 8 weeks. After 12 weeks, melanin index (MI) decreased significantly in both 2 groups, and the MI was significantly less on the combined side at week 12. Transepidermal water loss, roughness, skin hydration, skin elasticity, and erythema index showed no significant differences between 2 sides at baseline, 4, 8, and 12 weeks after treatment. Physicians' evaluations of photographs showed better results at week 12 with combined therapy: >25% improvement was observed in the MNs plus TA side in 25 patients, and in the TA side in only 10 patients. Subjective satisfaction scores on both sides increased significantly. The participants were more satisfied with the results of the combined therapy side than the control side. No obvious adverse reactions were observed throughout the study.Combined therapy with a functional microarray of MNs and topical TA solution is a promising treatment for melasma.

Texture etching of (100) silicon for solar cells

NASA Technical Reports Server (NTRS)

Dyer, L. D.

1985-01-01

A chemical means of creating the proper kind of light collection texture on (100) silicon slices is discussed. Texturing of (100) silicon surfaces in sodium or potassium hydroxides occurs by the growth of a reaction product in a random array of surface sites, which leads to pyramids remaining at the sites after other parts of the surface dissolve away. A new texture-promoting influence, a proximity effect, was discovered in this work. An attempt was made to quantify the various promotional effects. The purpose of the present paper is to: (1) explain in detail the attempt at understanding and quantifying texturing; (2) give an experimental description with observations on the proximity effect and the effect of additions of water glass that were discovered during this work; and (3) show that the precipitate or growth models account for almost all of the known promotional effects.

Solvent effects on the adsorption and self-organization of Mn12 on Au(111).

PubMed

Pineider, Francesco; Mannini, Matteo; Sessoli, Roberta; Caneschi, Andrea; Barreca, Davide; Armelao, Lidia; Cornia, Andrea; Tondello, Eugenio; Gatteschi, Dante

2007-11-06

A sulfur-containing single molecule magnet, [Mn12O12(O2CC6H4SCH3)16(H2O)4], was assembled from solution on a Au(111) surface affording both submonolayer and monolayer coverages. The adsorbate morphology and the degree of coverage were inspected by scanning tunneling microscopy (STM), while X-ray photoelectron spectroscopy (XPS) allowed the determination of the chemical nature of the adsorbate on a qualitative and quantitative basis. The properties of the adsorbates were found to be strongly dependent on the solvent used to dissolve the magnetic complex. In particular, systems prepared from tetrahydrofuran solutions gave arrays of isolated and partially ordered clusters on the gold substrate, while samples prepared from dichloromethane exhibited a homogeneous monolayer coverage of the whole Au(111) surface. These findings are relevant to the optimization of magnetic addressing of single molecule magnets on surfaces.

40 CFR 430.40 - Applicability; description of the dissolving sulfite subcategory.

Code of Federal Regulations, 2011 CFR

2011-07-01

... dissolving sulfite subcategory. 430.40 Section 430.40 Protection of Environment ENVIRONMENTAL PROTECTION... CATEGORY Dissolving Sulfite Subcategory § 430.40 Applicability; description of the dissolving sulfite... at dissolving sulfite mills. ...

40 CFR 430.40 - Applicability; description of the dissolving sulfite subcategory.

Code of Federal Regulations, 2010 CFR

2010-07-01

... dissolving sulfite subcategory. 430.40 Section 430.40 Protection of Environment ENVIRONMENTAL PROTECTION... CATEGORY Dissolving Sulfite Subcategory § 430.40 Applicability; description of the dissolving sulfite... at dissolving sulfite mills. ...

A comparative study on the transdermal penetration effect of gaseous and aqueous plasma reactive species

NASA Astrophysics Data System (ADS)

Liu, Xin; Gan, Lu; Ma, Mingyu; Zhang, Song; Liu, Jingjing; Chen, Hongxiang; Liu, Dawei; Lu, Xinpei

2018-02-01

To improve the depth of plasma active species in the skin, it is very important to develop skin disease treatment using plasma. In this article, an air plasma source was used to work directly with the skin of a mouse. A tortuous pathway, hair follicles, electroporation and a microneedle do not aid the transdermal delivery of gaseous plasma active species, therefore these gaseous plasma active species cannot penetrate mouse skin with a thickness of ~0.75 mm. The plasma activated water (PAW) produced by the air plasma source was used to study the transdermal penetration of the aqueous plasma activated species. This aqueous plasma activated species can penetrate the skin through hair follicles, intercellular and transcellular routes. The pH of the PAW did not affect the penetration efficiency of the aqueous plasma active species.

Micromachined electrical cauterizer

DOEpatents

Lee, Abraham P.; Krulevitch, Peter A.; Northrup, M. Allen

1999-01-01

A micromachined electrical cauterizer. Microstructures are combined with microelectrodes for highly localized electro cauterization. Using boron etch stops and surface micromachining, microneedles with very smooth surfaces are made. Micromachining also allows for precision placement of electrodes by photolithography with micron sized gaps to allow for concentrated electric fields. A microcauterizer is fabricated by bulk etching silicon to form knife edges, then parallelly placed microelectrodes with gaps as small as 5 .mu.m are patterned and aligned adjacent the knife edges to provide homeostasis while cutting tissue. While most of the microelectrode lines are electrically insulated from the atmosphere by depositing and patterning silicon dioxide on the electric feedthrough portions, a window is opened in the silicon dioxide to expose the parallel microelectrode portion. This helps reduce power loss and assist in focusing the power locally for more efficient and safer procedures.

Micromachined electrical cauterizer

DOEpatents

Lee, A.P.; Krulevitch, P.A.; Northrup, M.A.

1999-08-31

A micromachined electrical cauterizer is disclosed. Microstructures are combined with microelectrodes for highly localized electro cauterization. Using boron etch stops and surface micromachining, microneedles with very smooth surfaces are made. Micromachining also allows for precision placement of electrodes by photolithography with micron sized gaps to allow for concentrated electric fields. A microcauterizer is fabricated by bulk etching silicon to form knife edges, then parallelly placed microelectrodes with gaps as small as 5 {mu}m are patterned and aligned adjacent the knife edges to provide homeostasis while cutting tissue. While most of the microelectrode lines are electrically insulated from the atmosphere by depositing and patterning silicon dioxide on the electric feedthrough portions, a window is opened in the silicon dioxide to expose the parallel microelectrode portion. This helps reduce power loss and assist in focusing the power locally for more efficient and safer procedures. 7 figs.

Protocol for chromosome-specific probe construction using PRINS, micromanipulation and DOP-PCR techniques.

PubMed

Passamani, Paulo Z; Carvalho, Carlos R; Soares, Fernanda A F

2018-01-01

Chromosome-specific probes have been widely used in molecular cytogenetics, being obtained with different methods. In this study, a reproducible protocol for construction of chromosome-specific probes is proposed which associates in situ amplification (PRINS), micromanipulation and degenerate oligonucleotide-primed PCR (DOP-PCR). Human lymphocyte cultures were used to obtain metaphases from male and female individuals. The chromosomes were amplified via PRINS, and subcentromeric fragments of the X chromosome were microdissected using microneedles coupled to a phase contrast microscope. The fragments were amplified by DOP-PCR and labeled with tetramethyl-rhodamine-5-dUTP. The probes were used in fluorescent in situ hybridization (FISH) procedure to highlight these specific regions in the metaphases. The results show one fluorescent red spot in male and two in female X chromosomes and interphase nuclei.

Lessons from mosquitoes' painless piercing.

PubMed

Gurera, Dev; Bhushan, Bharat; Kumar, Navin

2018-05-18

Arthropods are the largest group of the living organisms. They attack other organisms by biting, stinging, or piercing and sucking. Among various medically important arthropods, which feed on living hosts, mosquitoes' piercing spread viruses which have been reported to cause the highest number of deaths annually. The primary cause of the deaths is malaria, which is spread by infected mosquitoes' piercing. This study aims at elucidating lessons from mosquitoes' painless piercing. Mosquitoes pierce using their fascicle, which is a bundle of coherently functioning six stylets. Based on experiments and available literature, it is presented that mosquitoes painlessly pierce using a combination of the numbing, the fascicle's serrated design, the vibratory actuation, and the graded and frequency-dependent mechanical properties of the labrum. Based on this understanding, a mosquito-inspired microneedle design has also been proposed. Copyright © 2018 Elsevier Ltd. All rights reserved.

Intradermal inactivated poliovirus vaccine: a preclinical dose-finding study.

PubMed

Kouiavskaia, Diana; Mirochnitchenko, Olga; Dragunsky, Eugenia; Kochba, Efrat; Levin, Yotam; Troy, Stephanie; Chumakov, Konstantin

2015-05-01

Intradermal delivery of vaccines has been shown to result in dose sparing. We tested the ability of fractional doses of inactivated poliovirus vaccine (IPV) delivered intradermally to induce levels of serum poliovirus-neutralizing antibodies similar to immunization through the intramuscular route. Immunogenicity of fractional doses of IPV was studied by comparing intramuscular and intradermal immunization of Wistar rats using NanoPass MicronJet600 microneedles. Intradermal delivery of partial vaccine doses induced antibodies at titers comparable to those after immunization with full human dose delivered intramuscularly. The results suggest that intradermal delivery of IPV may lead to dose-sparing effect and reduction of the vaccination cost. Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.

40 CFR 430.40 - Applicability; description of the dissolving sulfite subcategory.

Code of Federal Regulations, 2014 CFR

2014-07-01

... dissolving sulfite subcategory. 430.40 Section 430.40 Protection of Environment ENVIRONMENTAL PROTECTION... SOURCE CATEGORY Dissolving Sulfite Subcategory § 430.40 Applicability; description of the dissolving... production of pulp at dissolving sulfite mills. ...

40 CFR 430.40 - Applicability; description of the dissolving sulfite subcategory.

Code of Federal Regulations, 2012 CFR

2012-07-01

... dissolving sulfite subcategory. 430.40 Section 430.40 Protection of Environment ENVIRONMENTAL PROTECTION... SOURCE CATEGORY Dissolving Sulfite Subcategory § 430.40 Applicability; description of the dissolving... production of pulp at dissolving sulfite mills. ...

40 CFR 430.40 - Applicability; description of the dissolving sulfite subcategory.

Code of Federal Regulations, 2013 CFR

2013-07-01

... dissolving sulfite subcategory. 430.40 Section 430.40 Protection of Environment ENVIRONMENTAL PROTECTION... SOURCE CATEGORY Dissolving Sulfite Subcategory § 430.40 Applicability; description of the dissolving... production of pulp at dissolving sulfite mills. ...

Mineral Adsorbents for Removal of Metals in Urban Runoff

NASA Astrophysics Data System (ADS)

Bjorklund, Karin; Li, Loretta

2014-05-01

The aim of this research was to determine the capacity of four different soil minerals to adsorb metals frequently detected in urban runoff. These are low-cost, natural and commercially available soil minerals. Contaminated surface runoff from urban areas is a major cause of concern for water quality and aquatic ecosystems worldwide. Pollution in urban areas is generated by a wide array of non-point sources, including vehicular transportation and building materials. Some of the most frequently detected pollutants in urban runoff are metals. Exhaust gases, tire wear and brake linings are major sources of such metals as Pb, Zn and Cu, while impregnated wood, plastics and galvanized surfaces may release As, Cd, Cr and Zn. Many metals have toxic effects on aquatic plants and animals, depending on metal speciation and bioavailability. The removal efficiency of pollutants in stormwater depends on treatment practices and on the properties the pollutant. The distribution of metals in urban runoff has shown, for example, that Pb is predominantly particle-associated, whereas Zn and Cd are present mainly in dissolved form. Many metals are also attached to colloids, which may act as carriers for contaminants, thereby facilitating their transport through conventional water treatment processes. Filtration of stormwater is one of the most promising techniques for removal of particulates, colloidal and truly dissolved pollutants, provided that effective filtration and adsorption media are used. Filtration and infiltration are used in a wide array of stormwater treatment methods e.g. porous paving, infiltration drains and rain gardens. Several soil minerals were investigated for their potential as stormwater filter materials. Laboratory batch tests were conducted to determine the adsorption capacity of these minerals. A synthetic stormwater was tested, with spiked concentrations corresponding to levels reported in urban runoff, ranging from 50-1,500 µg/L for Zn; 5-250 µg/L for Cu, 2-20 µg/L for Cd and 10-150 µg/L for Ni and Pb. Humic acids were used to imitate natural stormwater contaminated with natural organic matter. The adsorption kinetics was also investigated through a sequence (10-120 min) of batch tests. By studying the capacity of a range of sorbents in batch tests under identical conditions, the most promising sorbent can be identified. The research is ongoing. Preliminary results will be presented.

Structurally integrated organic light emitting device-based sensors for gas phase and dissolved oxygen.

PubMed

Shinar, Ruth; Zhou, Zhaoqun; Choudhury, Bhaskar; Shinar, Joseph

2006-05-24

A compact photoluminescence (PL)-based O2 sensor utilizing an organic light emitting device (OLED) as the light source is described. The sensor device is structurally integrated. That is, the sensing element and the light source, both typically thin films that are fabricated on separate glass substrates, are attached back-to-back. The sensing elements are based on the oxygen-sensitive dyes Pt- or Pd-octaethylporphyrin (PtOEP or PdOEP, respectively), which are embedded in a polystyrene (PS) matrix, or dissolved in solution. Their performance is compared to that of a sensing element based on tris(4,7-diphenyl-l,10-phenanthroline) Ru II (Ru(dpp)) embedded in a sol-gel film. A green OLED light source, based on tris(8-hydroxy quinoline Al (Alq3), was used to excite the porphyrin dyes; a blue OLED, based on 4,4'-bis(2,2'-diphenylviny1)-1,1'-biphenyl, was used to excite the Ru(dpp)-based sensing element. The O2 level was monitored in the gas phase and in water, ethanol, and toluene solutions by measuring changes in the PL lifetime tau of the O2-sensitive dyes. The sensor performance was evaluated in terms of the detection sensitivity, dynamic range, gas flow rate, and temperature effect, including the temperature dependence of tau in pure Ar and O2 atmospheres. The dependence of the sensitivity on the preparation procedure of the sensing film and on the PS and dye concentrations in the sensing element, whether a solid matrix or solution, were also evaluated. Typical values of the detection sensitivity in the gas phase, S(g) identical with tau(0% O2)/tau(100% O2), at 23 degrees C, were approximately 35 to approximately 50 for the [Alq3 OLED[/[PtOEP dye] pair; S(g) exceeded 200 for the Alq3/PdOEP sensor. For dissolved oxygen (DO) in water and ethanol, S(DO) (defined as the ratio of tau in de-oxygenated and oxygen-saturated solutions) was approximately 9.5 and approximately 11, respectively, using the PtOEP-based film sensor. The oxygen level in toluene was measured with PtOEP dissolved directly in the solution. That sensor exhibited a high sensitivity, but a limited dynamic range. Effects of aggregation of dye molecules, sensing film porosity, and the use of the OLED-based sensor arrays for O2 and multianalyte detection are also discussed.

40 CFR 430.10 - Applicability; description of the dissolving kraft subcategory.

Code of Federal Regulations, 2012 CFR

2012-07-01

... dissolving kraft subcategory. 430.10 Section 430.10 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... CATEGORY Dissolving Kraft Subcategory § 430.10 Applicability; description of the dissolving kraft subcategory. The provisions of this subpart apply to discharges resulting from the production of dissolving...

40 CFR 430.10 - Applicability; description of the dissolving kraft subcategory.

Code of Federal Regulations, 2014 CFR

2014-07-01

... dissolving kraft subcategory. 430.10 Section 430.10 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... CATEGORY Dissolving Kraft Subcategory § 430.10 Applicability; description of the dissolving kraft subcategory. The provisions of this subpart apply to discharges resulting from the production of dissolving...

40 CFR 430.10 - Applicability; description of the dissolving kraft subcategory.

Code of Federal Regulations, 2013 CFR

2013-07-01

... dissolving kraft subcategory. 430.10 Section 430.10 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... CATEGORY Dissolving Kraft Subcategory § 430.10 Applicability; description of the dissolving kraft subcategory. The provisions of this subpart apply to discharges resulting from the production of dissolving...

Dissolved trace elements in a nitrogen-polluted river near to the Liaodong Bay in Northeast China.

PubMed

Bu, Hongmei; Song, Xianfang; Guo, Fen

2017-01-15

Dissolved trace element concentrations (Ba, Fe, Mn, Si, Sr, and Zn) were investigated in the Haicheng River near to the Liaodong Bay in Northeast China during 2010. Dissolved Ba, Fe, Mn, and Sr showed significant spatial variation, whereas dissolved Fe, Mn, and Zn displayed seasonal variations. Conditions such as water temperature, pH, and dissolved oxygen were found to have an important impact on redox reactions involving dissolved Ba, Fe, and Zn. Dissolved Fe and Mn concentrations were regulated by adsorption or desorption of Fe/Mn oxyhydroxides and the effects of organic carbon complexation on dissolved Ba and Sr were found to be significant. The sources of dissolved trace elements were found to be mainly from domestic sewage, industrial waste, agricultural surface runoff, and natural origin, with estimated seasonal and annual river fluxes established as important inputs of dissolved trace elements from the Haicheng River into the Liaodong Bay or Bohai Sea. Copyright © 2016 Elsevier Ltd. All rights reserved.

40 CFR 430.10 - Applicability; description of the dissolving kraft subcategory.

Code of Federal Regulations, 2011 CFR

2011-07-01

... dissolving kraft subcategory. 430.10 Section 430.10 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... Dissolving Kraft Subcategory § 430.10 Applicability; description of the dissolving kraft subcategory. The provisions of this subpart apply to discharges resulting from the production of dissolving pulp at kraft...

40 CFR 430.10 - Applicability; description of the dissolving kraft subcategory.

Code of Federal Regulations, 2010 CFR

2010-07-01

... dissolving kraft subcategory. 430.10 Section 430.10 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... Dissolving Kraft Subcategory § 430.10 Applicability; description of the dissolving kraft subcategory. The provisions of this subpart apply to discharges resulting from the production of dissolving pulp at kraft...

Geochemical and hydrological characterization of shallow aquifer water following a nearby deep CO2 injection in Wellington, Kansas

NASA Astrophysics Data System (ADS)

Datta, S.; Andree, I.; Johannesson, K. H.; Kempton, P. D.; Barker, R.; Birdie, T. R.; Watney, W. L.

2017-12-01

Salinization or CO2 leakage from local Enhanced Oil Recovery (EOR) projects has become a possible source for contamination and water quality degradation for local irrigation or potable well users in Wellington, Kansas. Shallow domestic and monitoring wells, as well as surface water samples collected from the site, were analyzed for a wide array of geochemical proxies including major and trace ions, rare earth elements (REE), stable isotopes, dissolved organic carbon and dissolved hydrocarbons; these analytes were employed as geotracers to understand the extent of hydrologic continuity throughout the Paleozoic stratigraphic section. Previous research by Barker et al. (2012) laid the foundation through a mineralogical and geochemical investigation of the Arbuckle injection zone and assessment of overlying caprock integrity, which led to the conclusion that the 4,910-5,050' interval will safely sequester CO2 with high confidence of a low leakage potential. EOR operations using CO2 as the injectant into the Mississippian 3,677-3,706' interval was initiated in Jan 2016. Two groundwater sampling events were conducted to investigate any temporal changes in the surface and subsurface waters. Dissolved (Ca+Mg)/Na and Na/Cl mass ratio values of two domestic wells and one monitoring well ranged from 0.67 to 2.01 and 0.19 to 0.39, respectively, whereas a nearby Mississippian oil well had values of 0.20 and 0.62, respectively . δ18O and δ2H ranged from -4.74 to -5.41 ‰VSMOW and -31.4 to -34.3 ‰VSMOW, respectively, among the domestic wells and shallowest monitoring well. Conservative ion relationships in drill-stem-test waters from Arbuckle and Mississippian injection zones displayed significant variability, indicating limited vertical hydrologic communication. Total aquifer connectivity is inconclusive based on the provided data; however, a paleoterrace and incised valley within the study site are thought to be connected through a Mississippian salt plume migration passing through the major domestic wells and a well at 200 ft depth. REE patterns of the shallow monitoring wells indicate a different water source than the domestic wells in the study area.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jull, A.J.T.

Since 1981 we have operated an NSF Accelerator Mass Spectrometry (AMS) Facility at the University of Arizona. The AMS method allows us to use very small samples of carbon, <1 mg for radiocarbon dating in contrast to earlier counting techniques. This has opened a vast array of applications of radiocarbon dating that was difficult to do before AMS because of sample size limitations of decay counting. Some of the many applications of AMS include paleoclimatic studies, archaeological research and the age of first settlement of North America by man, dating of art works and artifacts, fall times and terrestrial residencemore » ages of meteorites, production of {sup 14}C in lunar samples by galactic and solar cosmic rays, studies of in situ {sup 14}C produced by cosmic ray spallation in rocks and ice, and studies of {sup 14}C in groundwater dissolved inorganic carbon and dissolved organic carbon. At our laboratory, we have also successfully applied AMS {sup 14}C to dating of many types of textiles, including silks and linens, art works, documents and artifacts fabricated from wood, parchment, ivory, and bone. The results for many of these samples are often important in questions of the authenticity of these works of art and artifacts. Our studies have encompassed a wide range of art works ranging from the Dead Sea Scrolls, the Shroud of Turin, and the Chinese silk trade to the works of Raphael, Rembrandt, and Picasso. Recently, we also dated the Vinland Map, a controversial document that shows the eastern coast of North America apparently using information from Viking voyages.« less

Distinguishing dissolved organic matter at its origin: size and optical properties of leaf-litter leachates.

PubMed

Cuss, C W; Guéguen, C

2013-09-01

Dissolved organic matter (DOM) was leached from eight distinct samples of leaves taken from six distinct trees (red maple, bur oak at three times of the year, two sugar maple and two white spruce trees from disparate soil types). Multiple samples were taken over 72-96h of leaching. The size and optical properties of leachates were assessed using asymmetrical flow field-flow fractionation (AF4) coupled to diode-array ultraviolet/visible absorbance and excitation-emission matrix fluorescence detectors (EEM). The fluorescence of unfractionated samples was also analyzed. EEMs were analyzed using parallel factor analysis (PARAFAC) and principal component analysis (PCA) of proportional component loadings. Both the unfractionated and AF4-fractionated leachates had distinct size and optical properties. The 95% confidence ranges for molecular weight distributions were determined as: 210-440Da for spruce, 540-920Da for sugar maple, 630-800Da for spring oak leaves, 930-950Da for senescent oak, 1490-1670 for senescent red maple, and 3430-4270Da for oak leaves that were collected from the ground after spring thaw. In most cases the fluorescence properties of leachates were different for individuals from different soil types and across seasons; however, PCA of PARAFAC loadings revealed that the observed distinctiveness was chiefly species-based. Strong correlations were found between the molecular weight distribution of both unfractionated and fractionated leachates and their principal component loadings (R(2)=0.85 and 0.95, respectively). It is concluded that results support a species-based origin for differences in optical properties. Copyright © 2013 Elsevier Ltd. All rights reserved.

Characterization of dissolved organic matter in fogwater by excitation-emission matrix fluorescence spectroscopy

NASA Astrophysics Data System (ADS)

Birdwell, Justin E.; Valsaraj, Kalliat T.

Dissolved organic matter (DOM) present in fogwater samples collected in southeastern Louisiana and central-eastern China has been characterized using excitation-emission matrix fluorescence spectroscopy. The goal of the study was to illustrate the utility of fluorescence for obtaining information on the large fraction of organic carbon in fogwaters (typically >40% by weight) that defies characterization in terms of specific chemical compounds without the difficulty inherent in obtaining sufficient fogwater volume to isolate DOM for assessment using other spectroscopic and chemical analyses. Based on the findings of previous studies using other characterization methods, it was anticipated that the unidentified organic carbon fraction would have characteristic peaks associated with humic substances and fluorescent amino acids. Both humic- and protein-like fluorophores were observed in the fogwater spectra and fluorescence-derived indices for the fogwater had similar values to those of soil and sediment porewater. Greater biological character was observed in samples with higher organic carbon concentrations. Fogwaters are shown to contain a mixture of terrestrially- and microbially-derived fluorescent organic material, which is expected to be derived from an array of different sources, such as suspended soil and dust particles, biogenic emissions and organic substances generated by atmospheric processes. The fluorescence results indicate that much of the unidentified organic carbon present in fogwater can be represented by humic-like and biologically-derived substances similar to those present in other aquatic systems, though it should be noted that fluorescent signatures representative of DOM produced by atmospheric processing of organic aerosols may be contributing to or masked by humic-like fluorophores.

Preferential adsorption of fluorescing fulvic and humic acid components on activated carbon using flow field-flow fractionation analysis.

PubMed

Schmit, Kathryn H; Wells, Martha J M

2002-02-01

Activated carbon treatment of drinking water is used to remove natural organic matter (NOM) precursors that lead to the formation of disinfection byproducts. The innate hydrophobic nature and macromolecular size of NOM render it amenable to sorption by activated carbon. Batch equilibrium and minicolumn breakthrough adsorption studies were performed using granular activated carbon to treat NOM-contaminated water. Ultraviolet (UV) absorption spectroscopy and flow field-flow fractionation analysis using tandem diode-array and fluorescence detectors were used to monitor the activated carbon sorption of NOM. Using these techniques, it was possible to study activated carbon adsorption properties of UV absorbing, fluorescing and nonfluorescing, polyelectrolytic macromolecules fractionated from the total macromolecular and nonmacromolecular composition of NOM. Adsorption isotherms were constructed at pH 6 and pH 9. Data were described by the traditional and modified Freundlich models. Activated carbon capacity and adsorbability were compared among fractionated molecular subsets of fulvic and humic acids. Preferential adsorption (or adsorptive fractionation) of polyelectrolytic, fluorescing fulvic and humic macromolecules on activated carbon was observed. The significance of observing preferential adsorption on activated carbon of fluorescing macromolecular components relative to nonfluorescing components is that this phenomenon changes the composition of dissolved organic matter remaining in equilibrium in the aqueous phase relative to the composition that existed in the aqueous phase prior to adsorption. Likewise, it changes the composition of dissolved organic matter remaining in equilibrium in the aqueous phase relative to the adsorbed phase. This research increases our understanding of NOM interactions with activated carbon which may lead to improved methods of potable water production.

Characterization of dissolved organic matter in fogwater by excitation-emission matrix fluorescence spectroscopy

USGS Publications Warehouse

Birdwell, J.E.; Valsaraj, K.T.

2010-01-01

Dissolved organic matter (DOM) present in fogwater samples collected in southeastern Louisiana and central-eastern China has been characterized using excitation-emission matrix fluorescence spectroscopy. The goal of the study was to illustrate the utility of fluorescence for obtaining information on the large fraction of organic carbon in fogwaters (typically >40% by weight) that defies characterization in terms of specific chemical compounds without the difficulty inherent in obtaining sufficient fogwater volume to isolate DOM for assessment using other spectroscopic and chemical analyses. Based on the findings of previous studies using other characterization methods, it was anticipated that the unidentified organic carbon fraction would have characteristic peaks associated with humic substances and fluorescent amino acids. Both humic- and protein-like fluorophores were observed in the fogwater spectra and fluorescence-derived indices for the fogwater had similar values to those of soil and sediment porewater. Greater biological character was observed in samples with higher organic carbon concentrations. Fogwaters are shown to contain a mixture of terrestrially- and microbially-derived fluorescent organic material, which is expected to be derived from an array of different sources, such as suspended soil and dust particles, biogenic emissions and organic substances generated by atmospheric processes. The fluorescence results indicate that much of the unidentified organic carbon present in fogwater can be represented by humic-like and biologically-derived substances similar to those present in other aquatic systems, though it should be noted that fluorescent signatures representative of DOM produced by atmospheric processing of organic aerosols may be contributing to or masked by humic-like fluorophores. ?? 2010.