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    Zebrafish needle EMG: a new tool for high-throughput drug screens. Cho Sung-Joon,Nam Tai-Seung,Byun Donghak,Choi Seok-Yong,Kim Myeong-Kyu,Kim Sohee Journal of neurophysiology Zebrafish models have recently been highlighted as a valuable tool in studying the molecular basis of neuromuscular diseases and developing new pharmacological treatments. Needle electromyography (EMG) is needed not only for validating transgenic zebrafish models with muscular dystrophies (MD), but also for assessing the efficacy of therapeutics. However, performing needle EMG on larval zebrafish has not been feasible due to the lack of proper EMG sensors and systems for such small animals. We introduce a new type of EMG needle electrode to measure intramuscular activities of larval zebrafish, together with a method to hold the animal in position during EMG, without anesthetization. The silicon-based needle electrode was found to be sufficiently strong and sharp to penetrate the skin and muscles of zebrafish larvae, and its shape and performance did not change after multiple insertions. With the use of the proposed needle electrode and measurement system, EMG was successfully performed on zebrafish at 30 days postfertilization (dpf) and at 5 dpf. Burst patterns and spike morphology of the recorded EMG signals were analyzed. The measured single spikes were triphasic with an initial positive deflection, which is typical for motor unit action potentials, with durations of ∼10 ms, whereas the muscle activity was silent during the anesthetized condition. These findings confirmed the capability of this system of detecting EMG signals from very small animals such as 5 dpf zebrafish. The developed EMG sensor and system are expected to become a helpful tool in validating zebrafish MD models and further developing therapeutics. 10.1152/jn.00538.2015
    Towards pain-free diagnosis of skin diseases through multiplexed microneedles: biomarker extraction and detection using a highly sensitive blotting method. Ng Keng Wooi,Lau Wing Man,Williams Adrian C Drug delivery and translational research Immunodiagnostic microneedles provide a novel way to extract protein biomarkers from the skin in a minimally invasive manner for analysis in vitro. The technology could overcome challenges in biomarker analysis specifically in solid tissue, which currently often involves invasive biopsies. This study describes the development of a multiplex immunodiagnostic device incorporating mechanisms to detect multiple antigens simultaneously, as well as internal assay controls for result validation. A novel detection method is also proposed. It enables signal detection specifically at microneedle tips and therefore may aid the construction of depth profiles of skin biomarkers. The detection method can be coupled with computerised densitometry for signal quantitation. The antigen specificity, sensitivity and functional stability of the device were assessed against a number of model biomarkers. Detection and analysis of endogenous antigens (interleukins 1α and 6) from the skin using the device was demonstrated. The results were verified using conventional enzyme-linked immunosorbent assays. The detection limit of the microneedle device, at ≤10 pg/mL, was at least comparable to conventional plate-based solid-phase enzyme immunoassays. 10.1007/s13346-015-0231-5
    Intradermal insulin infusion achieves faster insulin action than subcutaneous infusion for 3-day wear. Rini Christopher James,McVey Elaine,Sutter Diane,Keith Stephen,Kurth Heinz-Joerg,Nosek Leszek,Kapitza Christoph,Rebrin Kerstin,Hirsch Laurence,Pettis Ronald J Drug delivery and translational research Rapid uptake previously demonstrated by intradermal (ID) drug administration indicates compound delivery within the dermis may have clinical and pharmacological advantages for certain drug therapies. This study is the first clinical trial to evaluate continuous microneedle-based drug infusion, device wearability, and intradermal microneedle insulin kinetics over a multi-day (72 h) wear period. This was a single center, open-label, two-period crossover study in T1DM patients on continuous subcutaneous insulin infusion (CSII). Patients received treatment during interventional visits: one SC and one ID basal/bolus infusion of insulin aspart (NovoRapid® U-100) administered over 3 days in a randomized order. Twenty-eight patients were randomized and exposed to trial product, and 23 completed the study. Bolus insulin infusions were given prior to standardized breakfast and lunch test meals on each of the three treatment days. Blood samples were drawn at predefined time points for measurements of insulin aspart and blood glucose in serum. The primary endpoint insulin Tmax demonstrated that ID bolus infusion was associated with a significantly shorter Tmax with statistically significantly smaller intra-subject variability, compared to SC infusion, and this difference was maintained over three treatment days. Analyses of secondary PK endpoints corresponded with the primary endpoint findings. Postprandial glycemic response was significantly less pronounced after ID bolus: For most endpoints ID vs. SC, differences were statistically significant within the 0-1.5 or 0-2 h time period. Intradermal delivery of insulin is a viable delivery route alternative providing reduced time for insulin absorption with less intra-subject variability and lower glycemic response. 10.1007/s13346-015-0239-x
    Microneedles: an innovative platform for gene delivery. McCaffrey Joanne,Donnelly Ryan F,McCarthy Helen O Drug delivery and translational research The advent of microneedle (MN) technology has provided a revolutionary platform for the delivery of therapeutic agents, particularly in the field of gene therapy. For over 20 years, the area of gene therapy has undergone intense innovation and progression which has seen advancement of the technology from an experimental concept to a widely acknowledged strategy for the treatment and prevention of numerous disease states. However, the true potential of gene therapy has yet to be achieved due to limitations in formulation and delivery technologies beyond parenteral injection of the DNA. Microneedle-mediated delivery provides a unique platform for the delivery of DNA therapeutics clinically. It provides a means to overcome the skin barriers to gene delivery and deposit the DNA directly into the dermal layers, a key site for delivery of therapeutics to treat a wide range of skin and cutaneous diseases. Additionally, the skin is a tissue rich in immune sentinels, an ideal target for the delivery of a DNA vaccine directly to the desired target cell populations. This review details the advancement of MN-mediated DNA delivery from proof-of-concept to the delivery of DNA encoding clinically relevant proteins and antigens and examines the key considerations for the improvement of the technology and progress into a clinically applicable delivery system. 10.1007/s13346-015-0243-1
    Effect of microporation on passive and iontophoretic delivery of diclofenac sodium. Patel Hiren,Joshi Abhay,Joshi Amit,Stagni Grazia Drug development and industrial pharmacy Skin pretreatment with a microneedle roller (microporation (MP)) appears a simple and inexpensive technique to increase transdermal delivery of topically applied drug products. This study investigates the effect of MP on the passive and iontophoretic delivery of diclofenac (DCF) by quantifying dermis and plasma levels of DCF in a rabbit model. New Zealand albino female rabbits received either: (i) a topical application of 4 g of Voltaren® 1% gel with or without pretreatment with a microroller (0.5 mm needle length; density 23 microneedles per cm(2) area) or (ii) a DCF solution (40 mg/2.5 mL) via iontophoresis (IOMED transQ(E) medium size patch), with or without microroller pretreatment. A 300 µA/cm(2) cathodic current was applied for 20 min for a total of 80 mA. DCF concentrations were monitored in dermis with microdialysis sampling every 20 min for 5 h. Plasma samples were collected over the same period. In the passive delivery studies, microroller pretreatment increased Cmax by 1.5- and 2.0-fold in skin and plasma, respectively, and AUC by 1.5- and 2.4-fold in skin and plasma, respectively. In the iontophoresis delivery studies, microporation increased Cmax by 2.0-fold both in skin and in plasma, and AUC by 1.1- and 1.8-fold in skin and plasma, respectively. In conclusion, microneedle pretreatment increased significantly the systemic exposure of DCF from either passive or iontophoretic delivery, whereas the effect in skin was less pronounced. 10.3109/03639045.2015.1019353
    Vaccination with human papillomavirus pseudovirus-encapsidated plasmids targeted to skin using microneedles. 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 PloS one 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. 10.1371/journal.pone.0120797
    Effects of Jae-Seng Acupuncture Treatment on the Improvement of Nasolabial Folds and Eye Wrinkles. Cho Jin Hyong,Lee Ho Jin,Chung Kyu Jin,Park Byung Chun,Chang Mun Seog,Park Seong Kyu Evidence-based complementary and alternative medicine : eCAM The microneedle therapy system (MTS), a mechanical method involving making minute multiple holes in the skin, reportedly improves skin condition, such as by reducing flushing and melanin. A newly attempted bloodletting therapy, Jae-Seng Acupuncture, has several advantages over traditional mechanical punching methods because it allows the practitioner to regulate the depth and direction of needle stimulations and to choose whether to stimulate the muscle layers. This study was conducted to determine the efficacy of Jae-Seng Acupuncture in the treatment of nasolabial folds and eye wrinkles. The nasolabial folds and eye wrinkles of 107 patients ranging in age from their 20s to their 70s were subjected to DermaVision, a digital skin image analyzer, before the treatment and one to six months after treatment. Additionally, stimulation of the meridians, such as Taeyang, Tongjaryo, Chongmyong, Sungup, Sabaek, Yonghyang, Chichang, Taeyong, was performed to improve the function of the stomach, large intestine. Analyses of the images indicate that Jae-Seng Acupuncture improved nasolabial folds and eye wrinkles, suggesting that this technique is a safe and effective method for the improvement of facial skin conditions. 10.1155/2015/273909
    Effect of Osmotic Pressure on the Stability of Whole Inactivated Influenza Vaccine for Coating on Microneedles. Choi Hyo-Jick,Song Jae-Min,Bondy Brian J,Compans Richard W,Kang Sang-Moo,Prausnitz Mark R PloS one 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 (Ea = 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. 10.1371/journal.pone.0134431
    Inkjet printing of transdermal microneedles for the delivery of anticancer agents. Uddin Md Jasim,Scoutaris Nicolaos,Klepetsanis Pavlos,Chowdhry Babur,Prausnitz Mark R,Douroumis Dennis International journal of pharmaceutics A novel inkjet printing technology is introduced as a process to coat metal microneedle arrays with three anticancer agents 5-fluororacil, curcumin and cisplatin for transdermal delivery. The hydrophilic graft copolymer Soluplus(®) was used as a drug carrier and the coating formulations consisted of drug-polymer solutions at various ratios. A piezoelectric dispenser jetted microdroplets on the microneedle surface to develop uniform, accurate and reproducible coating layers without any material losses. Inkjet printing was found to depend on the nozzle size, the applied voltage (mV) and the duration of the pulse (μs). The drug release rates were determined in vitro using Franz type diffusion cells with dermatomed porcine skin. The drug release rates depended on the drug-polymer ratio, the drug lipophilicity and the skin thickness. All drugs presented increased release profiles (750 μm skin thickness), which were retarded for 900 μm skin thickness. Soluplus assisted the drug release especially for the water insoluble curcumin and cisplatin due to its solubilizing capacity. Inkjet printing has been shown to be an effective technology for coating of metal microneedles which can then be used for further transdermal drug delivery applications. 10.1016/j.ijpharm.2015.01.038
    Effective and lesion-free cutaneous influenza vaccination. Wang Ji,Li Bo,Wu Mei X Proceedings of the National Academy of Sciences of the United States of America 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. 10.1073/pnas.1500408112
    Use of hollow microneedles for targeted delivery of phenylephrine to treat fecal incontinence. Jun Hyesun,Han Mee-Ree,Kang Nae-Gyu,Park Jung-Hwan,Park Jung Ho Journal of controlled release : official journal of the Controlled Release Society A hollow microneedle (HM) was prepared to deliver a phenylephrine (PE) solution into the anal sphincter muscle as a method for treating fecal incontinence. The goal of this study was the local targeted delivery of PE into the sphincter muscle through the perianal skin with minimal pain using hollow microneedles, resulting in the increase of resting anal sphincter pressure. PE was administered on the left and the right sides of the anus of a rat through the perianal skin using 1.5mm long HM. An in vivo imaging system study was conducted after injection of Rhodamine B, and a histological study was performed after injection of gentian violet. The resting anal sphincter pressure in response to various drug doses was measured by using an air-charged catheter. Anal pressure change produced by HM administration was compared with change produced by intravenous injection (IV), subcutaneous (SC) injection and intramuscular (IM) injection. The change in mean blood pressure produced by HM administration as a function of PE dose was compared with change produced by PBS injection. A pharmacokinetic study of the new HM administration method was performed. A model drug solution was localized in the muscle layer under the perianal skin at the injection site and then diffused out over time. HM administration of PE induced significant contraction of internal anal sphincter pressure over 12h after injection, and the maximum anal pressure was obtained between 5 and 6h. Compared to IV, SC and IM treatments, HM treatment produced greater anal pressure. There was no increase in blood pressure after HM administration of PE within the range of predetermined concentration. Administration of 800μg/kg of PE using HM produced 0.81±0.38h of tmax. Our study suggests that HM administration enables local delivery of a therapeutic dose of PE to the anal sphincter muscle layer with less pain. This new treatment has great potential as a clinical application because of the ease of the procedure, minimal pain, and dose-dependent response. 10.1016/j.jconrel.2015.03.031
    Poly-γ-glutamic acid microneedles with a supporting structure design as a potential tool for transdermal delivery of insulin. Chen Mei-Chin,Ling Ming-Hung,Kusuma Setiawan Jati Acta biomaterialia Incomplete insertion is a common problem associated with polymer microneedles (MNs) that results in a limited drug delivery efficiency and wastage of valuable medication. This paper presents a fully insertable MN system that is composed of poly-γ-glutamic acid (γ-PGA) MNs and polyvinyl alcohol (PVA)/polyvinyl pyrrolidone (PVP) supporting structures. The PVA/PVP supporting structures were designed to provide an extended length for counteracting skin deformation during insertion and mechanical strength for fully inserting the MNs into the skin. When inserted into the skin, both the supporting structures and MNs can be dissolved in the skin within 4min, thus quickly releasing the entire drug load from the MNs. To evaluate the feasibility and reproducibility of using the proposed system for treating diabetes, we administered insulin-loaded MNs to diabetic rats once daily for 2days. The results indicated that the hypoglycemic effect in the rats receiving insulin-loaded MNs was comparable to that observed in rats receiving subcutaneous insulin injections. The relative pharmacological availability and relative bioavailability of the insulin were in the range of 90-97%, indicating that the released insulin retained its pharmacological activity. We observed no significant differences in the plasma insulin concentration profiles between the first and second administrations, confirming the stability and accuracy of using the proposed MN system for insulin delivery. These results indicated that the γ-PGA MNs containing the supporting structure design enable complete and efficient delivery of encapsulated bioactive molecules and have great potential for the relatively rapid and convenient transdermal delivery of protein drugs. STATEMENT OF SIGNIFICANCE:Incomplete insertion of microneedles largely limits drug delivery efficiency and wastage of valuable medication. To address this problem, we developed a fully insertable poly-glutamic acid microneedles with a supporting structure design to ensure complete and efficient delivery of encapsulated drugs. The supporting structures were designed to provide an extended length for counteracting skin compressive deformation during puncture and mechanical strength for fully inserting the microneedles into the skin. When inserted into the skin, both the supporting structures and microneedles can be dissolved in the skin within 4min, thus quickly releasing the entire drug load. This study demonstrated that the proposed microneedle system featuring this unique design allows more convenient and efficient self-administration of drugs into the skin. 10.1016/j.actbio.2015.06.021
    Structural characterisation and transdermal delivery studies on sugar microneedles: experimental and finite element modelling analyses. Loizidou Eriketi Z,Williams Nicholas A,Barrow David A,Eaton Mark J,McCrory John,Evans Sam L,Allender Chris J European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V Dissolving microneedles are especially attractive for transdermal drug delivery as they are associated with improved patient compliance and safety. Furthermore, microneedles made of sugars offer the added benefit of biomolecule stabilisation making them ideal candidates for delivering biological agents such as proteins, peptides and nucleic acids. In this study, we performed experimental and finite element analyses to study the mechanical properties of sugar microneedles and evaluate the effect of sugar composition on microneedle ability to penetrate and deliver drug to the skin. Results showed that microneedles made of carboxymethylcellulose/maltose are superior to those made of carboxymethylcellulose/trehalose and carboxymethylcellulose/sucrose in terms of mechanical strength and the ability to deliver drug. Buckling was predicted to be the main mode of microneedle failure and the order of buckling was positively correlated to the Young's modulus values of the sugar constituents of each microneedle. 10.1016/j.ejpb.2014.11.023
    Microneedles for drug delivery via the gastrointestinal tract. Traverso Giovanni,Schoellhammer Carl M,Schroeder Avi,Maa Ruby,Lauwers Gregory Y,Polat Baris E,Anderson Daniel G,Blankschtein Daniel,Langer Robert Journal of pharmaceutical sciences Both patients and physicians prefer the oral route of drug delivery. The gastrointestinal (GI) tract, though, limits the bioavailability of certain therapeutics because of its protease and bacteria-rich environment as well as general pH variability from pH 1 to 7. These extreme environments make oral delivery particularly challenging for the biologic class of therapeutics. Here, we demonstrate proof-of-concept experiments in swine that microneedle-based delivery has the capacity for improved bioavailability of a biologically active macromolecule. Moreover, we show that microneedle-containing devices can be passed and excreted from the GI tract safely. These findings strongly support the success of implementation of microneedle technology for use in the GI tract. 10.1002/jps.24182
    Substrate Deformation Predicts Neuronal Growth Cone Advance. Athamneh Ahmad I M,Cartagena-Rivera Alexander X,Raman Arvind,Suter Daniel M Biophysical journal 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 10(0)-10(2) 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. 10.1016/j.bpj.2015.08.013
    IgG-loaded hyaluronan-based dissolving microneedles for intradermal protein delivery. Mönkäre Juha,Reza Nejadnik M,Baccouche Khalil,Romeijn Stefan,Jiskoot Wim,Bouwstra Joke A Journal of controlled release : official journal of the Controlled Release Society Dissolving microneedles are an attractive approach for non-invasive delivery of drugs via the skin, particularly when the doses are in the microgram or low-milligram range. The aim of the study was to develop hyaluronan-based, monoclonal IgG-loaded microneedles for intradermal delivery enabling efficient penetration and rapid dissolution in the skin while preserving protein stability. Microscopic analysis showed successful preparation of sharp microneedles with the tip length of ~280 μm and with up to 10% (w/w) of IgG content. The water content of the microneedles was ~12% and was not affected by the protein content. The protein distribution was uniform within microneedle tips and individual arrays but some array-to-array variation of IgG level within a single preparation batch was detected. After dissolution of microneedle arrays in PBS, N80% of protein was recovered and no conformational changes were detected by fluorescence spectroscopy. At submicron level, only weak and reversible interaction between HA and IgG was found by asymmetric flow field flow fractionation analysis after the dissolution of prepared microneedles. Although, the formation of insoluble micron-size particles was detected by flow imaging microscopy the IgG amount incorporated into these particles was negligible (b5%). Finally, microneedles were able to penetrate into the epidermis of ex vivo human skin followed by the rapid dissolution of the microneedle tips in the skin. After 10 min of application, the majority of the original tip length was dissolved and IgG and hyaluronan were co-deposited until a depth of 150-200 μm in the skin. In conclusion, developed hyaluronan-based dissolving microneedles allow rapid noninvasive intradermal protein delivery. 10.1016/j.jconrel.2015.10.002
    Modelling of dissolving microneedles for transdermal drug delivery: theoretical and experimental aspects. Kim Kwang Seok,Ita Kevin,Simon Laurent European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences A mathematical model was developed to predict the amount of drug delivered into the skin via the dissolution of a microneedle (MN). This approach differs markedly from previous research which focused on similar phenomena but failed to include a biological membrane. Dimensionless governing equations were derived to help predict the needle height and fate of the active ingredient in the skin layer after application of the device. Simulation studies with fentanyl revealed that the drug concentration was proportional to its mass fraction in the MN. The effect of the pitch on skin permeation was mildly nonlinear. A larger amount of fentanyl was delivered from microneedle arrays with smaller pitch size. The dissolution process was independent of changes in the elimination rate constant. An optimization algorithm was applied to show how to recover this parameter from needle height--time data. 10.1016/j.ejps.2014.12.008
    Silver/silver chloride microneedles can detect penetration through the round window membrane. Wazen Joseph M,Stevens James P,Watanabe Hirobumi,Kysar Jeffrey W,Lalwani Anil K Journal of biomedical materials research. Part B, Applied biomaterials HYPOTHESIS:Silver-plated microneedles can be used to confirm penetration of semi-permeable membranes such as the round window membrane (RWM) by detection of voltage change at the moment of perforation. BACKGROUND:The introduction of microperforations in the RWM can significantly enhance intracochlear delivery of therapeutics. However, the moment of needle penetration through the RWM cannot be reliably detected by visualization or sensation alone. We explore the ability of electrochemical detection of penetration in defining the precise instant a microneedle enters the inner ear. METHODS:0.2 mm diameter stainless steel Minutien pins were electroplated with copper, then silver. Pins were then soaked in bleach for 24 h to complete Ag/AgCl plating. Experiments were performed using a 3 mL Franz cell diffusion system with 1%, 2%, 3%, 4%, and 5% saline solution in the donor chamber and artificial perilymph solution in the receptor chamber separated by 5-μm pore synthetic membrane. Continuous voltage measurements were made throughout the process of membrane penetration by the microneedle (N = 6 for each saline concentration). RESULTS:Silver-plated needles were able to detect an instantaneous change in voltage when traversing the membrane from saline solution into artificial perilymph. As calculated, the magnitude of the change in voltage upon penetration increased with increasing saline concentration and was stable across trials. CONCLUSION:Ag/AgCl coated microneedles are effective in detecting the moment of penetration across semi-permeable membranes. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 307-311, 2017. 10.1002/jbm.b.33557
    Transdermal Delivery of Functional Collagen Via Polyvinylpyrrolidone Microneedles. 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 Annals of biomedical engineering 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. 10.1007/s10439-015-1353-0
    Solid Microneedles for Transdermal Delivery of Amantadine Hydrochloride and Pramipexole Dihydrochloride. Hoang Mylien T,Ita Kevin B,Bair Daniel A Pharmaceutics The aim of this project was to study the influence of microneedles on transdermal delivery of amantadine hydrochloride and pramipexole dihydrochloride across porcine ear skin in vitro. Microchannel visualization studies were carried out and characterization of the microchannel depth was performed using confocal laser scanning microscopy (CLSM) to demonstrate microchannel formation following microneedle roller application. We also report, for the first time, the use of TA.XT Plus Texture Analyzer to characterize burst force in pig skin for transdermal drug delivery experiments. This is the force required to rupture pig skin. The mean passive flux of amantadine hydrochloride, determined using a developed LC-MS/MS technique, was 22.38 ± 4.73 µg/cm²/h, while the mean flux following the use of a stainless steel microneedle roller was 49.04 ± 19.77 µg/cm²/h. The mean passive flux of pramipexole dihydrochloride was 134.83 ± 13.66 µg/cm²/h, while the flux following the use of a stainless steel microneedle roller was 134.04 ± 0.98 µg/cm²/h. For both drugs, the difference in flux values following the use of solid stainless steel microneedle roller was not statistically significantly (p > 0.05). Statistical analysis was carried out using the Mann-Whitney Rank sum test. 10.3390/pharmaceutics7040379
    Toward Biofunctional Microneedles for Stimulus Responsive Drug Delivery. Cahill Ellen M,O'Cearbhaill Eoin D Bioconjugate chemistry Microneedles have recently been adopted for use as a painless and safe method of transdermal therapeutic delivery through physically permeating the stratum corneum. While microneedles create pathways to introduce drugs, they can also act as conduits for biosignal sensing. Here, we explore the development of microneedles as both biosensing and drug delivery platforms. Microneedle sensors are being developed for continuous monitoring of biopotentials and bioanalytes through the use of conductive and electrochemically reactive biomaterials. The range of therapeutics being delivered through microneedle devices has diversified, while novel bioabsorbable microneedles are undergoing first-in-human clinical studies. We foresee that future microneedle platform development will focus on the incorporation of biofunctional materials, designed to deliver therapeutics in a stimulus responsive fashion. Biofunctional microneedle patches will require improved methods of attaching to and conforming to epithelial tissues in dynamic environments for longer periods of time and thus present an assortment of new design challenges. Through the evolution of biomaterial development and microneedle design, biofunctional microneedles are proposed as a next generation of stimulus responsive drug delivery systems. 10.1021/acs.bioconjchem.5b00211
    Bioceramic microneedles with flexible and self-swelling substrate. Cai Bing,Xia Wei,Bredenberg Susanne,Li Hao,Engqvist Håkan European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V To reduce the effort required to penetrate the skin and optimize drug release profiles, bioceramic microneedle arrays with higher-aspect-ratio needles and a flexible and self-swelling substrate have been developed. Swelling of the substrate can assist in separating it from the needles and leave them in the skin as a drug depot. The preparation procedures for this bioceramic microneedle are described in the paper. Clonidine hydrochloride, the model drug, was released in a controlled manner by the microneedle device in vitro. Results showed that the microneedle array with a flexible and self-swelling substrate released the drug content faster than the array with a rigid substrate. Disintegration of the needle material and diffusion of the drug molecules are believed as the main control mechanisms of the drug release from these microneedle arrays. Ex vivo skin penetration showed that they can effectively penetrate the stratum corneum without an extra device. This work represents a progression in the improvement of bioceramic microneedles for transdermal drug delivery. 10.1016/j.ejpb.2015.06.016
    A patchless dissolving microneedle delivery system enabling rapid and efficient transdermal drug delivery. Lahiji Shayan F,Dangol Manita,Jung Hyungil Scientific reports Dissolving microneedles (DMNs) are polymeric, microscopic needles that deliver encapsulated drugs in a minimally invasive manner. Currently, DMN arrays are superimposed onto patches that facilitate their insertion into skin. However, due to wide variations in skin elasticity and the amount of hair on the skin, the arrays fabricated on the patch are often not completely inserted and large amount of loaded materials are not delivered. Here, we report "Microlancer", a novel micropillar based system by which patients can self-administer DMNs and which would also be capable of achieving 97 ± 2% delivery efficiency of the loaded drugs regardless of skin type or the amount of hair on the skin in less than a second. 10.1038/srep07914
    Dissolving microneedle-based intradermal delivery of interferon-α-2b. Chen Jianmin,Qiu Yuqin,Zhang Suohui,Gao Yunhua Drug development and industrial pharmacy The dermal and transdermal delivery of protein pharmaceuticals faces enormous challenges, and at the same time, has very significant potential for the non-invasive treatment of both localized and systemic diseases. To demonstrate the pharmaceutical usefulness of dissolving microneedles (MNs) containing interferon-α-2b (IFN), IFN MNs were prepared using a new method. IFN were encapsulated in MNs with dose from 4.94 ± 0.64 to 23.79 ± 2.48 μg, and in vitro release test showed the efficiency reached 49.2%. After percutaneous administration of IFN MNs to rats, serum IFN levels were measured for 12 h. The peak serum IFN level, maximum drug concentration (Cmax), and the time to reach maximum concentration (Tmax), were 11.58 ± ng/ml and 40 min, respectively, for high-dose MNs group. The area under the curve (AUC) of MNs group was 28.85 ng·h/ml, while intramuscular injection (IM) group with equal dose was 31.17 ng·h/ml. Immunogenicity analysis showed the anti-IFN antibody got back to normal level at ninth week, and there was no difference between male and female rats. IFN MNs showed good stability for 2 months and no damage to the administered rats' skin. The results demonstrated the IFN MNs have a great potential to provide an alternative to IM. 10.3109/03639045.2015.1096282
    Non-insulated microneedle fractional radiofrequency for the treatment of scars and photoaging. Naouri M,Mazer J M Journal of the European Academy of Dermatology and Venereology : JEADV 10.1111/jdv.12890
    Polymeric Microneedle Array Fabrication by Photolithography. Kathuria Himanshu,Kochhar Jaspreet Singh,Fong Michelle Hui Min,Hashimoto Michinao,Iliescu Ciprian,Yu Hanry,Kang Lifeng Journal of visualized experiments : JoVE This manuscript describes the fabrication of polymeric microneedle (MN) arrays by photolithography. It involves a simple mold-free process by using a photomask consisting of embedded micro-lenses. Embedded micro-lenses were found to influence MN geometry (sharpness). Robust MN arrays with tip diameters ranging between 41.5 µm ± 8.4 µm and 71.6 µm ± 13.7 µm, with two different lengths (1,336 µm ± 193 µm and 957 µm ± 171 µm) were fabricated. These MN arrays may provide potential applications in delivery of low molecular and macromolecular therapeutic agents through skin. 10.3791/52914
    Microneedle Coating Techniques for Transdermal Drug Delivery. Haj-Ahmad Rita,Khan Hashim,Arshad Muhammad Sohail,Rasekh Manoochehr,Hussain Amjad,Walsh Susannah,Li Xiang,Chang Ming-Wei,Ahmad Zeeshan Pharmaceutics 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. 10.3390/pharmaceutics7040486
    Novel use of pectin as a microneedle base. Demir Yusuf Kemal,Kerimoglu Oya Chemical & pharmaceutical bulletin Hydrocolloid pectin formulation was utilized as a novel base for fabricating biodegradable micro-needle (MN) arrays. The pectin MNs were, on average, found to be 897.71 ± 3.48 µm in height and 234.31 ± 2.27 µm in base width, with an inter base spacing of 498.66 ± 1.60 µm, and corresponding to an aspect ratio of 3.83 ± 0.04. Bovine serum albumin (BSA) and pectin gel interaction was found to be dependent on the loaded protein amount. By contrast, regardless of the amount of BSA incorporated, pectin MNs competed with BSA to form a complex with Cu(2+) ions in a bicinchoninic acid (BCA) kit. The glass transition of the pectin MN base was found to be 145.15 ± 12.09, with a delta Cp of 2.60 ± 0.02 J g(-1) K(-1). Because pectin MNs are skin friendly and naturally occurring, with biodegradable and hydrocolloidal features, they are promising vehicle for the controlled release of macromolecules. 10.1248/cpb.c14-00759
    Fabrication of a novel partially dissolving polymer microneedle patch for transdermal drug delivery. Lee I-Chi,He Jheng-Siou,Tsai Meng-Tsan,Lin Kai-Che Journal of materials chemistry. B Polymer microneedles (MNs) have gained increasing attention as a minimally invasive method for efficiently delivering drugs and vaccines in a patient-friendly manner. Herein, an easy and mild process with O plasma treatment was used to fabricate polyvinylpyrrolidone (PVP)-polyvinyl alcohol (PVA) MN patches, and efficient, sustained transdermal delivery was achieved. The diffusion rate of the entrained molecules could be controlled by adjusting the ratio of PVP-PVA. Optical coherence tomography was used to monitor the in vitro penetration in real time and to measure the penetration depth. Rhodamine 6G and fluorescein isothiocyanate-labeled bovine serum albumin (BSA-FITC) were used to explore the potential for using partially dissolving MNs as a transdermal delivery device. Confocal microscopy images revealed that the model drug can gradually diffuse from the puncture sites to a deeper depth. The drug-release profile also demonstrated that the PVP-PVA MNs can provide a successful and sustained release and that the transdermal delivery rate was regulated by the PVP-PVA ratio. Furthermore, the two-stage processing strategy developed in this study provides a simple and easy method for localizing the drug in the needle. The partially dissolving MNs developed in this study may serve as a promising device for controlled drug release and for biological storage applications. 10.1039/c4tb01555j
    Near-Infrared Light-Activatable Microneedle System for Treating Superficial Tumors by Combination of Chemotherapy and Photothermal Therapy. Chen Mei-Chin,Lin Zhi-Wei,Ling Ming-Hung ACS nano Because of the aggressive and recurrent nature of cancers, repeated and multimodal treatments are often necessary. Traditional cancer therapies have a risk of serious toxicity and side effects. Hence, it is crucial to develop an alternative treatment modality that is minimally invasive, effectively treats cancers with low toxicity, and can be repeated as required. We developed a light-activatable microneedle (MN) system that can repeatedly and simultaneously provide photothermal therapy and chemotherapy to superficial tumors and exert synergistic anticancer effects. This system consists of embeddable polycaprolactone MNs containing a photosensitive nanomaterial (lanthanum hexaboride) and an anticancer drug (doxorubicin; DOX), and a dissolvable poly(vinyl alcohol)/polyvinylpyrrolidone supporting array patch. Because of this supporting array, the MNs can be completely inserted into the skin and embedded within the target tissue for locoregional cancer treatment. When exposed to near-infrared light, the embedded MN array uniformly heats the target tissue to induce a large thermal ablation area and then melts at 50 °C to release DOX in a broad area, thus destroying tumors. This light-activated heating and releasing behavior can be precisely controlled and switched on and off on demand for several cycles. We demonstrated that the MN-mediated synergistic therapy completely eradicated 4T1 tumors within 1 week after a single application of the MN and three cycles of laser treatment. No tumor recurrence and no significant body weight loss of mice were observed. Thus, the developed light-activatable MN with a unique embeddable feature offers an effective, user-friendly, and low-toxicity option for patients requiring long-term and multiple cancer treatments. 10.1021/acsnano.5b05043
    A facile system to evaluate in vitro drug release from dissolving microneedle arrays. Larrañeta Eneko,Stewart Sarah,Fallows Steven J,Birkhäuer Lena L,McCrudden Maeliosa T C,Woolfson A David,Donnelly Ryan F International journal of pharmaceutics The use of biological tissues in the in vitro assessments of dissolving (?) microneedle (MN) array mechanical strength and subsequent drug release profiles presents some fundamental difficulties, in part due to inherent variability of the biological tissues employed. As a result, these biological materials are not appropriate for routine used in industrial formulation development or quality control (QC) tests. In the present work a facile system using Parafilm M(®) (PF) to test drug permeation performance using dissolving MN arrays is proposed. Dissolving MN arrays containing 196 needles (600 μm needle height) were inserted into a single layer of PF and a hermetic "pouch" was created including the array inside. The resulting system was placed in a dissolution bath and the release of model molecules was evaluated. Different MN formulations were tested using this novel setup, releasing between 40 and 180 μg of their cargos after 6h. The proposed system is a more realistic approach for MN testing than the typical performance test described in the literature for conventional transdermal patches. Additionally, the use of PF membrane was tested either in the hermetic "pouch" and using Franz Cell methodology yielding comparable release curves. Microscopy was used in order to ascertain the insertion of the different MN arrays in the PF layer. The proposed system appears to be a good alternative to the use of Franz cells in order to compare different MN formulations. Given the increasing industrial interest in MN technology, the proposed system has potential as a standardised drug/active agent release test for quality control purposes. 10.1016/j.ijpharm.2015.11.038
    A novel option for treatment of primary axillary hyperhidrosis: fractionated microneedle radiofrequency. Fatemi Naeini F,Pourazizi M,Abtahi-Naeini B,Nilforoushzadeh M A,Najafian J Journal of postgraduate medicine 10.4103/0022-3859.153111
    Histopathological evidence of efficacy of microneedle radiofrequency for treatment of axillary hyperhidrosis. Naeini Farahnaz Fatemi,Saffaei Ali,Pourazizi Mohsen,Abtahi-Naeini Bahareh Indian journal of dermatology, venereology and leprology 10.4103/0378-6323.154789
    Microneedle Electrode Array for Electrical Impedance Myography to Characterize Neurogenic Myopathy. Li Zhao,Li Yi,Liu Mingsheng,Cui Liying,Yu Yude Annals of biomedical engineering Electrical impedance myography (EIM) is a noninvasive technique for neuromuscular assessment, wherein a low-intensity alternating current is applied to a muscle, and the consequent surface voltage patterns are evaluated. Commercial wet electrodes are most commonly used for EIM. However, these electrodes are not suitable for use on small muscles, as they do not effectively solve the problem of high electrode-skin contact impedance (ESCI) that negatively influences the quality of recorded biopotentials. To address this problem, we fabricated a novel microneedle electrode array (MEA) that consists of 124-µm-long microneedles. Compared to wet electrodes, the MEA could pierce through the outer skin surface in a painless and micro-invasive manner, and could thus effectively reduce ESCI. The MEA has excellent test-retest reproducibility, with intraclass correlation coefficients exceeding 0.920. When used in combination with EIM, the MEA differentiated the affected muscles from the unaffected muscles in patients with neurogenic myopathy, by using EIM parameters of reactance and phase (p = 0.023 and 0.008, respectively). Thus, the novel MEA is a practical and reusable device for EIM assessment in cases of neurogenic myopathy. However, further refinement of the electrode is needed to enhance the clinical application of the system. 10.1007/s10439-015-1466-5
    Fabrication of photomasks consisting microlenses for the production of polymeric microneedle array. Kathuria Himanshu,Fong Michelle H M,Kang Lifeng Drug delivery and translational research A photomask consisting plano-convex microlenses for the production of polymeric microneedles was fabricated from a microinjection array. The microinjection array was first fabricated using photolithographical approach and subsequently assembled onto a polydimethylsiloxane (PDMS) stamp. Poly (ethylene glycol) diacrylate (PEGDA) solution was loaded into the microinjection stamp. The microinjection stamp was then applied onto a coverslip to dispense the polymer solution, producing liquid microdroplets. They were then irradiated to form plano-convex microlenses. These microlenses were evaluated for their geometric properties and were fabricated into photomasks. The photomask consisting microlenses was used to fabricate polymeric microneedles that were evaluated and tested for skin penetration efficiency. 10.1007/s13346-015-0245-z
    Microneedle-array patches loaded with hypoxia-sensitive vesicles provide fast glucose-responsive insulin delivery. Cegla Jaimini Annals of clinical biochemistry 10.1177/0004563215605691
    Investigation of Plasma Treatment on Micro-Injection Moulded Microneedle for Drug Delivery. Nair Karthik,Whiteside Benjamin,Grant Colin,Patel Rajnikant,Tuinea-Bobe Cristina,Norris Keith,Paradkar Anant Pharmaceutics Plasma technology has been widely used to increase the surface energy of the polymer surfaces for many industrial applications; in particular to increase in wettability. The present work was carried out to investigate how surface modification using plasma treatment modifies the surface energy of micro-injection moulded microneedles and its influence on drug delivery. Microneedles of polyether ether ketone and polycarbonate and have been manufactured using micro-injection moulding and samples from each production batch have been subsequently subjected to a range of plasma treatment. These samples were coated with bovine serum albumin to study the protein adsorption on these treated polymer surfaces. Sample surfaces structures, before and after treatment, were studied using atomic force microscope and surface energies have been obtained using contact angle measurement and calculated using the Owens-Wendt theory. Adsorption performance of bovine serum albumin and release kinetics for each sample set was assessed using a Franz diffusion cell. Results indicate that plasma treatment significantly increases the surface energy and roughness of the microneedles resulting in better adsorption and release of BSA. 10.3390/pharmaceutics7040471
    A comparative study of microneedle-based cutaneous immunization with other conventional routes to assess feasibility of microneedles for allergy immunotherapy. Shakya Akhilesh Kumar,Gill Harvinder Singh Vaccine Feasibility of microneedles (MNs) for cutaneous allergen specific immunotherapy (ASI) is demonstrated by comparing against currently practiced subcutaneous (SC) allergen immunotherapy, and the intramuscular (IM) and intraperitoneal (IP) routes. In Balb/c mice with ovalbumin (Ova, 25 μg) as the allergen MNs-Ova without alum induced anti-Ova IgG response comparable to IM but higher than SC and IP groups (250 μg alum was additionally used for SC, IM and IP groups). MNs-Ova induced higher anti-Ova IgG1 and IgG2a responses in comparison to other routes; however IgG2b and IgG3 responses were significantly lower than the IP group. As in SC group, anti-Ova IgE and IgA were low for MNs-Ova. Furthermore, MNs-Ova induced expression of IL-5, IL-13, IFN-γ and IL-1β cytokines in serum, but at significantly lower levels than other routes. Overall, MNs-Ova induced allergen-specific IgG antibodies, and activated the Th1 pathway (evidenced by higher IgG2a levels), suggesting their potential use for painless ASI. 10.1016/j.vaccine.2015.06.042
    Design of a Dissolving Microneedle Platform for Transdermal Delivery of a Fixed-Dose Combination of Cardiovascular Drugs. Quinn Helen L,Bonham Louise,Hughes Carmel M,Donnelly Ryan F Journal of pharmaceutical sciences 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. 10.1002/jps.24563
    Early priming with inactivated poliovirus vaccine (IPV) and intradermal fractional dose IPV administered by a microneedle device: A randomized controlled trial. Anand Abhijeet,Zaman K,Estívariz Concepción F,Yunus Mohammad,Gary Howard E,Weldon William C,Bari Tajul I,Steven Oberste M,Wassilak Steven G,Luby Stephen P,Heffelfinger James D,Pallansch Mark A Vaccine INTRODUCTION:Inactivated poliovirus vaccine (IPV) introduction and phased oral poliovirus vaccine (OPV) cessation are essential for eradication of polio. METHODS:Healthy 6-week old infants in Bangladesh were randomized to one of five study arms: receipt of trivalent OPV (tOPV) or bivalent OPV (bOPV) at ages 6, 10 and 14 weeks, intramuscular IPV or intradermal one-fifth fractional dose IPV (f-IPV) at ages 6 and 14 weeks, or f-IPV at ages 6 and 14 weeks with bOPV at age 10 weeks (f-IPV/bOPV). All participants received tOPV at age 18 weeks. RESULTS:Of 975 infants randomized, 95% (922) completed follow-up. Type 1 seroconversion after 3 doses at 6, 10 and 14 weeks was higher with bOPV compared with tOPV (99% vs 94%, p=0.019). Seroconversions to types 1 and 3 after 2 IPV doses at ages 6 and 14 weeks were no different than after 3 doses of tOPV or bOPV at ages 6, 10 and 14 weeks. A priming response, seroconversion 1 week after IPV at 14 weeks among those who did not seroconvert after IPV at 6 weeks, was observed against poliovirus types 1, 2 and 3 in 91%, 84% and 97%, respectively. Compared with IPV, f-IPV failed non-inferiority tests for seroconversion with 1 or 2 doses and priming after 1 dose. DISCUSSION:The findings demonstrate considerable priming with IPV at age 6 weeks, comparable immunogenicity of tOPV and bOPV, and inferior immunogenicity of one-fifth f-IPV compared with IPV. If IPV induced priming at age 6 weeks is similar to that at age 14 weeks, IPV could be administered at a younger age and possibly with a higher coverage. 10.1016/j.vaccine.2015.09.039
    Intradermal vaccination using the novel microneedle device MicronJet600: Past, present, and future. Levin Yotam,Kochba Efrat,Hung Ivan,Kenney Richard Human vaccines & immunotherapeutics 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. 10.1080/21645515.2015.1010871
    Review of patents for microneedle application devices allowing fluid injections through the skin. Lhernould Marion S,Tailler Serge,Deleers Michel,Delchambre Alain Recent patents on drug delivery & formulation Microneedles have been developed in the past few years as a new means of transdermal drug delivery. They indeed present many advantages compared to injections using hypodermic needles (reduced risk of contamination and epidermic reactions), but mostly bring comfort and compliance to patients. Microneedles may be plain, opening pathways for medications to dissolve into the skin, or hollow, allowing fluid to actually enter the dermis or the hypodermis. This review focuses on the latter type of microneedles and two issues with their application: first, ensuring correct insertion into the skin (controlled and repeatable insertion depth, mainly); and second, ensuring correct fluid delivery to the dermis (controlled infusion rate). This paper thus focuses on recently published patents for hollow microneedle applicators-i.e., microneedles applicators that allow fluid delivery to the skin. Descriptions are given of several of the most relevant patents concerning this. The benefits and drawbacks of the different solutions are also described. 10.2174/1872211309666150313155503
    A microneedle-based method for the characterization of diffusion in skin tissue using doxorubicin as a model drug. Mansoor Iman,Lai Jacqueline,Ranamukhaarachchi Sahan,Schmitt Veronika,Lambert Dana,Dutz Jan,Häfeli Urs O,Stoeber Boris Biomedical microdevices Hollow microneedles can overcome the stratum corneum (SC) barrier and deposit a compound directly into the viable epidermis or the dermis, unlike adhesive patches that rely on drug diffusion across the SC. The traditional one-dimensional methods used to study the diffusivity of drugs across the skin layers are not very accurate for hollow microneedles, since the ejection of compounds out of microneedle lumens resembles a point-source spreading in all directions and is highly dependent on injection depth. This paper presents a technique that is useful for studying drug injection using hollow microneedles at various depths below the SC. This technique uses confocal microscopy to image the distribution of a fluorescent compound in the skin after injection. The fluorescence distribution in the skin is observed over time and applied to a spherical Gaussian diffusion model for limited source diffusion to determine the diffusion coefficient of the compound in the skin. Applied to freshly excised pig skin, the diffusion coefficient for the anti-cancer drug doxorubicin was measured as 4.61 × 10(-9) cm(2)/s, while the diffusion coefficient in previously refrigerated or frozen pig skin was 1.31 × 10(-8) cm(2)/s and 4.21 × 10(-8) cm(2)/s, respectively. Our data suggests that skin storage conditions can substantially alter the diffusion of drugs. The use of refrigerated and, even more so, previously frozen skin should be avoided for quantitative transdermal drug delivery studies. 10.1007/s10544-015-9967-4
    Microstereolithography and characterization of poly(propylene fumarate)-based drug-loaded microneedle arrays. Lu Yanfeng,Mantha Satya Nymisha,Crowder Douglas C,Chinchilla Sofia,Shah Kush N,Yun Yang H,Wicker Ryan B,Choi Jae-Won Biofabrication Drug-loaded microneedle arrays for transdermal delivery of a chemotherapeutic drug were fabricated using multi-material microstereolithography (μSL). These arrays consisted of twenty-five poly(propylene fumarate) (PPF) microneedles, which were precisely orientated on the same polymeric substrate. To control the viscosity and improve the mechanical properties of the PPF, diethyl fumarate (DEF) was mixed with the polymer. Dacarbazine, which is widely used for skin cancer, was uniformly blended into the PPF/DEF solution prior to crosslinking. Each microneedle has a cylindrical base with a height of 700 μm and a conical tip with a height of 300 μm. Compression test results and characterization of the elastic moduli of the PPF/DEF (50:50) and PPF/drug mixtures indicated that the failure force was much larger than the theoretical skin insertion force. The release kinetics showed that dacarbazine can be released at a controlled rate for five weeks. The results demonstrated that the PPF-based drug-loaded microneedles are a potential method to treat skin carcinomas. In addition, μSL is an attractive manufacturing technique for biomedical applications, especially for micron-scale manufacturing. 10.1088/1758-5090/7/4/045001
    Improvement of transdermal delivery of sumatriptan succinate using a novel self-dissolving microneedle array fabricated from sodium hyaluronate in rats. Wu Dan,Quan Ying-shu,Kamiyama Fumio,Kusamori Kosuke,Katsumi Hidemasa,Sakane Toshiyasu,Yamamoto Akira Biological & pharmaceutical bulletin The purpose of the present study was to develop an alternative transdermal formulation containing sumatriptan succinate (SS) for the treatment of migraine. Novel self-dissolving SS-loaded microneedle arrays (MNs) were fabricated from sodium hyaluronate and their efficacy for transdermal delivery of SS was characterized. The resulting MNs maintained their skin piercing abilities for at least 30 min after being placed at a high relative humidity of 75%. Rapid release of SS from the MNs was also observed in vitro. Optical coherence tomography images demonstrated that MNs were able to successfully pierce into rat skin without any bending or cracking, and needles were completely dissolved within 1 h. MNs significantly increased transepidermal water loss; however, skin barrier function gradually recovered to control levels within 24 h, in contrast to the skin damage observed after tape stripping treatment. These findings indicated that the micropores created by MNs quickly resealed, and that the skin damage was reversible. Furthermore, a dose-dependent plasma concentration of SS was obtained after transdermal delivery using SS-loaded MNs in rats. Absorption of SS delivered by MNs was similar to that observed after subcutaneous injection and was associated with high bioavailability (ca. 90%), which was much higher than that produced by oral administration. These findings suggested that application of SS-loaded MNs to the skin provided an effective alternative approach to enhance the transdermal delivery of SS without serious skin damage, and would be likely to improve patient compliance. 10.1248/bpb.b14-00502
    Biocompatible Mater Constructed Microneedle Arrays as a Novel Vaccine Adjuvant- Delivery System for Cutaneous and Mucosal Vaccination. Wang Ting,Wang Ning Current pharmaceutical design Vaccination is the most cost-effective and the best prophylactic strategy for the treatment of many diseases and, therefore, is widely used to improve human health. However, currently, most vaccines are given by injection which has a number of intrinsic disadvantages, such as inoculation needing professionals, waste metal needle pollution and infection, and low vaccination compliance. To overcome these drawbacks, in the past two decades a variety of microneedles have been developed and these are increasingly being widely tried to deliver vaccines due to many prominent advantages, such as their convenience, and effectiveness, over other delivery systems. In particular, the biocompatible material-constituted microneedle arrays (bioMMAs) that are fabricated with biocompatible materials in the form of a matrix or formulated micro/nanoparticles, such as liposomes, PLA/PLGA/ chitosan nanoparticles, hydrogels, polyelectrolyte multiplelayers (PEMs), plasmids, and nonvirulent pathogens, have proven an effective and stable vaccine adjuvant-delivery system (VADS) allowing painless vaccination via the cutaneous or mucosal route by minimally trained workers or by self-administration. When given to mammals through the skin or oral mucosa where affluent professional antigen-presenting cells (APCs), such as Langerhans cells, dendritic cells and macrophages, are actively patrolling for immune surveillance, the bioMMAs can efficiently elicit robust systemic as well as mucosal immunoresponses against the loaded antigens. In addition, when different vaccine adjuvants, such as TLR (toll-like receptor) ligands, have been incorporated, the bioMMAs can govern and redirect the immunoresponse toward a Th1, Th2 or a mixed Th1/Th2 pathway to establish cellular and humoral immunity to the target pathogens. In this review, various types of bioMMAs used as a VADS are described to show the latest advances and their diverse uses and potential applications in vaccine-related fields.
    Considerations in the sterile manufacture of polymeric microneedle arrays. McCrudden Maelíosa T C,Alkilani Ahlam Zaid,Courtenay Aaron J,McCrudden Cian M,McCloskey Bronagh,Walker Christine,Alshraiedeh Nida,Lutton Rebecca E M,Gilmore Brendan F,Woolfson A David,Donnelly Ryan F Drug delivery and translational research We describe, for the first time, considerations in the sterile manufacture of polymeric microneedle arrays. Microneedles (MN) made from dissolving polymeric matrices and loaded with the model drugs ovalbumin (OVA) and ibuprofen sodium and hydrogel-forming MN composed of "super-swelling" polymers and their corresponding lyophilised wafer drug reservoirs loaded with OVA and ibuprofen sodium were prepared aseptically or sterilised using commonly employed sterilisation techniques. Moist and dry heat sterilisation, understandably, damaged all devices, leaving aseptic production and gamma sterilisation as the only viable options. No measureable bioburden was detected in any of the prepared devices, and endotoxin levels were always below the US Food & Drug Administration limits (20 endotoxin units/device). Hydrogel-forming MN were unaffected by gamma irradiation (25 kGy) in terms of their physical properties or capabilities in delivering OVA and ibuprofen sodium across excised neonatal porcine skin in vitro. However, OVA content in dissolving MN (down from approximately 101.1 % recovery to approximately 58.3 % recovery) and lyophilised wafer-type drug reservoirs (down from approximately 99.7 % recovery to approximately 60.1 % recovery) was significantly reduced by gamma irradiation, while the skin permeation profile of ibuprofen sodium from gamma-irradiated dissolving MN was markedly different from their non-irradiated counterparts. It is clear that MN poses a very low risk to human health when used appropriately, as evidenced here by low endotoxin levels and absence of microbial contamination. However, if guarantees of absolute sterility of MN products are ultimately required by regulatory authorities, it will be necessary to investigate the effect of lower gamma doses on dissolving MN loaded with active pharmaceutical ingredients and lyophilised wafers loaded with biomolecules in order to avoid the expense and inconvenience of aseptic processing. 10.1007/s13346-014-0211-1
    VoluDerm microneedle technology for skin treatments-in vivo histological evidence. Gershonowitz Amikam,Gat Andrea Journal of cosmetic and laser therapy : official publication of the European Society for Laser Dermatology INTRODUCTION:The growing demand for skin rejuvenation procedures with minimal down time and low risk has led to the development of fractional radiofrequency (RF) systems. The new VoluDerm™ RF microneedle technology creates minute columns of tissue thermal microablation. Treatment triggers natural fractional healing, resulting in dermal volumizing and skin renewal. This preclinical research assessed the safety and efficacy of the VoluDerm through histological evaluation of morphological changes in the target tissue. METHODS:Following approval of protocol by ethical committee, treatments were conducted on two domestic pigs using VoluDerm disposable tips. Histological samples of 14, 7, 4 days and immediately after treatment with various energy settings were analyzed. RESULTS:Immediate VoluDerm epidermal and dermal effects, and progress of healing process, as function of time following treatment (days 4 and 7), were demonstrated. Histology analysis of samples of 14 days demonstrated complete healing for all energy levels. SUMMARY:This in vivo histology confirmed the safe and effective performance of the VoluDerm treatment. A fractional pattern of affected areas, surrounded by healthy tissue, was demonstrated. Healing process proved natural dermal renewal and epidermal complete regeneration. Histology supports clinical advantages of the VoluDerm natural-looking skin enhancement, with none to minimal pain and no downtime. 10.3109/14764172.2014.957219
    Dissolving microneedle delivery of nanoparticle-encapsulated antigen elicits efficient cross-priming and Th1 immune responses by murine Langerhans cells. Zaric Marija,Lyubomska Oksana,Poux Candice,Hanna Mary L,McCrudden Maeliosa T,Malissen Bernard,Ingram Rebecca J,Power Ultan F,Scott Christopher J,Donnelly Ryan F,Kissenpfennig Adrien The Journal of investigative dermatology Dendritic cells (DCs) of the skin have an important role in skin-mediated immunity capable of promoting potent immune responses. We availed of polymeric dissolving microneedle (MN) arrays laden with nano-encapsulated antigen to specifically target skin DC networks. This modality of immunization represents an economic, efficient, and potent means of antigen delivery directly to skin DCs, which are inefficiently targeted by more conventional immunization routes. Following MN immunization, Langerhans cells (LCs) constituted the major skin DC subset capable of cross-priming antigen-specific CD8+ T cells ex vivo. Although all DC subsets were equally efficient in priming CD4+ T cells, LCs were largely responsible for orchestrating the differentiation of CD4+ IFN-γ- and IL-17-producing effectors. Importantly, depletion of LCs prior to immunization had a profound effect on CD8+ CTL responses in vivo, and vaccinated animals displayed reduced protective anti-tumor and viral immunity. Interestingly, this cross-priming bias was lost following MN immunization with soluble antigen, suggesting that processing and cross-presentation of nano-particulate antigen is favored by LCs. Therefore, these studies highlight the importance of LCs in skin immunization strategies and that targeting of nano-particulate immunogens through dissolvable polymeric MNs potentially provides a promising technological platform for improved vaccination strategies. 10.1038/jid.2014.415
    Electromagnetic Initiation and Propagation of Bipolar Radiofrequency Tissue Reactions via Invasive Non-Insulated Microneedle Electrodes. Na Jongju,Zheng Zhenlong,Dannaker Christopher,Lee Sang Eun,Kang Jin-Soo,Cho Sung Bin Scientific reports Radiofrequency (RF) energy can be emitted into the skin, either non- or invasively, via a monopolar mode that utilizes an active electrode and a grounded electrode or via a bipolar mode that employs two active electrodes. In this experimental study of RF tissue reactions, bipolar RF energy was emitted in vivo to micropig skin at varying microneedle penetration depths, signal amplitudes, and conduction times. Immediately after RF treatment, skin samples exhibited RF-induced coagulation columns of thermal injury, separately generated around each microneedle in the dermis. In ex vivo bovine liver tissue, the thermal coagulation columns were found to be concentrated maximally around the pointed tips of each electrode. After a RF conduction time of 2 seconds, the individual areas of thermal coagulation began to converge with neighboring RF-induced coagulation columns; the convergence of coagulation columns was found to start from the tips of neighboring electrodes. 10.1038/srep16735
    Laser-engineered dissolving microneedle arrays for protein delivery: potential for enhanced intradermal vaccination. McCrudden Maelíosa T C,Torrisi Barbara M,Al-Zahrani Sharifah,McCrudden Cian M,Zaric Marija,Scott Christopher J,Kissenpfennig Adrien,McCarthy Helen O,Donnelly Ryan F The Journal of pharmacy and pharmacology OBJECTIVES:We aimed to highlight the utility of novel dissolving microneedle (MN)-based delivery systems for enhanced transdermal protein delivery. Vaccination remains the most accepted and effective approach in offering protection from infectious diseases. In recent years, much interest has focused on the possibility of using minimally invasive MN technologies to replace conventional hypodermic vaccine injections. METHODS:The focus of this study was exploitation of dissolving MN array devices fabricated from 20% w/w poly(methyl vinyl ether/maleic acid) using a micromoulding technique, for the facilitated delivery of a model antigen, ovalbumin (OVA). KEY FINDINGS:A series of in-vitro and in-vivo experiments were designed to demonstrate that MN arrays loaded with OVA penetrated the stratum corneum and delivered their payload systemically. The latter was evidenced by the activation of both humoral and cellular inflammatory responses in mice, indicated by the production of immunoglobulins (IgG, IgG1, IgG2a) and inflammatory cytokines, specifically interferon-gamma and interleukin-4. Importantly, the structural integrity of the OVA following incorporation into the MN arrays was maintained. CONCLUSION:While enhanced manufacturing strategies are required to improve delivery efficiency and reduce waste, dissolving MN are a promising candidate for 'reduced-risk' vaccination and protein delivery strategies. 10.1111/jphp.12248
    Treatment of periorbital wrinkles with a novel fractional radiofrequency microneedle system in dark-skinned patients. Lee Seung Jae,Kim Jung-In,Yang You Jin,Nam Jae Hui,Kim Won-Serk Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.] BACKGROUND:Periorbital wrinkles as a result of photoaging are a frequent cosmetic concern. Recently, the fractional radiofrequency microneedle system was introduced as a new device for facial rejuvenation, and it has received much recognition for its unique "deep dermal heating with epidermal sparing" feature. OBJECTIVE:The purpose of this study was to examine the clinical efficacy and safety of the system for the treatment of periorbital wrinkles in Korean patients. MATERIALS AND METHODS:Twenty Korean patients (Fitzpatrick skin Type IV-V) with varying degrees of periorbital wrinkles were enrolled in this study. The patients were treated 3 times at 4-week intervals with the system. Changes in periorbital wrinkling were evaluated by 2 independent experts with digital images of the subjects' faces using a 5-point Wrinkle Assessment Scale. At the end of the study, the patients rated their satisfaction with the overall treatment outcome on a numerical scale. RESULTS:All patients completed the treatment regimen and were satisfied with the treatment. Most patients improved according to clinical and photographic assessments performed 6 months after the treatment. Two patients (10%) reported mild hyperpigmentation. CONCLUSION:The system may be an effective and safe treatment option for periorbital wrinkles in dark-skinned Korean patients. 10.1097/DSS.0000000000000216
    Lidocaine permeation from a lidocaine NaCMC/gel microgel formulation in microneedle-pierced skin: vertical (depth averaged) and horizontal permeation profiles. Nayak Atul,Short Liam,Das Diganta B Drug delivery and translational research 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. 10.1007/s13346-015-0229-z
    One-touch-activated blood multidiagnostic system using a minimally invasive hollow microneedle integrated with a paper-based sensor. Li Cheng Guo,Joung Hyou-Arm,Noh Hyungrye,Song Mun-Bum,Kim Min-Gon,Jung Hyungil Lab on a chip The development of real-time innocuous blood diagnosis has been a long-standing goal in healthcare; an improved, miniature, all-in-one point-of-care testing (POCT) system with low cost and simplified operation is highly desired. Here, we present a one-touch-activated blood multidiagnostic system (OBMS) involving the synergistic integration of a hollow microneedle and paper-based sensor, providing a number of unique characteristics for simplifying the design of microsystems and enhancing user performance. In this OBMS, all functions of blood collection, serum separation, and detection were sequentially automated in one single device that only required one-touch activation by finger-power without additional operations. For the first time, we successfully demonstrated the operation of this system in vivo in glucose and cholesterol diagnosis, showing a great possibility for human clinical application and commercialization. Additionally, this novel system offers a new approach for the use of microneedles and paper sensors as promising intelligent elements in future real-time healthcare monitoring devices. 10.1039/c5lc00669d
    Microneedle Vaccination Elicits Superior Protection and Antibody Response over Intranasal Vaccination against Swine-Origin Influenza A (H1N1) in Mice. Shin Ju-Hyung,Park Jae-Keun,Lee Dong-Hun,Quan Fu-Shi,Song Chang-Seon,Kim Yeu-Chun PloS one Influenza is one of the critical infectious diseases globally and vaccination has been considered as the best way to prevent. In this study, immunogenicity and protection efficacy between intranasal (IN) and microneedle (MN) vaccination was compared using inactivated swine-origin influenza A/H1N1 virus vaccine. Mice were vaccinated by MN or IN administration with 1 μg of inactivated H1N1 virus vaccine. Antigen-specific antibody responses and hemagglutination-inhibition (HI) titers were measured in all immunized sera after immunization. Five weeks after an immunization, a lethal challenge was performed to evaluate the protective efficacy. Furthermore, mice were vaccinated by IN administration with higher dosages (> 1 μg), analyzed in the same manner, and compared with 1 μg-vaccine-coated MN. Significantly higher antigen-specific antibody responses and HI titer were measured in sera in MN group than those in IN group. While 100% protection, slight weight loss, and reduced viral replication were observed in MN group, 0% survival rate were observed in IN group. As vaccine dose for IN vaccination increased, MN-immunized sera showed much higher antigen-specific antibody responses and HI titer than other IN groups. In addition, protective immunity of 1 μg-MN group was similar to those of 20- and 40 μg-IN groups. We conclude that MN vaccination showed more potential immune response and protection than IN vaccination at the same vaccine dosage. 10.1371/journal.pone.0130684
    Microneedle biosensor for real-time electrical detection of nitric oxide for in situ cancer diagnosis during endomicroscopy. Keum Do Hee,Jung Ho Sang,Wang Taejun,Shin Myeong Hwan,Kim Young-Eun,Kim Ki Hean,Ahn G-One,Hahn Sei Kwang Advanced healthcare materials A dual-diagnostic system of endom-icroscope and microneedle sensor is developed to demonstrate high-resolution imaging combined with electrical real-time detection of NO released from cancer tissues. The dual-diagnostic system can be a new platform for facile, precise, rapid, and accurate detection of cancers in various biomedical applications. 10.1002/adhm.201500012
    Microneedle patch delivery to the skin of virus-like particles containing heterologous M2e extracellular domains of influenza virus induces broad heterosubtypic cross-protection. Kim Min-Chul,Lee Jeong Woo,Choi Hyo-Jick,Lee Yu-Na,Hwang Hye Suk,Lee Jongsang,Kim Cheol,Lee Jong Seok,Montemagno Carlo,Prausnitz Mark R,Kang Sang-Moo Journal of controlled release : official journal of the Controlled Release Society A broadly cross-protective influenza vaccine that can be administrated by a painless self-immunization method would be a value as a potential universal mass vaccination strategy. This study developed a minimally-invasive microneedle (MN) patch for skin vaccination with virus-like particles containing influenza virus heterologous M2 extracellular (M2e) domains (M2e5x VLPs) as a universal vaccine candidate without adjuvants. The stability of M2e5x VLP-coated microneedles was maintained for 8weeks at room temperature without losing M2e antigenicity and immunogenicity. MN skin immunization induced strong humoral and mucosal M2e antibody responses and conferred cross-protection against heterosubtypic H1N1, H3N2, and H5N1 influenza virus challenges. In addition, M2e5x VLP MN skin vaccination induced T-helper type 1 responses such as IgG2a isotype antibodies and IFN-γ producing cells at higher levels than those by conventional intramuscular injection. These potential immunological and logistic advantages for skin delivery of M2e5x VLP MN vaccines could offer a promising approach to develop an easy-to-administer universal influenza vaccine. 10.1016/j.jconrel.2015.05.278
    Clinical study and stability assessment of a novel transcutaneous influenza vaccination using a dissolving microneedle patch. Hirobe Sachiko,Azukizawa Hiroaki,Hanafusa Takaaki,Matsuo Kazuhiko,Quan Ying-Shu,Kamiyama Fumio,Katayama Ichiro,Okada Naoki,Nakagawa Shinsaku Biomaterials 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. 10.1016/j.biomaterials.2015.04.007
    Curved Microneedle Array-Based sEMG Electrode for Robust Long-Term Measurements and High Selectivity. Kim Minjae,Kim Taewan,Kim Dong Sung,Chung Wan Kyun Sensors (Basel, Switzerland) 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. 10.3390/s150716265
    Controlled release of a model vaccine by nanoporous ceramic microneedle arrays. Boks Martine A,Unger Wendy W J,Engels Steef,Ambrosini Martino,Kooyk Yvette van,Luttge Regina International journal of pharmaceutics Current vaccination technology can advance from the use of novel ceramic nanoporous microneedle arrays (npMNA), where the material serves as a storage reservoir for vaccines. Moreover, npMNA will enhance vaccine efficacy by more precisely reaching skin dendritic cells, the kickstarters of T and B cell immunity. In the present study we assessed the efficacy of vaccination using npMNAs by in vivo application of OVA257-264 peptides mixed with agonistic anti-CD40 antibodies as adjuvant. The induction of OVA-specific CD8(+) T cells via npMNA was comparable with the frequency induced via intradermal injection using needle-syringe. However, only when expanding the vaccination area by using two npMNAs the frequencies of induced IFN-γ-specific effector CD8(+) T cells were comparable with those induced via needle-syringe injection. Analysis of vaccine release from npMNA in a human ex vivo skin explant model revealed that OVA257-264 peptides were indeed delivered intradermal, and release also increased by prolonging the npMNA application time on the human skin. Together, our studies demonstrate the potential of npMNA for vaccine delivery in human skin and in vivo induction of CD8(+) effector T cell responses. 10.1016/j.ijpharm.2015.06.025
    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. Tanaka Yohei Lasers in surgery and medicine BACKGROUND AND OBJECTIVE: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. STUDY DESIGN/MATERIALS AND METHODS: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. RESULTS: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. CONCLUSION: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. 10.1002/lsm.22401
    Spreading of a Lidocaine Formulation on Microneedle-Treated Skin. Nayak Atul,Das Diganta B,Chao Tzu C,Starov Victor M Journal of pharmaceutical sciences 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. 10.1002/jps.24625
    Parents' perceptions of microneedle-mediated monitoring as an alternative to blood sampling in the monitoring of their infants. Mooney Karen,McElnay James C,Donnelly Ryan F The International journal of pharmacy practice OBJECTIVES:Microneedle (MN) arrays could offer a pain-free, minimally invasive approach to monitoring. This is envisaged to be particularly beneficial for younger patients, but parents' views to date are unknown. The aim of this study was to explore parental perceptions of MN-mediated ISF monitoring, as an alternative to the use of conventional blood sampling, and to understand the important factors for technique approval. METHODS:Semi-structured interviews were conducted with parents with recent experience of a premature birth. Recruitment was through the Northern Ireland premature infant charity, Tinylife. Interviews progressed until data saturation was reached and thematic analysis employed. KEY FINDINGS:The study included 16 parents. Parental support for MN-mediated monitoring was evident, alongside the unpopularity of traditional blood sampling in neonates. Factors facilitating MN approval included the opportunity for pain reduction, the simplicity of the procedure, the potential for increased parental involvement and the more favourable appearance, owing to the minute size of MNs and similarities with a sticking plaster. Confirmation of correct application, a pain-free patch removal and endorsement from trusted healthcare professionals were important. CONCLUSION:These findings will inform researchers in the field of MN development and enlighten practitioners regarding parental distress resulting from conventional blood sampling. Further work is necessary to understand MN acceptability among practitioners. This work should assist in the development of an acceptable MN device and facilitate the reduction of parental distress. AUTHOR:The abbreviations section has been deleted, and the full forms of the terms mentioned therein have been incorporated in the text. Please confirm if this is okay. 10.1111/ijpp.12195
    Hydrogel-Forming Microneedle Arrays Allow Detection of Drugs and Glucose In Vivo: Potential for Use in Diagnosis and Therapeutic Drug Monitoring. 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 PloS one 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. 10.1371/journal.pone.0145644
    Microneedle-assisted microparticle delivery by gene guns: experiments and modeling on the effects of particle characteristics. Zhang Dongwei,Rielly Chris D,Das Diganta B Drug delivery Microneedles (MNs) have been shown to enhance the penetration depths of microparticles delivered by gene gun. This study aims to investigate the penetration of model microparticle materials, namely, tungsten (<1 μm diameter) and stainless steel (18 and 30 μm diameters) into a skin mimicking agarose gel to determine the effects of particle characteristics (mainly particle size). A number of experiments have been processed to analyze the passage percentage and the penetration depth of these microparticles in relation to the operating pressures and MN lengths. A comparison between the stainless steel and tungsten microparticles has been discussed, e.g. passage percentage, penetration depth. The passage percentage of tungsten microparticles is found to be less than the stainless steel. It is worth mentioning that the tungsten microparticles present unfavourable results which show that they cannot penetrate into the skin mimicking agarose gel without the help of MN due to insufficient momentum due to the smaller particle size. This condition does not occur for stainless steel microparticles. In order to further understand the penetration of the microparticles, a mathematical model has been built based on the experimental set up. The penetration depth of the microparticles is analyzed in relation to the size, operating pressure and MN length for conditions that cannot be obtained in the experiments. In addition, the penetration depth difference between stainless steel and tungsten microparticles is studied using the developed model to further understand the effect of an increased particle density and size on the penetration depth. 10.3109/10717544.2014.887158
    Feasibility study for intraepidermal delivery of proteins using a solid microneedle array. Witting Madeleine,Obst Katja,Pietzsch Markus,Friess Wolfgang,Hedtrich Sarah International journal of pharmaceutics Solid microneedles (MN) are a promising tool for dermal drug delivery. Particular focus lies on the field of vaccination due to pain-free, safe, hygienic and patient compliant antigen deposition. Diverse coating techniques and formulations have been developed to preserve vaccine activity and to enable targeted drug deposition in the skin. Process and long-term storage stability of coated MN, however, have not yet been studied in detail. Hence, a feasibility study was conducted determining the appropriate needle length (300 μm) for local intraepidermal protein delivery. Moreover, a protein-stabilizing coating formulation was developed. Coating of the MN resulted in protein concentrations between 10 and 23 μg, 90% of the bioactivity of the model protein asparaginase was maintained for 3 months. Skin experiments verified the intraepidermal deposition of 68.0 ± 11.7% of the coated model protein after single application. Slightly increased interleukin 8 levels right after MN insertion indicated minor skin irritation due to the mechanical piercing stress. Thus, specifically highlighting protein stabilization during storage, we demonstrated that selective intraepidermal deposition of proteins or peptides' using solid MN is a feasible approach. 10.1016/j.ijpharm.2015.03.046
    Microneedle delivery of autoantigen for immunotherapy in type 1 diabetes. Zhao Xin,Birchall James C,Coulman Sion A,Tatovic Danijela,Singh Ravinder K,Wen Li,Wong F Susan,Dayan Colin M,Hanna Stephanie J Journal of controlled release : official journal of the Controlled Release Society Antigen specific immunotherapy mediated via the sustained generation of regulatory T cells arguably represents the ideal therapeutic approach to preventing beta cell destruction in type 1 diabetes. However, there is a need to enhance the efficacy of this approach to achieve disease modification in man. Previous studies suggest that prolonged expression of self-antigen in skin in a non-inflammatory context is beneficial for tolerance induction. We therefore sought to develop a dry-coated microneedle (MN) delivery system and combine it with topical steroid to minimise local inflammation and promote prolonged antigen presentation in the skin. Here we show that a combination of surface-modified MNs coated with appropriate solvent systems can deliver therapeutically relevant quantities of peptide to mouse and human skin even with hydrophobic peptides. Compared to conventional "wet" intradermal (ID) administration, "dry" peptide delivered via MNs was retained for longer in the skin and whilst topical hydration of the skin with vehicle or steroid accelerated loss of ID-delivered peptide from the skin, MN delivery of peptide was unaffected. Furthermore, MN delivery resulted in enhanced presentation of antigen to T cells in skin draining lymph nodes (LNs) both 3 and 10days after administration. Repeated administration of islet antigen peptide via MN was effective at reducing antigen-specific T cell proliferation in the pancreatic LN, although topical steroid therapy did not enhance this. Taken together, these data show auto-antigenic peptide delivery into skin using coated MNs results in prolonged retention and enhanced antigen presentation compared to conventional ID delivery and this approach may have potential in individuals identified as being at a high risk of developing type 1 diabetes and other autoimmune diseases. 10.1016/j.jconrel.2015.12.040
    4-n-butylresorcinol dissolving microneedle patch for skin depigmentation: a randomized, double-blind, placebo-controlled trial. Kim Suyong,Yang Huisuk,Kim Miroo,Baek Ji Hwoon,Kim So Jeong,An Sang Mi,Koh Jae Sook,Seo Ransug,Jung Hyungil Journal of cosmetic dermatology BACKGROUND:For effective skin depigmentation, the skin depigmentation agent must be delivered to melanocytes, where melanin is synthesized. Although dissolving microneedle (DMN) is one of the best transdermal drug delivery systems to deliver the active compound, no clinical trial has been conducted in terms of safety and efficacy. OBJECTIVES:To assess the clinical efficacy and safety of a DMN patch that contained 4-n-butylresorcinol, a skin depigmentation agent. METHODS:In the safety assessment, 31 subjects were selected for primary skin irritation test using Frosch & Kligman's method and 50 women for the cumulative irritation test and sensitization potential test using a modification of the Shelanski-Shelanski method. In the efficacy assessment, the 4-n-butylresorcinol DMN patch was compared with a control (DMN without 4-n-butylresorcinol) in our double-blind, placebo-controlled study with 45 subjects by measuring two parameters, the melanin index and individual typology angle value, during 8 weeks of administration. RESULTS:The 4-n-butylresorcinol DMN patch was shown to be safe based on the results of the safety assessment and was more than two times effective than the control patch. CONCLUSION:The 4-n-butylresorcinol DMN patch was effective and safe for skin depigmentation through targeting melanocytes and could be a useful functional cosmetic product. 10.1111/jocd.12178
    Development of cup shaped microneedle array for transdermal drug delivery. Vinayakumar Kadayar B,Hegde Gopal M,Ramachandra Subbaraya G,Nayak Mangalore M,Dinesh Narasimhian S,Rajanna Konandur Biointerphases Microneedle technology is one of the attractive methods in transdermal drug delivery. However, the clinical applications of this method are limited owing to: complexity in the preparation of multiple coating solutions, drug leakage while inserting the microneedles into the skin and the outer walls of the solid microneedle can hold limited quantity of drug. Here, the authors present the fabrication of an array of rectangular cup shaped silicon microneedles, which provide for reduced drug leakage resulting in improvement of efficiency of drug delivery and possibility of introducing multiple drugs. The fabricated solid microneedles with rectangular cup shaped tip have a total height of 200 μm. These cup shaped tips have dimensions: 60 × 60 μm (length × breadth) with a depth of 60 μm. The cups are filled with drug using a novel in-house built drop coating system. Successful drug dissolution was observed when the coated microneedle was used on mice. Also, using the above method, it is possible to fill the cups selectively with different drugs, which enables simultaneous multiple drug delivery. 10.1116/1.4919779
    A self-powered one-touch blood extraction system: a novel polymer-capped hollow microneedle integrated with a pre-vacuum actuator. Li Cheng Guo,Dangol Manita,Lee Chang Yeol,Jang Mingyu,Jung Hyungil Lab on a chip Blood is the gold standard sample medium that can provide a wide variety of useful biological information for the diagnosis of various diseases. For portable point-of-care diagnosis, blood extraction systems have attracted attention as easier, safer, and more rapid methods of collecting small blood volumes. In this paper, we introduce a novel self-powered one-touch blood extraction system created by assembling a smart polymer-capped hollow microneedle in a pre-vacuum polydimethylsiloxane actuator. The optimized hollow microneedle was precisely fabricated by drawing lithography for minimally invasive blood extraction, with a length of 1800 μm, an inner diameter of 60 μm, an outer diameter of 130 μm, and a bevel angle of 15°. The system utilizes only a single step for operation; a finger press activates the blood sampling process based on the negative pressure-driven force built into the pre-vacuum activated actuator. A sufficient volume of blood (31.3 ± 2.0 μl) was successfully extracted from a rabbit for evaluation using a micro total analysis system. The entire system was made of low-cost and disposable materials to achieve easy operation with a miniature structure and to meet the challenging requirements for single-use application in a point-of-care system without the use of any external power equipment. 10.1039/c4lc00937a
    Microneedle applications in improving skin appearance. McCrudden Maelíosa T C,McAlister Emma,Courtenay Aaron J,González-Vázquez Patricia,Singh Thakur Raghu Raj,Donnelly Ryan F Experimental dermatology Microneedles (MNs) are micron-sized, minimally invasive devices that breach the outermost layer of the skin, the stratum corneum (SC), creating transient, aqueous pores in the skin and facilitating the transport of therapeutic molecules into the epidermis. Following many years of extensive research in the area of MN-mediated trans- and intra-dermal drug delivery, MNs are now being exploited in the cosmeceutical industry as a means of disrupting skin cell architecture, inducing elastin and collagen expression and deposition. They are also being used as vehicles to deliver cosmeceutic molecules across the skin, in addition to their use in combinatorial treatments with topical agents or light sources. This review explores the chronology of microneedling methodologies, which has led to the emergence of MN devices, now extensively used in cosmeceutical applications. Recent developments in therapeutic molecule and peptide delivery to the skin via MN platforms are addressed and some commercially available MN devices are described. Important safety and regulatory considerations relating to MN usage are addressed, as are studies relating to public perception of MN, as these will undoubtedly influence the acceptance of MN products as they progress towards commercialisation. 10.1111/exd.12723
    Mannosylated and lipid A-incorporating cationic liposomes constituting microneedle arrays as an effective oral mucosal HBV vaccine applicable in the controlled temperature chain. Wang Ting,Zhen Yuanyuan,Ma Xiaoyu,Wei Biao,Li Shuqin,Wang Ning Colloids and surfaces. B, Biointerfaces To develop an effective, convenient and stable mucosal vaccine against hepatitis B virus (HBV), the mannose-PEG-cholesterol/lipid A-liposomes (MLLs) loaded with HBsAg were prepared by the procedure of emulsification-lyophilization and, subsequently, filled into the microholes of microneedle array reverse molds and dried to form the proHBsAg-MLLs microneedle arrays (proHMAs). The proHMAs were stable even at 40 °C for up to 3 days and hard enough to pierce porcine skin but, upon rehydration, rapidly dissolved recovering the HBsAg-MLLs without obvious changes in size and antigen association efficiency. Notably, immunization of mice only once with the proHMAs at oral mucosa induced robust systemic and widespread mucosal immunoresponses, as evidenced by the high levels of HBsAg-specific IgG in the sera and IgA in the salivary, intestinal and vaginal secretions. In addition, a strong cellular immunity against HBV had been established through a mixed Th1/Th2 response, as confirmed by a significant increase in CD8(+) T cells as well as the enhanced levels of IgG2a and IFN-γ in the treated mice. Thus, the proHMAs can be conveniently vaccinated via oral mucosal route to set up a multiple immune defense against HBV invasion and, in addition, may be a stable HBV vaccine applicable in the controlled temperature chain for wide distribution. 10.1016/j.colsurfb.2015.01.005
    Self-powered microneedle-based biosensors for pain-free high-accuracy measurement of glycaemia in interstitial fluid. Strambini L M,Longo A,Scarano S,Prescimone T,Palchetti I,Minunni M,Giannessi D,Barillaro G Biosensors & bioelectronics 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. 10.1016/j.bios.2014.11.010
    Application of Microneedle Arrays for Enhancement of Transdermal Permeation of Insulin: In Vitro Experiments, Scaling Analyses and Numerical Simulations. Leeladurga V,Teja U Chandra,Sultana S K Ashraf,Sudeep K,Anusha V Sai Sri,Han Tao,Nalluri Buchi N,Das Diganta B AAPS PharmSciTech The aim of this investigation is to study the effect of donor concentration and microneedle (MN) length on permeation of insulin and further evaluating the data using scaling analyses and numerical simulations. Histological evaluation of skin sections was carried to evaluate the skin disruption and depth of penetration by MNs. Scaling analyses were done using dimensionless parameters like concentration of drug (C t/C s), thickness (h/L) and surface area of the skin (S a/L (2)). Simulation studies were carried out using MATLAB and COMSOL software to simulate the insulin permeation using histological sections of MN-treated skin and experimental parameters like passive diffusion coefficient. A 1.6-fold increase in transdermal flux and 1.9-fold decrease in lag time values were observed with 1.5 mm MN when compared with passive studies. Good correlation (R (2) > 0.99) was observed between different parameters using scaling analyses. Also, the in vitro and simulated permeations profiles were found to be similar (f 2 ≥ 50). Insulin permeation significantly increased with increase in donor concentration and MN length (p < 0.05). The developed scaling correlations and numerical simulations were found to be accurate and would help researchers to predict the permeation of insulin with new dimensions of MN in optimizing insulin delivery. Overall, it can be inferred that the application of MNs can significantly enhance insulin permeation and may be an efficient alternative for injectable insulin therapy in humans. 10.1208/s12249-015-0416-8
    DNA-based vaccination against hepatitis B virus using dissolving microneedle arrays adjuvanted by cationic liposomes and CpG ODN. Qiu Yuqin,Guo Lei,Zhang Suohui,Xu Bai,Gao Yunhua,Hu Yan,Hou Jun,Bai Bingke,Shen Honghui,Mao Panyong Drug delivery DNA vaccines are simple to produce and can generate strong cellular and humoral immune response, making them attractive vaccine candidates. However, a major shortcoming of DNA vaccines is their poor immunogenicity when administered intramuscularly. Transcutaneous immunization (TCI) via microneedles is a promising alternative delivery route to enhance the vaccination efficacy. A novel dissolving microneedle array (DMA)-based TCI system loaded with cationic liposomes encapsulated with hepatitis B DNA vaccine and adjuvant CpG ODN was developed and characterized. The pGFP expression in mouse skin using DMA was imaged over time. In vivo immunity tests in mice were performed to observe the capability of DMA to induce immune response after delivery of DNA. The results showed that pGFP could be delivered into skin by DMA and expressed in skin. Further, the amount of expressed GFP was likely to peak at day 4. The immunity tests showed that the DMA-based DNA vaccination could induce effective immune response. CpG ODN significantly improved the immune response and achieved the shift of immune type from predominate Th2 type to a balance Th1/Th2 type. The cationic liposomes could further improve the immunogenicity of DNA vaccine. In conclusion, the novel DMA-based TCI system can effectively deliver hepatitis B DNA vaccine into skin, inducing effective immune response and change the immune type by adjuvant CpG ODN. 10.3109/10717544.2014.992497
    Hollow agarose microneedle with silver coating for intradermal surface-enhanced Raman measurements: a skin-mimicking phantom study. Yuen Clement,Liu Quan Journal of biomedical optics 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 there use 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. 10.1117/1.JBO.20.6.061102
    Paediatricians' opinions of microneedle-mediated monitoring: a key stage in the translation of microneedle technology from laboratory into clinical practice. Mooney Karen,McElnay James C,Donnelly Ryan F Drug delivery and translational research 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. 10.1007/s13346-015-0223-5
    A new paradigm for numerical simulation of microneedle-based drug delivery aided by histology of microneedle-pierced skin. Han Tao,Das Diganta Bhusan Journal of pharmaceutical sciences Microneedle (MN) is a relatively recent invention and an efficient technology for transdermal drug delivery (TDD). Conventionally, mathematical models of MNs drug delivery define the shape of the holes created by the MNs in the skin as the same as their actual geometry. Furthermore, the size of the MN holes in the skin is considered to be either the same or a certain fraction of the length of the MNs. However, the histological images of the MN-treated skin indicate that the real insertion depth is much shorter than the length of the MNs and the shapes may vary significantly from one case to another. In addressing these points, we propose a new approach for modeling MN-based drug delivery, which incorporates the histology of MN-pierced skin using a number of concepts borrowed from image processing tools. It is expected that the developed approach will provide better accuracy of the drug diffusion profile. A new computer program is developed to automatically obtain the outline of the MNs-treated holes and import these images into computer software for simulation of drug diffusion from MN systems. This method can provide a simple and fast way to test the quality of MNs design and modeling, as well as simulate experimental studies, for example, permeation experiments on MN-pierced skin using diffusion cell. The developed methodology is demonstrated using two-dimensional (2D) numerical modeling of flat MNs (2D). However, the methodology is general and can be implemented for three dimensional (3D) MNs if there is sufficient number of images for reconstructing a 3D image for numerical simulation. Numerical modeling for 3D geometry is demonstrated by using images of an ideal 3D MN. The methodology is not demonstrated for real 3D MNs, as there are not sufficient numbers of images for the purpose of this paper. 10.1002/jps.24425
    Investigation on fabrication process of dissolving microneedle arrays to improve effective needle drug distribution. Wang Qingqing,Yao Gangtao,Dong Pin,Gong Zihua,Li Ge,Zhang Kejian,Wu Chuanbin European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences The dissolving microneedle array (DMNA) offers a novel potential approach for transdermal delivery of biological macromolecular drugs and vaccines, because it can be as efficient as hypodermic injection and as safe and patient compliant as conventional transdermal delivery. However, effective needle drug distribution is the main challenge for clinical application of DMNA. This study focused on the mechanism and control of drug diffusion inside DMNA during the fabrication process in order to improve the drug delivery efficiency. The needle drug loading proportion (NDP) in DMNAs was measured to determine the influences of drug concentration gradient, needle drying step, excipients, and solvent of the base solution on drug diffusion and distribution. The results showed that the evaporation of base solvent was the key factor determining NDP. Slow evaporation of water from the base led to gradual increase of viscosity, and an approximate drug concentration equilibrium was built between the needle and base portions, resulting in NDP as low as about 6%. When highly volatile ethanol was used as the base solvent, the viscosity in the base rose quickly, resulting in NDP more than 90%. Ethanol as base solvent did not impact the insertion capability of DMNAs, but greatly increased the in vitro drug release and transdermal delivery from DMNAs. Furthermore, the drug diffusion process during DMNA fabrication was thoroughly investigated for the first time, and the outcomes can be applied to most two-step molding processes and optimization of the DMNA fabrication. 10.1016/j.ejps.2014.09.011
    Application of a three-microneedle device for the delivery of local anesthetics. Ishikawa Kayoko,Fukamizu Hidekazu,Takiguchi Tetsuya,Ohta Yusuke,Tokura Yoshiki Patient preference and adherence PURPOSE:We investigated the effectiveness of a newly developed device for the delivery of local anesthetics in the treatment of axillary osmidrosis and hyperhidrosis. We developed a device with three fine, stainless steel needles fabricated with a bevel angle facing outside ("three-microneedle device" [TMD]) to release a drug broadly and homogeneously into tissue in the horizontal plane. Use of this device could reduce the risk of complications when transcutaneous injections are undertaken. PATIENTS AND METHODS:Sixteen Japanese patients were enrolled. The mean volume of lidocaine hydrochloride per unit area needed to elicit anesthesia when using a TMD was compared with that the volume required when using a conventional 27-gauge needle. The visual analog scale (VAS) score of needlestick pain and injection-associated pain was also compared. RESULTS:The mean volume of lidocaine hydrochloride per unit area to elicit anesthesia using the TMD was significantly lower than that the volume required when using the conventional 27-gauge needle. The VAS score of needlestick pain for the TMD was significantly lower than that the VAS score for the 27-gauge needle. CONCLUSION:These data suggest that the TMD could be useful for the delivery of local anesthetics in terms of clinical efficacy and avoidance of adverse effects. 10.2147/PPA.S76540
    Electroencephalogram measurement from the hairy part of the scalp using polymer-based dry microneedle electrodes. Arai M,Kudo Y,Miki N Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference This paper reports a successful electroencephalogram (EEG) measurement from the hairy part of the scalp using a polymer-based dry microneedle electrode. The electrode consists of 25 pillars, each of which has a sharp microneedle on the top. Hairs are collected into the gaps of the pillars and the microneedles can reach the scalp surface. Since the microneedles can penetrate through the stratum corneum, no conductive gel is necessary to acquire high quality EEG. We experimentally investigated the pillar diameters in EEG measurement from the occipital region with hairs. The fabricated electrodes successfully measured EEG without any skin preparation or conductive gel. 10.1109/EMBC.2015.7319064
    Quality of life in patients with primary axillary hyperhidrosis before and after treatment with fractionated microneedle radiofrequency. Abtahi-Naeini Bahareh,Naeini Farahnaz Fatemi,Adibi Neda,Pourazizi Mohsen Journal of research in medical sciences : the official journal of Isfahan University of Medical Sciences BACKGROUND:Primary axillary hyperhidrosis (PAH) is a common condition with a great impact on the patient's quality of life (QOL). It is associated with serious social, emotional, and occupational distress. The aim of this study was to investigate the QOL in patients with PAH before and after treatment with fractionated microneedle radiofrequency (FMR). MATERIALS AND METHODS:We evaluated 25 patients with severe PAH. Each patient had three sessions of FMR treatment using a novel applicator at 3-week intervals. The study was based on Dermatology Life Quality Index (DLQI) Questionnaires. Patients were evaluated at baseline and 3 months after the last session. RESULTS:Our patients included 32% males and 68% females. The mean ± standard deviation (SD) age of subjects was 30.2 ± 6.27 years. The mean ± SD of the DLQI before and after treatment was 12.96 ± 5.93, and 4.29 ± 2.21, respectively. There was a statistically significant difference between the before and after intervention (P < 0.001). No major, permanent adverse effects were shown. CONCLUSION:Treatment with FMR can improve the DLQI of patients with PAH. 10.4103/1735-1995.166196
    Microwave-Assisted Preparation of Hydrogel-Forming Microneedle Arrays for Transdermal Drug Delivery Applications. Larrañeta Eneko,Lutton Rebecca E M,Brady Aaron J,Vicente-Pérez Eva M,Woolfson A David,Thakur Raghu Raj Singh,Donnelly Ryan F Macromolecular materials and engineering 1A microwave (MW)-assisted crosslinking process to prepare hydrogel-forming microneedle (MN) arrays was evaluated. Conventionally, such MN arrays are prepared using processes that includes a thermal crosslinking step. Polymeric MN arrays were prepared using poly(methyl vinyl ether-alt-maleic acid) crosslinked by reaction with poly(ethylene glycol) over 24 h at 80 °C. Polymeric MN arrays were prepared to compare conventional process with the novel MW-assisted crosslinking method. Infrared spectroscopy was used to evaluate the crosslinking degree, evaluating the area of the carbonyl peaks (2000-1500 cm). It was shown that, by using the MW-assisted process, MN with a similar crosslinking degree to those prepared conventionally can be obtained in only 45 min. The effects of the crosslinking process on the properties of these materials were also evaluated. For this purpose swelling kinetics, mechanical characterisation, and insertion studies were performed. The results suggest that MN arrays prepared using the MW assisted process had equivalent properties to those prepared conventionally but can be produced 30 times faster. Finally, an caffeine permeation across excised porcine skin was performed using conventional and MW-prepared MN arrays. The release profiles obtained can be considered equivalent, delivering in both cases 3000-3500 μg of caffeine after 24 h. 10.1002/mame.201500016
    Microneedle-array patches loaded with hypoxia-sensitive vesicles provide fast glucose-responsive insulin delivery. Yu Jicheng,Zhang Yuqi,Ye Yanqi,DiSanto Rocco,Sun Wujin,Ranson Davis,Ligler Frances S,Buse John B,Gu Zhen Proceedings of the National Academy of Sciences of the United States of America A glucose-responsive "closed-loop" insulin delivery system mimicking the function of pancreatic cells has tremendous potential to improve quality of life and health in diabetics. Here, we report a novel glucose-responsive insulin delivery device using a painless microneedle-array patch ("smart insulin patch") containing glucose-responsive vesicles (GRVs; with an average diameter of 118 nm), which are loaded with insulin and glucose oxidase (GOx) enzyme. The GRVs are self-assembled from hypoxia-sensitive hyaluronic acid (HS-HA) conjugated with 2-nitroimidazole (NI), a hydrophobic component that can be converted to hydrophilic 2-aminoimidazoles through bioreduction under hypoxic conditions. The local hypoxic microenvironment caused by the enzymatic oxidation of glucose in the hyperglycemic state promotes the reduction of HS-HA, which rapidly triggers the dissociation of vesicles and subsequent release of insulin. The smart insulin patch effectively regulated the blood glucose in a mouse model of chemically induced type 1 diabetes. The described work is the first demonstration, to our knowledge, of a synthetic glucose-responsive device using a hypoxia trigger for regulation of insulin release. The faster responsiveness of this approach holds promise in avoiding hyperglycemia and hypoglycemia if translated for human therapy. 10.1073/pnas.1505405112
    An economic model assessing the value of microneedle patch delivery of the seasonal influenza vaccine. Lee Bruce Y,Bartsch Sarah M,Mvundura Mercy,Jarrahian Courtney,Zapf Kristina M,Marinan Kathleen,Wateska Angela R,Snyder Bill,Swaminathan Savitha,Jacoby Erica,Norman James J,Prausnitz Mark R,Zehrung Darin Vaccine BACKGROUND:New vaccine technologies may improve the acceptability, delivery (potentially enabling self-administration), and product efficacy of influenza vaccines. One such technology is the microneedle patch (MNP), a skin delivery technology currently in development. Although MNPs hold promise in preclinical studies, their potential economic and epidemiologic impacts have not yet been evaluated. METHODS:We utilized a susceptible-exposed-infectious-recovered (SEIR) transmission model linked to an economic influenza outcomes model to assess the economic value of introducing the MNP into the current influenza vaccine market in the United States from the third-party payer and societal perspectives. We also explored the impact of different vaccination settings, self-administration, the MNP price, vaccine efficacy, compliance, and MNP market share. Outcomes included costs, quality-adjusted life years (QALYs), cases, and incremental cost-effectiveness ratios (ICERs; cost/QALY). RESULTS:With healthcare provider administration, MNP introduction would be cost-effective (ICERs ≤$23,347/QALY) at all MNP price points ($9.50-$30) and market shares (10-60%) assessed, except when compliance and efficacy were assumed to be the same as existing vaccines and the MNP occupied a 10% market share. If MNP self-administration were available (assuming the same efficacy as current technologies), MNP compliance or its efficacy would need to increase by ≥3% in order to be cost-effective (ICERs ≤$1401/QALY), assuming a 2% reduction in administration success with unsupervised self-administration. Under these conditions, MNP introduction would be cost-effective for all price points and market shares assessed. CONCLUSIONS:When healthcare providers administered the MNP, its introduction would be cost-effective or dominant (i.e., less costly and more effective) in the majority of scenarios assessed. If self-administration were available, MNP introduction would be cost-effective if it increased compliance enough to overcome any decrease in self-administration success or if the MNP presentation afforded an increase in efficacy over current delivery methods for influenza vaccines. 10.1016/j.vaccine.2015.02.076
    Skin vaccination with live virus vectored microneedle arrays induce long lived CD8(+) T cell memory. Becker Pablo D,Hervouet Catherine,Mason Gavin M,Kwon Sung-Yun,Klavinskis Linda S Vaccine 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. 10.1016/j.vaccine.2015.04.046
    Therapeutic intradermal delivery of tumor necrosis factor-alpha antibodies using tip-loaded dissolvable microneedle arrays. Korkmaz Emrullah,Friedrich Emily E,Ramadan Mohamed H,Erdos Geza,Mathers Alicia R,Burak Ozdoganlar O,Washburn Newell R,Falo Louis D Acta biomaterialia Tumor necrosis factor-alpha (TNF-α) specific antibodies (anti-TNF-α Ab) have been shown to be potent TNF inhibitors and effective therapeutics for a range of inflammatory diseases. Typically, these drugs are administered systemically, but systemic dosing sufficient to achieve locally effective concentrations in peripheral tissues has been associated with systemic immunosuppression and related adverse events. Here, we evaluated the use of tip-loaded dissolvable microneedle arrays (MNAs) for localized intradermal delivery of anti-TNF-α Ab. MNAs with obelisk shape microneedles that incorporate the antibody cargo in the needle tips were created from carboxymethylcellulose (CMC) using a micromilling/spin-casting fabrication method. We found that anti-TNF-α Ab integrated into MNAs using this room temperature fabrication process maintained conformationally dependent TNF-α binding activity. Further, these MNAs efficiently delivered anti-TNF-α antibodies to the dermis of human skin with clinically applicable release profiles. To evaluate MNA delivered anti-TNF-α Ab function, we applied anti-TNF-α Ab containing MNAs to established psoriasiform lesions on the skin of mice. MNA anti-TNF-α Ab treatment reduced key biomarkers of psoriasiform inflammation including epidermal thickness and IL-1β expression. Taken together, these results demonstrate efficient and biologically effective MNA delivery of anti-TNF-α Ab to the intradermal microenvironment of the skin in mice and humans, and support the development of MNA mediated antibody delivery for clinical applications. STATEMENT OF SIGNIFICANCE:Tumor necrosis factor-alpha (TNF-α) specific antibodies (anti-TNF-α Ab) have been shown to be potent TNF inhibitors and effective therapeutics for a range of inflammatory diseases. Typically, these drugs are administered systemically, but systemic dosing sufficient to achieve locally effective concentrations in peripheral tissues has been associated with systemic immunosuppression and related adverse events. Here we demonstrate efficient and biologically effective MNA delivery of anti-TNF-α Ab to the intradermal microenvironment of the skin in mice and humans. These results support the development of MNA mediated antibody delivery of therapeutic antibodies for clinical applications. 10.1016/j.actbio.2015.05.036
    Fractionated microneedle radiofrequency for treatment of primary axillary hyperhidrosis: A sham control study. Fatemi Naeini Farahnaz,Abtahi-Naeini Bahareh,Pourazizi Mohsen,Nilforoushzadeh Mohammad Ali,Mirmohammadkhani Majid The Australasian journal of dermatology BACKGROUND/ OBJECTIVE: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. METHODS: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. RESULTS: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. CONCLUSIONS: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. 10.1111/ajd.12260
    Opportunities and challenges in delivering influenza vaccine by microneedle patch. Jacoby Erica,Jarrahian Courtney,Hull Harry F,Zehrung Darin Vaccine INTRODUCTION:Simple and efficacious delivery methods for influenza vaccines are needed to improve health outcomes and manage possible pandemics both in the United States and globally. One approach to meeting these needs is the microneedle patch (MNP), a small array of micron-scale needles that is applied to the skin like a bandage. METHODS:To inform additional technical developments and the eventual introduction of MNPs for influenza vaccination, we interviewed key opinion leaders in the United States for insights into the opportunities and challenges associated with this technology, particularly its potential for self-administration. RESULTS:All interviewees expressed high support for administration of influenza vaccine in MNPs by health care providers and for self-administration in groups supervised by a provider. Self-administration via prescription and over-the-counter purchase of MNPs received lower levels of support. Interviewees also highlighted priorities that should be considered in the ongoing development of an influenza vaccine MNP, such as confirming efficacy and ensuring safety for self-administration. For patient and health care provider acceptability, important attributes are ease of use, short wear times, and an easily accessible application site. DISCUSSION AND CONCLUSIONS:Stakeholders agreed that using MNPs can help increase coverage, facilitate easy and safe delivery, reduce the cost of vaccination, and decrease the global morbidity and mortality associated with influenza. Another opportunity for this delivery method is the potential for self-administration. The prospect of reduced provider training requirements, increased thermostability, and high patient and provider acceptability makes it an attractive option for use in remote and low-resource settings worldwide. However, in addition to the technological challenges associated with producing the patch, developers must be mindful of cost considerations and key product attributes or requirements, such as usability, wear time, and proper disposal, that can affect how the product will be received in the marketplace. 10.1016/j.vaccine.2015.03.062
    A novel scalable manufacturing process for the production of hydrogel-forming microneedle arrays. Lutton Rebecca E M,Larrañeta Eneko,Kearney Mary-Carmel,Boyd Peter,Woolfson A David,Donnelly Ryan F International journal of pharmaceutics 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%. 10.1016/j.ijpharm.2015.08.049
    Development of a thermostable microneedle patch for influenza vaccination. Mistilis Matthew J,Bommarius Andreas S,Prausnitz Mark R Journal of pharmaceutical sciences The goal of this study is to develop thermostable microneedle patch formulations for influenza vaccine that can be partially or completely removed from the cold chain. During vaccine drying associated with microneedle patch manufacturing, ammonium acetate and 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) buffer salts stabilized influenza vaccine, surfactants had little effect during drying, drying temperature had weak effects on vaccine stability, and drying on polydimethylsiloxane (PDMS) led to increased stability compared with drying on stainless steel. A number of excipients, mostly polysaccharides and some amino acids, further stabilized the influenza vaccine during drying. Over longer time scales of storage, combinations of stabilizers preserved the most vaccine activity. Finally, dissolving microneedle patches formulated with arginine and calcium heptagluconate had no significant activity loss for all three strains of seasonal influenza vaccine during storage at room temperature for 6 months. We conclude that appropriately formulated microneedle patches can exhibit remarkable thermostability that could enable storage and distribution of influenza vaccine outside the cold chain. 10.1002/jps.24283
    Diclofenac enables unprecedented week-long microneedle-enhanced delivery of a skin impermeable medication in humans. Brogden Nicole K,Banks Stan L,Crofford Leslie J,Stinchcomb Audra L Pharmaceutical research PURPOSE: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. 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 h 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. 10.1007/s11095-013-1036-1
    Clinical improvement of striae distensae in Korean patients using a combination of fractionated microneedle radiofrequency and fractional carbon dioxide laser. Ryu Han-Won,Kim Sung-Ae,Jung Hye Ra,Ryoo Young-Wook,Lee Kyu-Suk,Cho Jae-We Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.] BACKGROUND:Striae distensae are dermal scars with flattening and atrophy of the epidermis. OBJECTIVE:To evaluate the efficacy and safety of combination therapy with fractionated microneedle radiofrequency (RF) and fractional carbon dioxide (CO2) laser in the treatment of striae distensae. MATERIALS AND METHODS:Thirty patients (30 female; mean age 33, range 21-51, Fitzpatrick skin type IV) with moderate to severe striae distensae were enrolled in this study. Patients were divided into three groups: fractional CO2 laser only (n = 10), microneedle RF only (n = 10), and combination (n = 10). RESULTS:Improvement was evaluated using a visual analogue scale (range 1-4). Mean clinical improvement score of the dermatologist was 2.2 in the fractional CO2 laser-treated group, 1.8 in the microneedle RF-treated group, and 3.4 in the combination group. Through skin biopsy, we observed thickened epidermis and a clear increase in the number of collagen fibers in the microneedle RF- and fractional CO2 combination-treated sites. Consistent with these results, greater expression of transforming growth factor-β1 and stratifin was observed in treated sites. CONCLUSION:Combination therapy of fractionated microneedle RF and fractional CO2 laser is a safe treatment protocol with a positive therapeutic effect on striae distensae. 10.1111/dsu.12268
    Faster pharmacokinetics and increased patient acceptance of intradermal insulin delivery using a single hollow microneedle in children and adolescents with type 1 diabetes. Norman James J,Brown Milton R,Raviele Nicholas A,Prausnitz Mark R,Felner Eric I Pediatric diabetes OBJECTIVE:In an effort to improve compliance with insulin therapy and to accelerate insulin pharmacokinetics, we tested the hypothesis that intradermal insulin delivery using a hollow microneedle causes less pain and leads to faster onset and offset of insulin pharmacokinetics in children and adolescents with type 1 diabetes (T1DM) compared with a subcutaneous, insulin pump catheter. RESEARCH DESIGN AND METHODS:In this repeated measures study, 16 children and adolescents with T1DM received Lispro insulin by microneedle and subcutaneous administration on separate days. Subjects rated the pain of insertion and infusion using a visual analog scale. Blood specimens were collected over 4 h to determine insulin and glucose concentrations. RESULTS:Microneedle insertion pain was significantly lower compared with insertion of the subcutaneous catheter (p = 0.005). Insulin onset time was 22 min faster (p = 0.0004) and offset time was 34 min faster (p = 0.017) after hollow microneedle delivery compared with subcutaneous delivery. CONCLUSIONS:In this study, intradermal insulin delivery using a single, hollow microneedle device resulted in less insertion pain and faster insulin onset and offset in children and adolescents with T1DM. A reduction in pain might improve compliance with insulin delivery. The faster onset and offset times of insulin action may enable closed-loop insulin therapy. 10.1111/pedi.12031
    Transdermal drug delivery using disk microneedle rollers in a hairless rat model. Kim Hyeong Mi,Lim Yun Young,An Joo-Hee,Kim Myeung Nam,Kim Beom Joon International journal of dermatology BACKGROUND:Transdermal drug delivery systems (TDDSs) represent more reliable and consistent methods of drug dosing than oral administration. However, TDDSs can administer only low molecular weight (MW) drugs and require a power source. Disk microneedle rollers facilitate the passage of low and high MW substances through the direct perforation of the stratum corneum and dermis, without stimulating dermal nerves. OBJECTIVES:We investigated in vitro whether disk microneedle rollers, developed for the Diskneedle Therapy System (DTS™) in South Korea, can deliver drugs effectively through the skin of hairless rats. METHODS:The disk microneedle rollers used in the DTS™ are metal and consist of several plates bearing microneedles of graded lengths (0.15 mm, 0.25 mm, 0.50 mm). To test in vitro permeation, the skin of a hairless rat was mounted in a Franz diffusion cell system and rolled with a disk roller without microneedles and with rollers fitted with microneedles of each size. Rhodamine B base (80 μl) was applied to the skin for 24 hours, 48 hours, and 72 hours, and dye permeation was detected at 543 nm. Dye binding to the skin was also confirmed using fluorescence microscopy at six hours after the application of rhodamine B. RESULTS:Use of the disk microneedle roller increased the skin penetrance of rhodamine B base in hairless rats in accordance with microneedle length, as assessed using a fluorescence penetration test. CONCLUSIONS:Disk microneedle rollers, as designed for the DTS™, can be used for transdermal drug delivery. Microneedles can be selected according to the length appropriate for each application. 10.1111/j.1365-4632.2011.05343.x
    Comparative study on efficacy and safety of 1550 nm Er:Glass fractional laser and fractional radiofrequency microneedle device for facial atrophic acne scar. Chae Woong Suk,Seong Jun Young,Jung Ha Na,Kong Sook Hyun,Kim Min Ho,Suh Ho Seok,Choi Yu Sung Journal of cosmetic dermatology BACKGROUND:The 1550 nm Er:Glass fractional laser is widely used for the treatment of atrophic acne scar. A novel fractional radiofrequency microneedle device has recently emerged as an alternative for treating acne scars. OBJECTIVES:To evaluate the clinical efficacy and safety of a Er:Glass fractional laser and fractional radiofrequency microneedle device in the treatment of facial atrophic acne scars and to assess the difference between the treatment modalities depending on facial compartment. METHODS:A total of 40 patients were equally randomized into two groups. Each group of 20 patients received three treatments at 4-week interval using Er:Glass fractional laser or fractional radiofrequency microneedle device. RESULTS:Scar severity scores (ECCA grading scale) improved by a mean of 25.0% and 18.6% in groups A and B, respectively (both P < 0.01). The difference in the degree of improvement was not statistically significant between the groups after three sessions of treatment. There were no significant side effects. CONCLUSION:Atrophic acne scars improved in both groups without significant side effects. Additionally, the fractional laser was a more effective treatment option for acne scars, but the fractional radiofrequency microneedle device offered good adherence and short downtime. 10.1111/jocd.12139
    Improved immunogenicity of individual influenza vaccine components delivered with a novel dissolving microneedle patch stable at room temperature. 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 Drug delivery and translational research 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 single radial diffusion (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 3 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. 10.1007/s13346-015-0228-0
    Histometric analysis of skin-radiofrequency interaction using a fractionated microneedle delivery system. Zheng Zhenlong,Goo Boncheol,Kim Do-Young,Kang Jin-Soo,Cho Sung Bin Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.] BACKGROUND:Fractionated microneedle radiofrequency (RF) devices have been reported to be effective in treatment of various dermatologic disorders. OBJECTIVES:To analyze histometric changes in skin-RF interactions using a fractionated microneedle delivery system. MATERIALS AND METHODS:RF energies were delivered using a fractionated microneedle device to an in vivo minipig model with penetration depths of 0.5, 1.0, 1.5, 2.0, 2.5, and 3.5 mm; RF conduction times of 20, 50, 100, and 1,000 ms; and energy levels of 5.0, 10.0, 20.0, 25.0, 37.5, and 50.0 V. RESULTS:Immediately after treatment, skin samples showed that the RF-induced coagulated columns in the dermis formed a cocoon-shaped zone of sublative thermal injury. Four days after the treatment, skin specimens demonstrated reepithelialization, and the dermal RF-induced coagulated columns showed mixed cellular infiltration, neovascularization, and granulation tissue formation. Microneedle depth and RF conduction times, but not energy level, significantly affected histometric values of RF-induced dermal coagulation. Microneedle RF treatment affected adnexal structures by coagulating follicular epithelium and perifollicular structures. CONCLUSIONS:Our data may be of use as an essential reference for choosing RF parameters in treatment of various skin conditions. 10.1111/dsu.12411
    In vivo, in situ imaging of microneedle insertion into the skin of human volunteers using optical coherence tomography. Coulman Siôn A,Birchall James C,Alex Aneesh,Pearton Marc,Hofer Bernd,O'Mahony Conor,Drexler Wolfgang,Považay Boris Pharmaceutical research PURPOSE:To gather sub-surface in situ images of microneedle-treated human skin, in vivo, using optical coherence tomography (OCT). This is the first study to utilise OCT to investigate the architectural changes that are induced in skin following microneedle application. METHODS:Steel, silicon and polymer microneedle devices, with different microneedle arrangements and morphologies, were applied to two anatomical sites in human volunteers following appropriate ethical approval. A state-of-the-art ultrahigh resolution OCT imaging system operating at 800 nm wavelength and <3 µm effective axial resolution was used to visualise the microneedle-treated area during insertion and/or following removal of the device, without any tissue processing. RESULTS:Transverse images of a microneedle device, in situ, were captured by the OCT system and suggest that the stratified skin tissue is compressed during microneedle application. Following removal of the device, the created microchannels collapse within the in vivo environment and, therefore, for all studied devices, microconduit dimensions are markedly smaller than the microneedle dimensions. CONCLUSIONS:Microchannels created in the upper skin layers by microneedles are less invasive than previous histology predicts. OCT has the potential to play a highly influential role in the future development of microneedle devices and other transdermal delivery systems. 10.1007/s11095-010-0167-x
    Microneedle array design determines the induction of protective memory CD8+ T cell responses induced by a recombinant live malaria vaccine in mice. 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 PloS one 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. 10.1371/journal.pone.0022442
    [Development of a novel transdermal delivery system of peptide and protein drugs using microneedle arrays]. Katsumi Hidemasa,Quan Ying-Shu,Kamiyama Fumio,Kusamori Kosuke,Sakane Toshiyasu,Yamamoto Akira Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan Transdermal delivery of peptide and protein drugs may be limited by the stratum corneum, which is a protective barrier against the entry of microorganisms and water. Many approaches have been utilized to promote peptide and protein drugs delivery across the stratum corneum, including chemical enhancer modification and physical disruption of barrier function. However, it has been difficult to achieve therapeutic levels of peptide and protein drugs via this route without any skin irritation. Recently, attention has been paid to the possibility of using microneedle arrays in delivering peptide and protein drugs into the skin. As a novel and minimally invasive approach, microneedle arrays are capable of creating superficial pathways across the skin for peptide and protein drugs to achieve enhanced transdermal drug delivery. This method combines the efficacy of conventional injection needles with the convenience of transdermal patches, while minimizing the disadvantages of these administration methods. Therefore, microneedle arrays are a very useful alternative method for delivering peptide and protein drugs from the skin into the systemic circulation without any serious damage to skin. In this review, recent challenges in the developments of microneedle arrays for the delivery of peptide and protein drugs are summarized. Then, future developments of microneedle arrays for the delivery of peptide and protein drugs are also discussed in order to improve their therapeutic efficacy and safety.
    Children's views on microneedle use as an alternative to blood sampling for patient monitoring. Mooney Karen,McElnay James C,Donnelly Ryan F The International journal of pharmacy practice OBJECTIVES: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. METHODS: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. KEY FINDINGS: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'. CONCLUSIONS: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. 10.1111/ijpp.12081
    Multiplexed and Switchable Release of Distinct Fluids from Microneedle Platforms via Conducting Polymer Nanoactuators for Potential Drug Delivery. Valdés-Ramírez Gabriela,Windmiller Joshua R,Claussen Jonathan C,Martinez Alexandra G,Kuralay Filiz,Zhou Ming,Zhou Nandi,Polsky Ronen,Miller Philip R,Narayan Roger,Wang Joseph Sensors and actuators. B, Chemical We report on the development of a microneedle-based multiplexed drug delivery actuator that enables the controlled delivery of multiple therapeutic agents. Two individually-addressable channels on a single microneedle array, each paired with its own reservoir and conducting polymer nanoactuator, are used to deliver various permutations of two unique chemical species. Upon application of suitable redox potentials to the selected actuator, the conducting polymer is able to undergo reversible volume changes, thereby serving to release a model chemical agent in a controlled fashion through the corresponding microneedle channels. Time-lapse videos offer direct visualization and characterization of the membrane switching capability and, along with calibration investigations, confirm the ability of the device to alternate the delivery of multiple reagents from individual microneedles of the array with higher precision and temporal resolution than conventional drug delivery actuators. Analytical modeling offers prediction of the volumetric flow rate through a single microneedle and accordingly can be used to assist in the design of subsequent microneedle arrays. The robust solid-state design and lack of mechanical components circumvent reliability issues that challenge fragile conventional microelectromechanical drug delivery devices. This proof-of-concept study demonstrates the potential of the drug delivery actuator system to aid in the rapid administration of multiple therapeutic agents and indicates the potential to counteract diverse biomedical conditions. 10.1016/j.snb.2011.11.085
    Ex vivo evaluation of a microneedle array device for transdermal application. Indermun Sunaina,Choonara Yahya E,Kumar Pradeep,du Toit Lisa C,Modi Girish,van Vuuren Sandy,Luttge Regina,Pillay Viness International journal of pharmaceutics A new approach of transdermal drug delivery is the use of microneedles. This promising technique offers the potential to be broadly used for drug administration as it enables the dramatic increase in permeation of medicaments across the stratum corneum. The potential of microneedles has evolved to spawn a plethora of potential transdermal applications. In order to advance the microneedle capabilities and possibly revolutionize advanced drug delivery, this study introduces a novel transdermal electro-modulated hydrogel-microneedle array (EMH-MNA) device composed of a nano-porous, embeddable ceramic microneedle array as well as an optimized EMH for the electro-responsive delivery of indomethacin through the skin. The ex vivo permeation as well as drug release experiments were performed on porcine skin tissue to ascertain the electro-responsive capabilities of the device. In addition, the microbial permeation ability of the microneedles across the viable epidermis in both microneedle-punctured skin as well as hypodermic needle-punctured skin was determined. Ex vivo evaluation of the EMH-MNA device across porcine skin demonstrated that without electro-stimulation, significantly less drug release was obtained (±0.4540mg) as compared to electro-stimulation (±2.93mg). 10.1016/j.ijpharm.2015.09.070
    An optimized hollow microneedle for minimally invasive blood extraction. Li Cheng Guo,Lee Chang Yeol,Lee Kwang,Jung Hyungil Biomedical microdevices The healthcare system relies widely on biochemical information obtained from blood sample extracted via hypodermic needles, despite the invasiveness and pain associated with this procedure. Therefore, an alternative micro-scale needle for minimally invasive blood sampling is highly desirable. Traditional fabrication techniques to create microneedles do not generate needles with the combined features of a sharp tip, long length, and hollow structure concurrently. Here, we report the fabrication of a microneedle long enough to reach blood vessels and sharp enough to minimize nerve contact for minimally invasive blood extraction. The microneedle structure was precisely controlled using a drawing lithography technique, and a sharp tip angle was introduced using a laser-cutting system. We investigated the characteristics of a microneedle with a length of 1,800 μm length, an inner diameter of 60 μm, a tip diameter of 120 μm, and a 15° bevel angle through in-vitro liquid extraction and mechanical strength analysis. We demonstrated that the proposed structure results in blood extraction at a reasonable rate, and that a microneedle with this geometry can reliably penetrate skin without breaking. We integrated this microneedle into a blood extraction device to extract a 20 μl volume of mouse blood in-vivo. Our optimized, hollow microneedle can potentially be incorporated with other cutting-edge technologies such as microactuators, biosensors, and microfluidic chips to create blood analysis systems for point-of-care diagnostics. 10.1007/s10544-012-9683-2
    Measles vaccination using a microneedle patch. Edens Chris,Collins Marcus L,Ayers Jessica,Rota Paul A,Prausnitz Mark R Vaccine 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. 10.1016/j.vaccine.2012.09.062
    Microneedle delivery: clinical studies and emerging medical applications. Pettis Ronald J,Harvey Alfred J Therapeutic delivery The concept of microneedle drug delivery was described three decades ago; however, effective clinical demonstration has only occurred within the past 10-15 years. Substantial progress in microneedle design and fabrication including extensive in vitro, ex vivo, and in vivo preclinical evaluation with various drugs, vaccines and other agents has transpired over the last decade. In contrast with this large volume of preclinical data, there are relatively few published microneedle clinical studies. To date, the clinical investigative focus has included testing to reduce dermal barrier properties and enhance transdermal delivery; evaluation of enhanced vaccine antigenicity, including development of the first commercial microneedle product for intradermal influenza vaccination; evaluation of altered microneedle protein pharmacokinetics and pharmacodynamics, especially for insulin; and evaluation of the pain and other perceptions associated with microneedle usage. This review summarizes the various aspects of microneedle clinical evaluation to date and identifies areas requiring further clinical evaluation. 10.4155/tde.12.13
    Determination of parameters for successful spray coating of silicon microneedle arrays. McGrath Marie G,Vrdoljak Anto,O'Mahony Conor,Oliveira Jorge C,Moore Anne C,Crean Abina M International journal of pharmaceutics Coated microneedle patches have demonstrated potential for effective, minimally invasive, drug and vaccine delivery. To facilitate cost-effective, industrial-scale production of coated microneedle patches, a continuous coating method which utilises conventional pharmaceutical processes is an attractive prospect. Here, the potential of spray-coating silicon microneedle patches using a conventional film-coating process was evaluated and the key process parameters which impact on coating coalescence and weight were identified by employing a fractional factorial design to coat flat silicon patches. Processing parameters analysed included concentration of coating material, liquid input rate, duration of spraying, atomisation air pressure, gun-to-surface distance and air cap setting. Two film-coating materials were investigated; hydroxypropylmethylcellulose (HPMC) and carboxymethylcellulose (CMC). HPMC readily formed a film-coat on silicon when suitable spray coating parameter settings were determined. CMC films required the inclusion of a surfactant (1%, w/w Tween 80) to facilitate coalescence of the sprayed droplets on the silicon surface. Spray coating parameters identified by experimental design, successfully coated 280μm silicon microneedle arrays, producing an intact film-coat, which follows the contours of the microneedle array without occlusion of the microneedle shape. This study demonstrates a novel method of coating microneedle arrays with biocompatible polymers using a conventional film-coating process. It is the first study to indicate the thickness and roughness of coatings applied to microneedle arrays. The study also highlights the importance of identifying suitable processing parameters when film coating substrates of micron dimensions. The ability of a fractional factorial design to identify these critical parameters is also demonstrated. The polymer coatings applied in this study can potentially be drug loaded for intradermal drug and vaccine delivery. 10.1016/j.ijpharm.2011.05.064
    The efficacy and safety of combined microneedle fractional radiofrequency and sublative fractional radiofrequency for acne scars in Asian skin. Park Jae Yang,Lee Eo Gin,Yoon Moon Soo,Lee Hee Jung Journal of cosmetic dermatology BACKGROUND: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. OBJECTIVE:To evaluate the efficacy and safety of combined microneedle and sublative fractional radiofrequency for acne scars in Asian skin. METHODS: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. RESULTS: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. CONCLUSION: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. 10.1111/jocd.12195
    [Effect of microneedle combined with Lauromacrogol on skin capillary network: experimental study]. Xu Sida,Wei Qiang,Fan Youfen,Chen Shihai,Liu Qingfeng,Yin Guoqiang,Liao Mingde,Sun Yu Zhonghua zheng xing wai ke za zhi = Zhonghua zhengxing waike zazhi = Chinese journal of plastic surgery OBJECTIVE:To explore the effect of microneedle combined with Lauromacrogol on skin capillary network. METHODS:24 male Leghone (1.5-2.0 kg in weight) were randomly divided into three groups as group A (microneedle combined with Lauromacrogol), B (microneedle combined with physiological saline) , and C(control). The cockscombs were treated. The specimens were taken on the 7th, 14th, 21th , and 28th day postoperatively. HE staining, immunohistochemical staining and special staining were performed for study of the number of capillary and collagen I/III , as well as elastic fibers. RESULTS:The color of cockscombs in group A became lightening after treatment. The number of capillary decreased as showing by HE staining. The collagen I and III in group B was significantly different from that in group A and C (P < 0.05). Special staining showed proliferation of elastic fibers in group B. CONCLUSIONS:It indicates that microneedle combined with Lauromacrogol could effectively reduce the capillary in cockscomb without any tissue fibrosis. Microneedle can stimulate the proliferation of elastic fiber, so as to improve the skin ageing process.
    Hydrogel-forming microneedle arrays exhibit antimicrobial properties: potential for enhanced patient safety. Donnelly Ryan F,Singh Thakur Raghu Raj,Alkilani Ahlam Zaid,McCrudden Maelíosa T C,O'Neill Shannon,O'Mahony Conor,Armstrong Keith,McLoone Nabla,Kole Prashant,Woolfson A David International journal of pharmaceutics 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 were 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 Candida albicans and Staphylococcus 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. 10.1016/j.ijpharm.2013.04.045
    Effect of microneedle geometry and supporting substrate on microneedle array penetration into skin. Kochhar Jaspreet Singh,Quek Ten Cheer,Soon Wei Jun,Choi Jaewoong,Zou Shui,Kang Lifeng Journal of pharmaceutical sciences Microneedles are being fast recognized as a useful alternative to injections in delivering drugs, vaccines, and cosmetics transdermally. Owing to skin's inherent elastic properties, microneedles require an optimal geometry for skin penetration. In vitro studies, using rat skin to characterize microneedle penetration in vivo, require substrates with suitable mechanical properties to mimic human skin's subcutaneous tissues. We tested the effect of these two parameters on microneedle penetration. Geometry in terms of center-to-center spacing of needles was investigated for its effect on skin penetration, when placed on substrates of different hardness. Both hard (clay) and soft (polydimethylsiloxane, PDMS) substrates underneath rat skin and full-thickness pig skin were used as animal models and human skins were used as references. It was observed that there was an increase in percentage penetration with an increase in needle spacing. Microneedle penetration with PDMS as a support under stretched rat skin correlated better with that on full-thickness human skin, while penetration observed was higher when clay was used as a substrate. We showed optimal geometries for efficient penetration together with recommendation for a substrate that could better mimic the mechanical properties of human subcutaneous tissues, when using microneedles fabricated from poly(ethylene glycol)-based materials. 10.1002/jps.23724
    Ovalbumin-coated pH-sensitive microneedle arrays effectively induce ovalbumin-specific antibody and T-cell responses in mice. van der Maaden Koen,Varypataki Eleni Maria,Romeijn Stefan,Ossendorp Ferry,Jiskoot Wim,Bouwstra Joke European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V The aim of this work was to study the applicability of antigen-coated pH-sensitive microneedle arrays for effective vaccination strategies. Therefore, a model antigen (ovalbumin) was coated onto pH-sensitive (pyridine-modified) microneedle arrays to test pH-triggered antigen release by applying the coated arrays onto ex vivo human skin, and by conducting a dermal immunization study in mice. The release of antigen into ex vivo human skin from the coated microneedles was determined by using radioactively labeled ovalbumin. To investigate the induction of antigen-specific IgG, and CD4(+) and CD8(+) T-cell responses, BALB/c mice were immunized with antigen-coated pH-sensitive microneedles by the 'coat and poke' approach. These responses were compared to responses induced by the 'poke and patch' approach, and subcutaneous and intradermal vaccination with classic hypodermic needles. The pH-sensitive microneedle arrays were efficiently coated with ovalbumin (95% coating efficiency) and upon application of six microneedle arrays 4.27 of 7 μg ovalbumin was delivered into the skin, showing a release efficiency of 70%. In contrast, the 'poke and patch' approach led to a delivery of only 6.91 of 100 μg ovalbumin (7% delivery efficiency). Immunization by means of ovalbumin-coated microneedles resulted in robust CD4(+) and CD8(+) T-cell responses comparable to those obtained after subcutaneous or intradermal immunization with conventional needles. Moreover, it effectively induced IgG responses; however, it required prime-boost immunizations before antibodies were produced. In conclusion, antigen delivery into ex vivo human skin by antigen-coated pH-sensitive microneedle arrays is more efficient than the 'poke-and-patch' approach and in vivo vaccination studies show the applicability of pH-sensitive microneedles for the induction of both T cell and B cell responses. 10.1016/j.ejpb.2014.05.003
    Enhanced delivery of hydrophilic peptides in vitro by transdermal microneedle pretreatment. Zhang Suohui,Qiu Yuqin,Gao Yunhua Acta pharmaceutica Sinica. B The aims of this study were to investigate the utility of solid microneedle arrays (150 µm in length) in enhancing transdermal delivery of peptides and to examine the relationship between peptide permeation rates and D2O flux. Four model peptides were used (Gly-Gln-Pro-Arg [tetrapeptide-3, 456.6 Da], Val-Gly-Val-Ala-Pro-Gly [hexapeptide, 498.6 Da], AC-Glu-Glu-Met-Gln-Arg-Arg-NH2 [acetyl hexapeptide-3, 889 Da] and Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly-NH2 [oxytocin, 1007.2 Da]). The influence of microneedle pretreatment on skin permeation was evaluated using porcine ear skin with Franze diffusion cell. Peptide permeation across the skin was significantly enhanced by microneedle pretreatment, and permeation rates were dependent on peptide molecular weights. A positive correlation between D2O flux and acetyl hexapeptide-3 clearances suggests that convective solvent flow contributes to the enhanced transdermal peptide delivery. It is concluded that solid microneedle arrays are effective devices to enhance skin delivery of peptides. 10.1016/j.apsb.2013.12.011
    Long-term protective immunity from an influenza virus-like particle vaccine administered with a microneedle patch. Quan Fu-Shi,Kim Yeu-Chun,Song Jae-Min,Hwang Hye Suk,Compans Richard W,Prausnitz Mark R,Kang Sang-Moo Clinical and vaccine immunology : CVI Skin vaccination with influenza virus-like particles (VLPs) using microneedles has been shown to induce protection similar to or better than that induced by intramuscular immunization. In this study, we examined the long-term protective efficacy of influenza (H1N1 A/PR/8/34) VLPs after skin vaccination using microneedle patches coated with the vaccine. Microneedle vaccination of mice in the skin induced 100% protection against lethal challenge infection with influenza A/PR/8/34 virus 14 months after a single vaccine dose. Influenza virus-specific total IgG response and hemagglutination inhibition (HAI) titers were maintained at high levels for over 1 year after microneedle vaccination. Microneedle vaccination also induced substantial levels of lung IgG and IgA antibody responses, and antibody-secreting plasma cells from spleen and bone marrow, as well as conferring effective control of lung viral loads, resulting in complete protection 14 months after vaccination. These strong and long-lasting immune responses were enabled in part by stabilization of the vaccine by formulation with trehalose during microneedle patch fabrication. Administration of the stabilized vaccine using microneedles was especially effective at enabling strong recall responses measured 4 days after lethal virus challenge, including increased HAI and antibody-secreting cells in the spleen and reduced viral titer and inflammatory response in the lung. The results in this study indicate that skin vaccination with VLP vaccine using a microneedle patch provides long-term protection against influenza in mice. 10.1128/CVI.00251-13
    Drug delivery into microneedle-porated nails from nanoparticle reservoirs. Chiu Wing Sin,Belsey Natalie A,Garrett Natalie L,Moger Julian,Price Gareth J,Delgado-Charro M Begoña,Guy Richard H Journal of controlled release : official journal of the Controlled Release Society This study demonstrates the potential of polymeric nanoparticles as drug reservoirs for sustained topical drug delivery into microneedle-treated human nail. Laser scanning confocal microscopy was used to image the delivery of a fluorescent model compound from nanoparticles into the nail. A label-free imaging technique, stimulated Raman scattering microscopy, was applied, in conjunction with two-photon fluorescence imaging, to probe the disposition of nanoparticles and an associated lipophilic 'active' in a microneedle-porated nail. The results provide clear evidence that the nanoparticles function as immobile reservoirs, sequestered on the nail surface and in the microneedle-generated pores, from which the active payload can be released and diffuse laterally into the nail over an extended period of time. 10.1016/j.jconrel.2015.10.026
    A novel microneedle array for the treatment of hydrocephalus. Oh Jonghyun,Liu Kewei,Medina Tim,Kralick Francis,Noh Hongseok Moses Microsystem technologies : sensors, actuators, systems integration We present a microfabricated 10 by 10 array of microneedles for the treatment of a neurological disease called communicating hydrocephalus. Together with the previously reported microvalve array, the current implantable microneedle array completes the microfabricated arachnoid granulations (MAGs) that mimic the function of normal arachnoid granulations (AGs). The microneedle array was designed to enable the fixation of the MAGs through dura mater membrane in the brain and thus provide a conduit for the flow of cerebrospinal fluid (CSF). Cone-shaped microneedles with hollow channels were fabricated using a series of microfabrication techniques: SU-8 photolithography for tapered geometry, reactive ion etching for sharpening the microneedles, 248 nm deep UV excimer laser machining for creating through-hole inside the microneedles, and metal sputtering for improved rigidity. Puncture tests were conducted using porcine dura mater and the results showed that the fabricated microneedle array is strong enough to pierce the dura mater. The biocompatibility test result showed that none of the 100 outlets of the microneedles exposed to the bloodstream were clogged significantly by blood cells. We believe that these test results demonstrate the potential use of the microneedle array as a new treatment of hydrocephalus. 10.1007/s00542-013-1988-4
    Dissolvable microneedle fabrication using piezoelectric dispensing technology. Allen Evin A,O'Mahony Conor,Cronin Michael,O'Mahony Thomas,Moore Anne C,Crean Abina M International journal of pharmaceutics Dissolvable microneedle (DMN) patches are novel dosage forms for the percutaneous delivery of vaccines. DMN are routinely fabricated by dispensing liquid formulations into microneedle-shaped moulds. The liquid formulation within the mould is then dried to create dissolvable vaccine-loaded microneedles. The precision of the dispensing process is critical to the control of formulation volume loaded into each dissolvable microneedle structure. The dispensing process employed must maintain vaccine integrity. Wetting of mould surfaces by the dispensed formulation is also an important consideration for the fabrication of sharp-tipped DMN. Sharp-tipped DMN are essential for ease of percutaneous administration. In this paper, we demonstrate the ability of a piezoelectric dispensing system to dispense picolitre formulation volumes into PDMS moulds enabling the fabrication of bilayer DMN. The influence of formulation components (trehalose and polyvinyl alcohol (PVA) content) and piezoelectric actuation parameters (voltage, frequency and back pressure) on drop formation is described. The biological integrity of a seasonal influenza vaccine following dispensing was investigated and maintained voltage settings of 30 V but undermined at higher settings, 50 and 80 V. The results demonstrate the capability of piezoelectric dispensing technology to precisely fabricate bilayer DMN. They also highlight the importance of identifying formulation and actuation parameters to ensure controlled droplet formulation and vaccine stabilisation. 10.1016/j.ijpharm.2015.12.052
    Microneedle technology for immunisation: Perception, acceptability and suitability for paediatric use. Marshall Sarah,Sahm Laura J,Moore Anne C Vaccine OBJECTIVE:To examine published research which explores the perception and acceptability of microneedle technology for immunisation and to investigate the suitability of this technology for paediatric use. METHODS:A series of keywords and their synonyms were combined in various combinations and permutations using Boolean operators to sequentially search four databases (PubMed, Web of Science, Embase and CINAHL). Following removal of duplications and irrelevant results, 12 research articles were included in the final literature review. RESULTS:The opinions of patients, parents, children and healthcare professionals (HCP) were collated. A positive perception and a high level of acceptability predominated. CONCLUSION:Microneedle technology research has been focussed on demonstrating efficacy with minimal focus on determining HCP/public perception and acceptability for paediatric use, exemplified by the paucity of studies presented in this review. Commercial viability will depend on HCP/public acceptability of microneedle technology. An effort must be made to identify the barriers to acceptance and to overcome them by increasing awareness and education in stakeholder groups pertaining to the paediatric population. 10.1016/j.vaccine.2015.12.002
    Microneedle-assisted delivery of verapamil hydrochloride and amlodipine besylate. Kaur Monika,Ita Kevin B,Popova Inna E,Parikh Sanjai J,Bair Daniel A European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V The aim of this project was to study the effect of stainless steel solid microneedles and microneedle rollers on percutaneous penetration of verapamil hydrochloride and amlodipine besylate. Verapamil, 2-(3,4-dimethooxyphenyl)-5-[2-(3,4 dimethoxyphenyl)ethyl-methyl-amino]-2-propan-2-yl-pentanenitrile is a calcium channel blocker agent that regulates high blood pressure by decreasing myocardial contractilty, heart rate and impulse conduction. Amlodipine, (R, S)-2-[(2-aminoethoxy) methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1, 4-dihydropyridine, is a calcium channel blocker that is used for the management of hypertension and ischemic heart disease. Passive penetration of verapamil and amlodipine across the skin is low. In vitro studies were performed with microneedle-treated porcine ear skin using vertical static Franz diffusion cells (PermeGear, Hellertown, PA, USA). The receiver chamber contained 5ml of PBS (pH7.4) and was constantly maintained at 37°C temperature with a water circulation jacket. The diffusion area of the skin was 1.77cm(2). The donor compartment was loaded with 1ml of the solution containing 2.5mg/ml of amlodipine besylate. The donor chamber was covered with parafilm to avoid evaporation. Passive diffusion across untreated porcine skin served as control. Aliquots were taken every 2h for 12h and analyzed by liquid chromatography-mass spectrometry. Transcutaneous flux of verapamil increased significantly from 8.75μg/cm(2)/h to 49.96μg/cm(2)/h across microneedle-roller treated porcine skin. Percutaneous flux of amlodipine besylate following the use of stainless steel microneedles was 22.39μg/cm(2)/h. Passive flux for the drug was 1.57μg/cm(2)/h. This enhancement of amlodipine flux was statistically significant. Transdermal flux of amlodipine with microneedle roller was 1.05μg/cm(2)/h in comparison with passive diffusion flux of 0.19μg/cm(2)/h. The difference in flux values was also statistically significant. Stainless steel solid microneedles and microneedle rollers increased percutaneous penetration of verapamil hydrochloride and amlodipine besylate. It may be feasible to develop transdermal microneedle patches for these drugs. 10.1016/j.ejpb.2013.10.007
    Microneedle-Mediated Delivery of Copper Peptide Through Skin. Li Hairui,Low Yong Sheng Jason,Chong Hui Ping,Zin Melvin T,Lee Chi-Ying,Li Bo,Leolukman Melvina,Kang Lifeng Pharmaceutical research PURPOSE:Copper peptide (GHK-Cu) plays an important role in skin regeneration and wound healing. However, its skin absorption remains challenging due to its hydrophilicity. Here we use polymeric microneedle array to pre-treat skin to enhance GHK-Cu skin penetration. METHODS:Two in vitro skin models were used to assess the capability of microneedles in facilitating skin delivery of GHK-Cu. Histological assay and confocal laser scanning microscopy were performed to characterize and quantify the microconduits created by the microneedles inside skin. Cellular and porcine models were used to evaluate the safety of microneedle-assisted copper peptide delivery. RESULTS:The depth and percentage of microneedle penetration were correlated with application forces, which in turn influenced the extent of enhancement in the skin permeability of GHK-Cu. In 9 h, 134 ± 12 nanomoles of peptide and 705 ± 84 nanomoles of copper permeated though the microneedle treated human skin, while almost no peptide or copper permeated through intact human skin. No obvious signs of skin irritation were observed with the use of GHK-Cu after microneedle pretreatment. CONCLUSIONS:It is effective and safe to enhance the skin permeation of GHK-Cu by using microneedles. This approach may be useful to deliver similar peptides or minerals through skin. 10.1007/s11095-015-1652-z
    The Troy Microneedle: A Rapidly Separating, Dissolving Microneedle Formed by Cyclic Contact and Drying on the Pillar (CCDP). Kim Miroo,Yang Huisuk,Kim Suyong,Lee Chisong,Jung Hyungil PloS one In dissolving microneedle (DMN)-mediated therapy, complete and rapid delivery of DMNs is critical for the desired efficacy. Traditional patch-based DMN delivery, however, may fail due to incomplete delivery from insufficient skin insertion or rapid separation of microneedles due to their strong bond to the backing film. Here, we introduce the Troy microneedle, which was created by cyclic contact and drying on the pillar (CCDP), and which enabled simultaneous complete and rapid delivery of DMN. This CCDP process could be flexibly repeated to achieve a specific desired drug dose in a DMN. We evaluated DMN separation using agarose gel, and the Troy microneedle achieved more complete and rapid separation than other, more deeply dipped DMN, primarily because of the Troy's minimal junction between the DMN and pillar. When Troy microneedles were applied to pig cadaver skin, it took only 15 s for over 90% of encapsulated rhodamine B to be delivered, compared to 2 h with application of a traditional DMN patch. In vivo skin penetration studies demonstrated rapid DMN-separation of Troy microneedles still in solid form before dissolution. The Troy microneedle overcomes critical issues associated with the low penetration efficiency of flat patch-based DMN and provides an innovative route for DMN-mediated therapy, combining patient convenience with the desire drug efficacy. 10.1371/journal.pone.0136513
    Human Growth Hormone Delivery with a Microneedle Transdermal System: Preclinical Formulation, Stability, Delivery and PK of Therapeutically Relevant Doses. Ameri Mahmoud,Kadkhodayan Miryam,Nguyen Joe,Bravo Joseph A,Su Rebeca,Chan Kenneth,Samiee Ahmad,Daddona Peter E Pharmaceutics 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. 10.3390/pharmaceutics6020220
    Development of a three-microneedle device for hypodermic drug delivery and clinical application. Fukamizu Hidekazu,Fujiwara Masao,Kim Taishi,Matsushita Yuki,Tokura Yoshiki Plastic and reconstructive surgery UNLABELLED:There is a potential use for intradermic or hypodermic drug delivery in skin surgery or aesthetic surgery. Hypodermic delivery with the use of a noninvasive device can be a more useful, reliable, and effective administration route to obtain higher compliance. The authors developed a microneedle device composed of three fine needles (three-microneedle device). The tip of each needle was fabricated with a bevel angle to release a drug broadly into the tissue in a horizontal fashion. In this study, the authors investigated the usefulness of this newly developed three-microneedle device for hypodermic liquid injection, focusing on the optimum insertion depth and the diffusion of injected materials to the tissue. The authors also assessed the efficacy of and patient satisfaction with three-microneedle device injections of botulinum toxin type A for wrinkle reduction in patients with glabellar rhytides. The three-microneedle device yielded consistent results in hypodermal diffusion. On India ink diffusion test and ultrasonographic imaging, three-microneedle device injection showed a broad diffusion in horizontal extension, as compared with usual 31-gauge needle injection. The efficiency and satisfaction of the patients receiving botulinum toxin type A with the three-microneedle device were highly rated. Three-microneedle device delivery enables accurate and broad diffusion of injected substances, thus reducing the total dose and/or injection number of drugs. CLINICAL QUESTION/LEVEL OF EVIDENCE:Therapeutic, IV. 10.1097/PRS.0b013e3182589f56
    Microneedle fractional radiofrequency increases epidermal hyaluronan and reverses age-related epidermal dysfunction. Lee Hee Jung,Seo Seong Rak,Yoon Moon Soo,Song Ji-Ye,Lee Eun Young,Lee Sang Eun Lasers in surgery and medicine BACKGROUND AND OBJECTIVE:Skin aging results in physiological alterations in keratinocyte activities and epidermal function, as well as dermal changes. Yet, the cellular and molecular mechanisms that cause epidermal dysfunction during skin aging are not well understood. Recently, the role of epidermal hyaluronan (HA) as an active regulator of dynamic cellular processes is getting attention and alterations in HA metabolism are thought to be important in age-related epidermal dysfunction. Microneedle fractional radiofrequency (RF) has shown effects for improving cutaneous aging. However, little is known about the effects of fractional RF on the epidermal HA and epidermal function. We investigated the effect of microneedle fractional RF on the expression of epidermal HA in young and aged mice epidermis. MATERIALS AND METHODS:We performed fractional RF on the dorsal skin of 30 8-week-old (young) hairless mice and 15 47-week-old (aged) C57BL/6J mice. Skin samples were collected on day 1, 3, and 7. HA content was measured by ELISA. Gene expressions of CD 44, HABP4, and HAS3 were measured using real time RT-PCR. Immunohistochemistry for detection of HA, CD44, PCNA, and filaggrin were performed. RESULTS:HA content and the mRNA levels of HABP4, CD44, and HAS3 were upregulated in the epidermis of both young and aged mice after microneedle fractional RF treatment. The expression was increased from day 1 after treatment and increased expression persisted on day 7. Fractional RF treatment significantly increased PCNA and filaggrin expression only in the aged mice skin. CONCLUSION:Microneedle fractional RF increased epidermal HA and CD44 expression in both young and aged mice and reversed age-related epidermal dysfunction especially in aged mice, suggesting a new mechanism involved in the skin rejuvenation effect of microneedle fractional RF. 10.1002/lsm.22420
    Induction of CD8(+) T cell responses and protective efficacy following microneedle-mediated delivery of a live adenovirus-vectored malaria vaccine. Pearson Frances E,O'Mahony Conor,Moore Anne C,Hill Adrian V S Vaccine 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. 10.1016/j.vaccine.2015.03.039
    Safety evaluation of stamp type digital microneedle devices in hairless mice. Park Kui Young,Jang Woo Sun,Lim Yun Young,Ahn Joo Hee,Lee Sang Jin,Kim Chan Woong,Kim Sung Eun,Kim Beom Joon,Kim Myeung Nam Annals of dermatology BACKGROUND:Microneedles provide a minimally invasive means to transport molecules into the skin. A number of specific strategies have been employed to use microneedles for transdermal delivery. OBJECTIVE:The purpose of this study was to investigate the safety of two new digital microneedle devices (Digital Hand® and Digital Pro®; Bomtech Electronics Co., Ltd., Seoul, Korea) for the perforation of skin in skin-hairless-1 mice. This device replaces conventional needles and is designed specifically for intradermal delivery. METHODS:We used two newly developed digital microneedle devices to perforate the skin of skin-hairless-1 mice. We conducted a comparative study of the two digital microneedle devices and DTS® (Disk type-microneedle Therapy System; DTS lab., Seoul, Korea). To evaluate skin stability, we performed visual and dermatoscopic inspections, measurements of transepidermal water loss, and biopsies. RESULTS:The two novel digital microneedle devices did not induce significant abnormalities of the skin on visual or dermatoscopic inspection, regardless of needle size (0.25~2.0 mm). No significant histopathological changes, such as inflammatory cell infiltration, desquamation of the stratum corneum, or disruption of the basal layer, were observed. The digital microneedle devices and microneedle therapy system produced similar results on measures of skin stability. CONCLUSION:These two novel digital microneedle devices are safe transdermal drug delivery systems. 10.5021/ad.2013.25.1.46
    Microneedle patches: usability and acceptability for self-vaccination against influenza. Norman James J,Arya Jaya M,McClain Maxine A,Frew Paula M,Meltzer Martin I,Prausnitz Mark R Vaccine While therapeutic drugs are routinely self-administered by patients, there is little precedent for self-vaccination. Convenient self-vaccination may expand vaccination coverage and reduce administration costs. Microneedle patches are in development for many vaccines, but no reports exist on usability or acceptability. We hypothesized that naïve patients could apply patches and that self-administered patches would improve stated intent to receive an influenza vaccine. We conducted a randomized, repeated measures study with 91 venue-recruited adults. To simulate vaccination, subjects received placebo microneedle patches given three times by self-administration and once by the investigator, as well as an intramuscular injection of saline. Seventy participants inserted patches with thumb pressure alone and the remainder used snap-based devices that closed shut at a certain force. Usability was assessed by skin staining and acceptability was measured with an adaptive-choice analysis. The best usability was seen with the snap device, with users inserting a median value of 93-96% of microneedles over three repetitions. When a self-administered microneedle patch was offered, intent to vaccinate increased from 44% to 65% (CI: 55-74%). The majority of those intending vaccination would prefer to self-vaccinate: 64% (CI: 51-75%). There were no serious adverse events associated with use of microneedle patches. The findings from this initial study indicate that microneedle patches for self-vaccination against influenza are usable and may lead to improved vaccination coverage. 10.1016/j.vaccine.2014.01.076
    A microneedle patch containing measles vaccine is immunogenic in non-human primates. Edens Chris,Collins Marcus L,Goodson James L,Rota Paul A,Prausnitz Mark R Vaccine Very high vaccination coverage is required to eliminate measles, but achieving high coverage can be constrained by the logistical challenges associated with subcutaneous injection. To simplify the logistics of vaccine delivery, a patch containing micron-scale polymeric needles was formulated to encapsulate the standard dose of measles vaccine (1000 TCID₅₀) and the immunogenicity of the microneedle patch was compared with subcutaneous injection in rhesus macaques. The microneedle patch was administered without reconstitution with diluent, dissolved in skin within 10 min, and caused only mild, transient skin erythema. Both groups of rhesus macaques generated neutralizing antibody responses to measles that were consistent with protection and the neutralizing antibody titers were equivalent. In addition, the microneedle patches maintained an acceptable level of potency after storage at elevated temperature suggesting improved thermostability compared to standard lyophilized vaccine. In conclusion, a measles microneedle patch vaccine was immunogenic in non-human primates, and this approach offers a promising delivery method that could help increase vaccination coverage. 10.1016/j.vaccine.2015.02.074
    Direct microneedle array fabrication off a photomask to deliver collagen through skin. Kochhar Jaspreet Singh,Anbalagan Parthiban,Shelar Sandeep Balu,Neo Jun Kai,Iliescu Ciprian,Kang Lifeng Pharmaceutical research PURPOSE:To fabricate microneedle arrays directly off a photomask using a simple photolithographical approach and evaluate their potential for delivering collagen. METHODS:A simple photolithographical approach was developed by using photomask consisting of embedded micro-lenses that govern microneedle geometry in a mould free process. Microneedle length was controlled by use of simple glass scaffolds as well as addition of backing layer. The fabricated arrays were tested for their mechanical properties by using a force gauge as well as insertion into human skin with trypan blue staining. Microneedle arrays were then evaluated for the delivery of fluorescent collagen, which was evaluated using a confocal laser scanning microscope. RESULTS:Microneedles with sharp tips ranging between 41.5 ± 8.4 μm and 71.6 ± 13.7 μm as well as of two different lengths of 1336 ± 193 μm and 957 ± 171 μm were fabricated by using the photomasks. The microneedles were robust and resisted fracture forces up to 25 N. They were also shown to penetrate cadaver human skin samples with ease; especially microneedle arrays with shorter length of 957 μm penetrated up to 72% of needles. The needles were shown to enhance permeation of collagen through cadaver rat skin, as compared to passive diffusion of collagen. CONCLUSIONS:A simple and mould free approach of fabricating polymeric microneedle array is proposed. The fabricated microneedle arrays enhance collagen permeation through skin. 10.1007/s11095-013-1275-1
    Enhanced Stability of Inactivated Influenza Vaccine Encapsulated in Dissolving Microneedle Patches. Chu Leonard Y,Ye Ling,Dong Ke,Compans Richard W,Yang Chinglai,Prausnitz Mark R Pharmaceutical research 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. 10.1007/s11095-015-1833-9
    [Development of a Futuristic Microneedle Based on Nanotechnology]. Tsuchiya Kazuyoshi Masui. The Japanese journal of anesthesiology The author proposes "the microtube production technique", which is based on "nanotechnology", to produce a microneedle which mimicks a female mosquito's labium to collect blood almost painlessly. The microneedle production technique is to deposit the microneedle material on a rotating wire substrate at a speed of 3-5 rpm by a sputtering deposition method and etch the wire substrate by a chemical solution after a heat treatment As the result, a titanium microneedle was produced (outer and inner diameter: 50 μm and 25 μm) in the same size of female mosquito's labium. In this paper, microtube production technique is introduced first as a key technology. The design technique of painless microneedle for blood extraction system based on quantitative pain assessment, are also proposed to produce solid type microneedle with trenches on the surface of the needle.
    Collection of analytes from microneedle patches. Romanyuk Andrey V,Zvezdin Vasiliy N,Samant Pradnya,Grenader Mark I,Zemlyanova Marina,Prausnitz Mark R Analytical chemistry Clinical medicine and public health would benefit from simplified acquisition of biological samples from patients that can be easily obtained at point of care, in the field, and by patients themselves. Microneedle patches are designed to serve this need by collecting dermal interstitial fluid containing biomarkers without the dangers, pain, or expertise needed to collect blood. This study presents novel methods to collect biomarker analytes from microneedle patches for analysis by integration into conventional analytical laboratory microtubes and microplates. Microneedle patches were made out of cross-linked hydrogel composed of poly(methyl vinyl ether-alt-maleic acid) and poly(ethylene glycol) prepared by micromolding. Microneedle patches were shown to swell with water up to 50-fold in volume, depending on degree of polymer cross-linking, and to collect interstitial fluid from the skin of rats. To collect analytes from microneedle patches, the patches were mounted within the cap of microcentrifuge tubes or formed the top of V-bottom multiwell microplates, and fluid was collected in the bottom of the tubes under gentle centrifugation. In another method, microneedle patches were attached to form the bottom of multiwell microplates, thereby enabling in situ analysis. The simplicity of biological sample acquisition using microneedle patches coupled with the simplicity of analyte collection from microneedles patches integrated into conventional analytical equipment could broaden the reach of future screening, diagnosis, and monitoring of biomarkers in healthcare and environmental/workplace settings. 10.1021/ac503823p
    Microneedle patches for vaccination in developing countries. Arya Jaya,Prausnitz Mark R Journal of controlled release : official journal of the Controlled Release Society Millions of people die of infectious diseases each year, mostly in developing countries, which could largely be prevented by the use of vaccines. While immunization rates have risen since the introduction of the Expanded Program on Immunization (EPI), there remain major challenges to more effective vaccination in developing countries. As a possible solution, microneedle patches containing an array of micron-sized needles on an adhesive backing have been developed to be used for vaccine delivery to the skin. These microneedle patches can be easily and painlessly applied by pressing against the skin and, in some designs, do not leave behind sharps waste. The patches are single-dose, do not require reconstitution, are easy to administer, have reduced size to simplify storage, transportation and waste disposal, and offer the possibility of improved vaccine immunogenicity, dose sparing and thermostability. This review summarizes vaccination challenges in developing countries and discusses advantages that microneedle patches offer for vaccination to address these challenges. We conclude that microneedle patches offer a powerful new technology that can enable more effective vaccination in developing countries. 10.1016/j.jconrel.2015.11.019
    Droplet-born air blowing: novel dissolving microneedle fabrication. Kim Jung Dong,Kim Miroo,Yang Huisuk,Lee Kwang,Jung Hyungil Journal of controlled release : official journal of the Controlled Release Society 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. 10.1016/j.jconrel.2013.05.026
    Inactivated polio vaccination using a microneedle patch is immunogenic in the rhesus macaque. Vaccine The phased replacement of oral polio vaccine (OPV) with inactivated polio vaccine (IPV) is expected to significantly complicate mass vaccination campaigns, which are an important component of the global polio eradication endgame strategy. To simplify mass vaccination with IPV, we developed microneedle patches that are easy to administer, have a small package size, generate no sharps waste and are inexpensive to manufacture. When administered to rhesus macaques, neutralizing antibody titers were equivalent among monkeys vaccinated using microneedle patches and conventional intramuscular injection for IPV types 1 and 2. Serologic response to IPV type 3 vaccination was weaker after microneedle patch vaccination compared to intramuscular injection; however, we suspect the administered type 3 dose was lower due to a flawed pre-production IPV type 3 analytical method. IPV vaccination using microneedle patches was well tolerated by the monkeys. We conclude that IPV vaccination using a microneedle patch is immunogenic in rhesus macaques and may offer a simpler method of IPV vaccination of people to facilitate polio eradication. 10.1016/j.vaccine.2015.01.089
    Microneedle-based drug and vaccine delivery via nanoporous microneedle arrays. van der Maaden Koen,Luttge Regina,Vos Pieter Jan,Bouwstra Joke,Kersten Gideon,Ploemen Ivo Drug delivery and translational research In the literature, several types of microneedles have been extensively described. However, porous microneedle arrays only received minimal attention. Hence, only little is known about drug delivery via these microneedles. However, porous microneedle arrays may have potential for future microneedle-based drug and vaccine delivery and could be a valuable addition to the other microneedle-based drug delivery approaches. To gain more insight into porous microneedle technologies, the scientific and patent literature is reviewed, and we focus on the possibilities and constraints of porous microneedle technologies for dermal drug delivery. Furthermore, we show preliminary data with commercially available porous microneedles and describe future directions in this field of research. 10.1007/s13346-015-0238-y
    Enhanced skin delivery of vismodegib by microneedle treatment. Nguyen Hiep X,Banga Ajay K Drug delivery and translational research The present study investigated the effects of microneedle treatment (maltose microneedles, Admin Pen™ 1200, and Admin Pen™ 1500) on in vitro transdermal delivery of vismodegib with different needle lengths, skin equilibration times, and microneedle insertion durations. The influence of microneedle treatment on the dimensions of microchannels (dye binding, calcein imaging, histology, and confocal microscopy studies), transepidermal water loss, and skin permeability of vismodegib was also evaluated. Skin viscoelasticity was assessed using a rheometer, and microneedle geometry was characterized by scanning electron microscopy. Permeation studies of vismodegib through dermatomed porcine ear skin were conducted using vertical Franz diffusion cells. Skin irritation potential of vismodegib formulation was assessed using an in vitro reconstructed human epidermis model. Results of the in vitro permeation studies revealed significant enhancement in permeation of vismodegib through microneedle-treated skin. As the needle length increased from 500 to 1100 and 1400 μm, drug delivery increased from 14.50 ± 2.35 to 32.38 ± 3.33 and 74.40 ± 15.86 μg/cm(2), respectively. Positive correlation between drug permeability and microneedle treatment duration was observed. The equilibration time was also found to affect the delivery of vismodegib. Thus, changes in microneedle length, equilibration time, and duration of treatment altered transdermal delivery of vismodegib. 10.1007/s13346-015-0241-3
    Parameter optimization toward optimal microneedle-based dermal vaccination. van der Maaden Koen,Varypataki Eleni Maria,Yu Huixin,Romeijn Stefan,Jiskoot Wim,Bouwstra Joke European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences Microneedle-based vaccination has several advantages over vaccination by using conventional hypodermic needles. Microneedles are used to deliver a drug into the skin in a minimally-invasive and potentially pain free manner. Besides, the skin is a potent immune organ that is highly suitable for vaccination. However, there are several factors that influence the penetration ability of the skin by microneedles and the immune responses upon microneedle-based immunization. In this study we assessed several different microneedle arrays for their ability to penetrate ex vivo human skin by using trypan blue and (fluorescently or radioactively labeled) ovalbumin. Next, these different microneedles and several factors, including the dose of ovalbumin, the effect of using an impact-insertion applicator, skin location of microneedle application, and the area of microneedle application, were tested in vivo in mice. The penetration ability and the dose of ovalbumin that is delivered into the skin were shown to be dependent on the use of an applicator and on the microneedle geometry and size of the array. Besides microneedle penetration, the above described factors influenced the immune responses upon microneedle-based vaccination in vivo. It was shown that the ovalbumin-specific antibody responses upon microneedle-based vaccination could be increased up to 12-fold when an impact-insertion applicator was used, up to 8-fold when microneedles were applied over a larger surface area, and up to 36-fold dependent on the location of microneedle application. Therefore, these influencing factors should be considered to optimize microneedle-based dermal immunization technologies. 10.1016/j.ejps.2014.08.004
    [Studies on transdermal delivery of ferulic acid through rat skin treated by microneedle arrays]. Yang Bing,Du Shou-ying,Bai Jie,Shang Ke-xin,Lu Yang,Li Peng-yue Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica In order to investigate the characteristics of transdermal delivery of ferulic acid under the treated of microneedle arrays and the influence on permeability of rat skin capillaries, improved Franz-cells were used in the transdermal delivery experiment with the rat skin of abdominal wall and the length of microneedle arrays, different insertion forces, retention time were studied in the influence of characteristics of transdermal delivery of FA. The amount of FA was determined by HPLC system. Intravenous injection Evans blue and FA was added after microneedle arrays treated. Established inflammation model was built by daubing dimethylbenzene. The amount of Evans blue in the rat skin was read at 590 nm wavelength with a Multiskan Go microplate reader. Compared with passive diffusion group the skin pretreated with microneedle arrays had a remarkable enhancement of FA transport (P <0.01). The accumulation of FA increased with the enhancement of insertion force as to as the increase of retention time. Microneedle arrays with different length had a remarkable enhancement of FA transport, but was not related to the increase of the length. The research of FA on the reduce of permeability of rat skin capillaries indicated that the skin pretreated with microneedle arrays could reduce the content of Evans blue in the skins of rat significantly compared with the untreated group. The permeation rate of ferulic acid transdermal delivery had remarkable increase under the treated of microneedle arrays and the length of microneedle arrays ,the retention time so as to the insertion force were important to the transdermal delivery of ferulic acid.
    Transdermal delivery of relatively high molecular weight drugs using novel self-dissolving microneedle arrays fabricated from hyaluronic acid and their characteristics and safety after application to the skin. Liu Shu,Jin Mei-na,Quan Ying-shu,Kamiyama Fumio,Kusamori Kosuke,Katsumi Hidemasa,Sakane Toshiyasu,Yamamoto Akira European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V The purpose of this study was to develop novel dissolving microneedle arrays fabricated from hyaluronic acid (HA) as a material and to improve the transdermal permeability of relatively high molecular weight drugs. In this study, fluorescein isothiocyanate-labeled dextran with an average molecular weight of 4kDa (FD4) was used as a model drug with a relatively high molecular weight. The microneedle arrays significantly increased transepidermal water loss (TEWL) and reduced transcutaneous electrical resistance (TER), indicating that they could puncture the skin and create drug permeation pathways successfully. Both TEWL and TER almost recovered to baseline levels in the microneedle array group, and relatively small pathways created by the microneedles rapidly recovered as compared with those created by a tape stripping treatment. These findings confirmed that the microneedle arrays were quite safe. Furthermore, we found that the transdermal permeability of FD4 using the microneedle arrays was much higher than that of the FD4 solution. Furthermore, we found that the microneedle arrays were much more effective for increasing the amount of FD4 accumulated in the skin. These findings indicated that using novel microneedle arrays fabricated from HA is a very useful and effective strategy to improve the transdermal delivery of drugs, especially relatively high molecular weight drugs without seriously damaging the skin. 10.1016/j.ejpb.2013.10.001
    Enhancing DNA delivery into the skin with a motorized microneedle device. Yan Guang,Arelly Naresh,Farhan Nashid,Lobo Shabbir,Li Henan European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences The purpose of this study was to evaluate a motorized microneedle device in delivery of DNA into skin for gene expression. A plasmid DNA encoding both luciferase (Luc) and enhanced green fluorescent protein (EGFP) was delivered into rat skin by puncturing the skin with the microneedle device. Puncturing rat skin with a pre-applied DNA solution on the skin showed much higher luciferase gene expression than that with the procedure of puncturing the skin first then applied the DNA solution. The microneedle puncturing method was more efficient than intradermal injection method in generating high gene expression in the skin. There was no significant difference in the skin gene expression when rat skin was punctured with the microneedle device of different microneedle lengths (0.25 mm, 0.5mm or 0.75 mm). On the other hand, there was a significant difference in the skin gene expression between the short (10s) and the long puncturing durations (30 or 60s), with longer puncturing duration showed higher gene expression. Puncturing the skin with longer needles (0.75 mm) caused some skin damage, while puncturing the skin with shorter microneedle length (0.25 mm) caused only minimal skin damage. The EGFP gene expression was observed predominately in the epidermis layer of the skin from the puncturing method in delivery of DNA into the skin. In summary, the motorized microneedle device could have great potential in skin gene delivery. 10.1016/j.ejps.2013.11.015
    In Vitro Skin Permeation Enhancement of Sumatriptan by Microneedle Application. Nalluri Buchi N,Anusha Sai Sri V,Bramhini Sri R,Amulya J,Sultana Ashraf S K,Teja Chandra U,Das Diganta B Current drug delivery Different dimensions of commercially available microneedle devices, namely, Admin- Patch(®) microneedle arrays (MN) (0.6, 0.9, 1.2 and 1.5 mm lengths) and Dermaroller(®) microneedle rollers (DR) (0.5 and 1mm lengths) were evaluated for their relative efficiency in enhancement of transdermal permeation of Sumatriptan (SMT). Solubility assessment of SMT was carried out using propylene glycol (PG), polyethylene glycol (PEG) in combination with saline (S) at different ratios and the order of solubility was found to be 70:30 > 80:20 > 90:10 %v/v in both PG:S and PEG:S. In vitro skin permeation studies were performed using PG:S (70:30 %v/v) as donor vehicle. A significant increase in cumulative amount of SMT permeated, steady state flux, permeability coefficient and diffusion coefficient values were observed after microneedle treatment, and the values were in the order of 1.5mm MN >1.2mm MN >0.9mm MN >1mm DR >0.6mm MN >0.5mm DR > passive permeation. Lag times were significantly shorter after longer microneedle application (0.24h for 1.5mm MN). Arrays were found to be superior to rollers with similar microneedle lengths in enhancing SMT permeation and may be attributed to higher density of microneedles and force of application onto skin. The in vitro flux values revealed that 2.5cm(2) area patch is sufficient for effective therapy after treatment of skin with 1.5mm MN. It may be inferred that microneedle application significantly enhances the transdermal penetration of SMT and that it may be feasible to deliver clinically relevant therapeutic levels of SMT using microneedle assisted transdermal delivery systems. 10.2174/1567201812666150304123150
    Microneedle characterisation: the need for universal acceptance criteria and GMP specifications when moving towards commercialisation. Lutton Rebecca E M,Moore Jessica,Larrañeta Eneko,Ligett Stephen,Woolfson A David,Donnelly Ryan F Drug delivery and translational research With interest in microneedles as a novel drug transdermal delivery system increasing rapidly since the late 1990s (Margetts and Sawyer Contin Educ Anaesthesia Crit Care Pain. 7(5):171-76, 2007), a diverse range of microneedle systems have been fabricated with varying designs and dimensions. However, there are still very few commercially available microneedle products. One major issue regarding microneedle manufacture on an industrial scale is the lack of specific quality standards for this novel dosage form in the context of Good Manufacturing Practice (GMP). A range of mechanical characterisation tests and microneedle insertion analysis techniques are used by researchers working on microneedle systems to assess the safety and performance profiles of their various designs. The lack of standardised tests and equipment used to demonstrate microneedle mechanical properties and insertion capability makes it difficult to directly compare the in use performance of candidate systems. This review highlights the mechanical tests and insertion analytical techniques used by various groups to characterise microneedles. This in turn exposes the urgent need for consistency across the range of microneedle systems in order to promote innovation and the successful commercialisation of microneedle products. 10.1007/s13346-015-0237-z
    Impact insertion of transfer-molded microneedle for localized and minimally invasive ocular drug delivery. Song Hyun Beom,Lee Kang Ju,Seo Il Ho,Lee Ji Yong,Lee Sang-Mok,Kim Jin Hyoung,Kim Jeong Hun,Ryu WonHyoung Journal of controlled release : official journal of the Controlled Release Society 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. 10.1016/j.jconrel.2015.04.041
    Improvement of Transdermal Delivery of Exendin-4 Using Novel Tip-Loaded Microneedle Arrays Fabricated from Hyaluronic Acid. Liu Shu,Wu Dan,Quan Ying-Shu,Kamiyama Fumio,Kusamori Kosuke,Katsumi Hidemasa,Sakane Toshiyasu,Yamamoto Akira Molecular pharmaceutics The purpose of this study was to evaluate the characteristics of exendin-4 tip-loaded microneedle arrays and to compare their acute efficacy with subcutaneous injections in type 2 diabetic GK/Slc rats. Fluorescein isothiocyanate labeled dextran with an average molecular weight of 4,000 (FD4) was selected as a model drug, and FD4 tip-loaded microneedle arrays were prepared in this study. In addition, intraperitoneal glucose tolerance tests after application of exendin-4 tip-loaded microneedle arrays were also compared with those after subcutaneous injection in type 2 diabetic GK/Slc rats. The release of FD4 from the tip-loaded microneedle arrays was very rapid, particularly in the initial 30 s, and most of the FD4 was released within 5 min. In addition, glucose tolerance was improved and the insulin secretion was enhanced after application of exendin-4 tip-loaded microneedle arrays, and these effects were comparable to those after subcutaneous injection of exendin-4. Similar plasma concentration profiles were seen after application of exendin-4 tip-loaded microneedle arrays, as was the case with subcutaneous injection in type 2 diabetic GK/Slc rats. These findings indicate that exendin-4 tip-loaded microneedle arrays can be used as an alternative to achieve sufficient delivery of exendin-4 for treatment of type 2 diabetes. To our knowledge, this is the first report of transdermal exendin-4 delivery using tip-loaded microneedle arrays. 10.1021/acs.molpharmaceut.5b00765