Microneedle Structures Research Articles

Implantable Electronic Medicine Enabled by Bioresorbable Microneedles for Wireless Electrotherapy and Drug Delivery.

A combined treatment using medication and electrostimulation increases its effectiveness in comparison with one treatment alone. However, the organic integration of two strategies in one miniaturized system for practical usage has seldom been reported. This article reports an implantable electronic medicine based on bioresorbable microneedle devices that is activated wirelessly for electrostimulation and sustainable delivery of anti-inflammatory drugs. The electronic medicine is composed of a radio frequency wireless power transmission system and a drug-loaded microneedle structure, all fabricated with bioresorbable materials. In a rat skeletal muscle injury model, periodic electrostimulation regulates cell behaviors and tissue regeneration while the anti-inflammatory drugs prevent inflammation, which ultimately enhance the skeletal muscle regeneration. Finally, the electronic medicine is fully bioresorbable, excluding the second surgery for device removal.

In-situ synthesis silver nanoparticles in chitosan/Bletilla striata polysaccharide composited microneedles for infected and susceptible wound healing

A novel antibacterial strategy is urgently required to develop for solving bacterial biofilm obstruction and bacterial drug resistance in the infected wound healing process. Herein, the Chitosan/Bletilla striata polysaccharide composited microneedles were prepared by chitosan, tannic acid, AgNO3 and Bletilla striata polysaccharide through step centrifugation. In our design system, the porous structure of microneedles gradually disappeared, and the mechanical properties were significantly improved after multiple fillings. Ag+ is reduced in-situ to silver nanoparticles by the abundant polyphenols of tannic acid, displaying antibacterial effects both in vitro and vivo, even for methicillin resistant Staphylococcus aureus. The addition of Bletilla striata polysaccharide increased the ability of piercing biofilm and promoted wound healing. The microneedles exhibited good biocompatibility and with function of piercing the bacterial biofilms, scavenging excessive free radicals, inhibiting inflammatory factors, and promoting wound healing. Therefore, the multifunctional composited microneedles show great potential to promote infected and susceptible wound healing.

Determination of Transdermal Rate of Metallic Microneedle Array through an Impedance Measurements-Based Numerical Check Screening Algorithm.

Microneedle systems have been widely used in health monitoring, painless drug delivery, and medical cosmetology. Although many studies on microneedle materials, structures, and applications have been conducted, the applications of microneedles often suffered from issues of inconsistent penetration rates due to the complication of skin-microneedle interface. In this study, we demonstrated a methodology of determination of transdermal rate of metallic microneedle array through impedance measurements-based numerical check screening algorithm. Metallic sheet microneedle array sensors with different sizes were fabricated to evaluate different transdermal rates. In vitro sensing of hydrogen peroxide confirmed the effect of transdermal rate on the sensing outcomes. An FEM simulation model of a microneedle array revealed the monotonous relation between the transdermal state and test current. Accordingly, two methods were primely derived to calculate the transdermal rate from the test current. First, an exact logic method provided the number of unpenetrated tips per sheet, but it required more rigorous testing results. Second, a fuzzy logic method provided an approximate transdermal rate on adjacent areas, being more applicable and robust to errors. Real-time transdermal rate estimation may be essential for improving the performance of microneedle systems, and this study provides various fundaments toward that goal.

High‐Performance Freshwater Harvesting System by Coupling Solar Desalination and Fog Collection with Hierarchical Porous Microneedle Arrays

AbstractThe maximizing daily freshwater yield on the ocean surface necessitates all‐day water harvesting technologies and materials. This is realizable by taking advantage of the natural sunlight and humid air, which can drive daytime solar desalination and nighttime fog collection, respectively. To this end, two types of hierarchically porous microneedle array structures, which demonstrate superior capabilities for efficient fog capturing and photothermal evaporation, respectively, are prepared. The gel‐forged microneedle arrays with Janus wettability are fabricated via a simple and controllable top‐down micro‐molding process on a porous platform, and porosity within microneedles is further achieved readily by additional freeze‐drying treatment. The developed microneedle structure shows an ultrahigh fog harvesting rate up to 30.5 kg m−2 h−1, enabling high flux water droplet harvesting from moisture during nighttime. In the daytime, a solar evaporation rate of 2.46 kg m−2 h−1 is realized due to the increased evaporative area of the porous microneedle arrays and enhanced photothermal conversion. By uniting these two water‐harvesting routes, a daily cycle can ideally deliver an overall water yield close to 200 kg m−2, which will offer a promising solution for sustaining future low‐cost and decentralized clean water production.

Transdermal Polymeric Microneedle Sensing Platform for Fentanyl Detection in Biofluid.

Opioid drugs are extremely potent synthetic analytes, and their abuse is common around the world. Hence, a rapid and point-of-need device is necessary to assess the presence of this compound in body fluid so that a timely countermeasure can be provided to the exposed individuals. Herein, we present an attractive microneedle sensing platform for the detection of the opioid drug fentanyl in real serum samples using an electrochemical detection method. The device contained an array of pyramidal microneedle structures that were integrated with platinum (Pt) and silver (Ag) wires, each with a microcavity opening. The working sensor was modified by graphene ink and subsequently with 4 (3-Butyl-1-imidazolio)-1-butanesulfonate) ionic liquid. The microneedle sensor showed direct oxidation of fentanyl in liquid samples with a detection limit of 27.8 μM by employing a highly sensitive square-wave voltammetry technique. The resulting microneedle-based sensing platform displayed an interference-free fentanyl detection in diluted serum without conceding its sensitivity, stability, and response time. The obtained results revealed that the microneedle sensor holds considerable promise for point-of-need fentanyl detection and opens additional opportunities for detecting substances of abuse in emergencies.

Light-regulated nitric oxide release from hydrogel-forming microneedles integrated with graphene oxide for biofilm-infected-wound healing

Nitric oxide (NO) is an antimicrobial agent that possesses tissue-regenerating ability. However, it also has a short half-life and storage difficulties as disadvantages to its application. To overcome these limitations, a new type of hydrogel-forming microneedle (HFMN) is proposed that can be fabricated by integrating polyvinyl alcohol (PVA) hydrogels (a highly biocompatible drug carrier) with S-nitrosoglutathione (GSNO, a NO releasing agent), and graphene oxide (GO) at freezing temperatures (GO-GNSO-HFMNs). Results show that GSNO-GO-HFMNs release NO gradually with increasing temperature and, more importantly, can be warmed up by mild infrared irradiation to accelerate subcutaneous release of NO from the heat-sensitive GSNO. Biofilm-infected wounds often present obstacles to drug delivery, whereas the microneedle (MN) structure disrupts the biofilm and directly releases NO into the wound. This inhibits bacterial growth and increases tissue regeneration while shortening the healing time of biofilm-infected wounds. Therefore, this type of patch can be regarded as a novel, heat-sensitive, light-regulated, NO-releasing MN patch.

Hierarchical Structure Fabrication of IPMC Strain Sensor With High Sensitivity

In this paper, a biological template method is introduced and investigated to fabricate ionic polymer-metal composite (IPMC) strain sensor with bionic hierarchical structures. We utilized the multi-level structure of reed leaf surface, which can improve the contact area between the substrate and the electrode layers. Hierarchical structures were observed on the IPMC samples, including pyramid strips with the width in the range of 60–80 μm as well as synaptic scatters with diameter around 10 μm. In addition, five kinds of sensors with different interface structures were obtained by combining the traditional microneedle roller roughening and chemical plating processes. It was found that the IPMC sensor with reed-leaf and microneedle structure on each side presented the best performance, along with a high linearity, a sensitivity of 62.5 mV/1% and a large generated voltage peak under given mechanical stimuli, which is 3.7 times that of the sample fabricated without roughening.

Microneedles in diagnosis and treatment: a review

Microneedles have been developed rapidly in the field of transdermal administration in the past few decades. In recent years, the development of microelectronics technology has expanded the applications of microneedles by combining with microelectronic systems, especially in biological diagnosis and treatment. Different types of microneedles have been designed to extract blood and tissue fluids for detection, or as electrodes to directly detect blood sugar, melanoma and pH in real-time in vivo, both show good prospects for real-time detection applications. In this paper, we review the design of materials and structure of microelectronic-based microneedles, and discuss their advances in biological diagnosis.

Fabrication and characteristic of flexible dry bioelectrodes with microstructures inspired by golden margined century plant leaf

To obtain a flexible dry bioelectrode with high performance, this paper proposes a flexible dry bioelectrode with microneedle structures inspired by golden margined century plant leaf. The microneedle structures are fabricated by laser processing method, and then embedded inside the flexible PDMS substrate. In this way, the flexible dry bioelectrode with curved-hook type microneedle structures is obtained. The mechanical and electrical properties of the bioelectrode are characterized. Our results show that the curved-hook type microneedle has a smaller penetration force (0.939 N) but bigger pullout force (0.149 N) compared with triangular microneedles. The curved-hook type microneedle structures allow better anti-destructive and bonding performance. Additionally, compared with traditional Ag/AgCl electrode, the developed flexible dry bioelectrodes exhibit better detection performance of EMG in both time and frequency domain.

Study on the fabrication and characterization of tip-loaded dissolving microneedles for transdermal drug delivery

In order to increase the utilization rate of drug carried by microneedles and reduce waste, a two-step casting method was proposed to fabricate tip-loaded dissolving microneedles in this paper. The tip-loaded dissolving microneedles, also named layered microneedles, was consisted of two layers. The tip layer of the microneedles carried model drug, while the backing layer was fabricated with pure dissolving material. Polyvinyl alcohol, polyvinylpyrrolidone and hyaluronic acid were used as the base materials to fabricate the dissolving layers of the microneedle patches. Rhodamine B was chosen as the model drug to show the layered structure of tip-loaded microneedles. The material formulation and fabricating conditions of the tip-loaded dissolving microneedles and their transdermal insulin delivery efficiency were systematically studied. Nanoindentation testing showed that the tips of all three kinds of dissolving microneedles can bear the maximum loading of 50 mN with no damages, indicated sufficient mechanical strength for smooth skin puncturing as the minimum pressure required was 10 mN only. Moreover, our fabricated tip-loaded dissolving microneedles can greatly reduce the drug waste cause by unused backing layer in normal microneedles and realize a 30% enhancement of drug delivery efficiency after puncture treatment.

Defect minimized Ag-ZnO microneedles for photocatalysis

A facile solution processing strategy has been developed for the formation of Ag-modified ZnO microneedles at various calcination temperatures such as 300, 500, and 700 °C (AZ3, AZ5, and AZ7 respectively). Due to the heavy doping of AgNO3, Ag+ ions have been incorporated in to the crystal lattice of ZnO in all the Ag-ZnO samples, which facilitated the formation of Ag-ZnO microneedle morphology with minimized defect states, and obviously, the plasmon peaks were observed due to Ag modification. These Ag-ZnO microneedle structures have been evaluated for their photocatalytic performance using methylene blue as model target contaminant and their activity was compared with the commercially available titania P25 photocatalyst. The photoactivity of all the Ag-ZnO microneedle structures was significantly higher than that of the commercially available P25 photocatalyst with the most active Ag-ZnO material having a photocatalytic activity ~ 1.4 times greater than that of P25 titania.

Stress and Deformation of Optimally Shaped Silicon Microneedles for Transdermal Drug Delivery

In this study, we demonstrated the fabrication of the concave conic shape microneedle with the aid of COMSOL Multiphysics simulation. The stress and buckling of the microneedle structure were simulated by applying various loads ranging from 50 to 800 g perpendiculars to the tip in order to predict the occurrence of microneedles structure deformation. The simulation study indicated that the surface buckling deformation does not occur to the microneedle structure with the increment of the load. The microneedles with dimensions of height and diameter tip ranging from 60 to 100 μm and 1 to 4 μm, respectively had been fabricated via an etching process in a mixture of hydrofluoric acid, nitric acid, and acetic acid. Three optimized microneedles but different in the structures were fabricated via the acidic etching process. The reproducibility of 3 different microneedle structures was 15, 20, and 60%, respectively. Stress and buckling analyses of the fabricated microneedles were further carried out on the rat skin. The obtained experimental results show promising applications for the deep dermis, stratum corneum to epidermis layer penetration.

Design and Optimize Solid Microneedle using Genetic Algorithm

Microneedle is an example of Transdermal drug delivery (TTD) device. It is known for eliminating pain and inconvenient intravenous injections. This study presents a work on design microneedle and optimize the designs using Genetic Algorithm (GA). At first, a few solid microneedles are designed with difference parameters, and the considered parameters involve are shape of the needle, materials, size of array, base of microneedle, height of microneedle and number of needles on the microneedle’s array base. The microneedle is designed to meet the output requirement which are the total deformation and equivalent stress. Pressure on the tip and size of microneedle base are set to be constant which are 3.18 MPa and 2500 μm × 2500 μm × 50 μm, respectively. Then, optimisation process is conducted on the designs using Genetic Algorithm. Based on the optimisation results, it showed that the optimum structure for the studied microneedles is canonical type, diameter and needle height are 500 μm and 500 μm, respectively, PVA material and involve with 3 number of needles. The results showed that GA is capable to achieve the output requirement and able to optimize the parameter of the microneedle structure.

A new way to control the internal structure of microneedles: a case of chitosan lactate

The internal structure of a chitosan lactate microneedle can be controlled according to the viscosity of chitosan lactic acid salt. Microneedles are one of the important future drug-dispensing devices for vaccination, diabetes treatment, and so on. Microneedles can be divided into several types, for instance, solid microneedles, coated microneedles, dissolving microneedles, and hollow microneedles. Among them, dissolving microneedles are widely used because they have also been designed to include a drug to be released into the skin by dissolution. Hydrogel biodegradable materials have been used as dissolving microneedles in previous works. However, key issues of dissolving microneedles are that 'they do not have enough mechanical strength on puncture performance. Although chitosan is a representative biodegradable polymer similar to polylactic acid (PLA), generally, a complex of chitosan nanoparticles and a drug is used in hydrogel-state microneedles. Chitosan microneedles are currently manufactured by using aqueous solutions of chitosan lactic acid salt. When the viscosity of the solution increases, the structure of microneedles changes. When the viscosity is high, chitosan microneedles become coated microneedles. When the viscosity is low, chitosan microneedles become hollow-structured ones. It is expected that many solid- or liquid-state drugs can be packaged into the hollow microneedles.

Low cost additive manufacturing of microneedle masters

PurposeMicroneedle patches are arrays of tiny needles that painlessly pierce the skin to deliver medication into the body. Biocompatible microneedles are usually fabricated via molding of a master structure. Microfabrication techniques used for fabricating these master structures are costly, time intensive, and require extensive expertise to control the structure’s geometry of the structure, despite evidence that microneedle geometry is a key design parameter. Here, a commercially available 3D printer is utilized, for the first time, to quickly and easily manufacture microneedle masters.Design/methodology/approachBecause commercially available 3D printers are not typically used for micron-scale fabrication, the influence of three different sources of error- stair-stepping, aliasing, and light abberations- on the resulting structure is investigated. A custom Matlab code is written to control the light intensity projected off of each individual micromirror (through grayscale) at a given time. The effect of the layer height, the number of layers, and grayscale on the sharpness, surface texture, and dimensional fidelity of the final structure is described.FindingsThe Autodesk Ember is successfully utilized to fabricate sharp microneedles with a tip radius of approximately 15 μm in less than 30 min per patch (as compared to weeks to months for existing approaches). Utilization of grayscale improves surface texture and sharpness, and dimensional fidelity within ±5% of desired dimensions is achieved.Originality/valueThe described 3D printing technique enables investigators to accurately fabricate microneedles within minutes at low cost. Rapid, iterative optimization of microneedle geometry through 3D printing will accelerate microneedle research through improved understanding of the relationship between microneedle structure and function.

Glassy carbon microneedles\u2014new transdermal drug delivery device derived from a scalable C-MEMS process

Because carbon is the basic element of all life forms and has been successfully applied as a material for medical applications, it is desirable to investigate carbon for drug delivery applications, as well. In this work, we report the fabrication of a hollow carbon microneedle array with flow channels using a conventional carbon-microelectromechanical system (C-MEMS) process. This process utilizes the scalable and irreversible step of pyrolysis, where prepatterned SU-8 microneedles (precursor) are converted to glassy carbon structures in an inert atmosphere at high temperature (900 °C) while retaining their original shape upon shrinkage. Once converted to glassy carbon, the microneedles inherit the unique properties of hardness, biocompatibility, and thermal and chemical resistance associated with this material. A comparative study of hardness and Young’s modulus for carbon microneedles and SU-8 microneedles was performed to evaluate the increased strength of the microneedles induced by the C-MEMS process steps. Structural shrinkage of the carbon microneedles upon pyrolysis was observed and estimated. Material characterizations including energy-dispersive X-ray spectroscopy (EDX) and Raman spectroscopy were carried out to estimate the atomic percentage of carbon in the microneedle structure and its crystalline nature, respectively. Our investigations confirm that the microneedles are glassy in nature. Compression and bending tests were also performed to determine the maximum forces that the carbon microneedles can withstand, and it was found that these forces were approximately two orders of magnitude higher than the resistive forces presented by skin. A microneedle array was inserted into mouse skin multiple times and was successfully removed without the breakage of any microneedles.

Fabrication of Functional Film Provided with Microneedle Array By Thermal Imprint Method

Introduction In recent years, researches on the formation of surface microstructure by precision processing technology are progressing. Microneedle arrays which are one of the microstructures have attracted attention in the fields of beauty and medical care. Currently, fabrication of microneedle arrays with various materials is being studied. However, in a microneedle array made of a metal or an inorganic material, when a needle is broken in the skin, there is a risk that the needle may remain in the body. On the other hand, microneedle arrays with polymeric materials typified by plastics, especially biocompatible materials, are relatively safe due to biocompatibility or biodegradability, even if needles remain in the skin. Therefore, in this research, we applied a microneedle array on the surface of biocompatible plastic film using the thermal imprinting process and investigated the influence of molding conditions on transferability of molded products. Method As a sample, polyvinyl alcohol (PVA) (Mowiflex C17 CP-1000, manufactured by Kuraray Co., Ltd.) was used. Films (thiukness 300 μm, 500 μm) were prepared with a vacuum heat press machine (manufactured by Imoto Seisakusho). A mold of a microneedle array structure (independent microprojection structure array, hollow structure, height 90 μm, internal diameter 20 μm) was used. The needle array structure was transferred onto the PVA film with a vacuum small hot press machine (manufactured by Izumi Tec). A pressed set temperature was 90, 100, 110, 120 ° C, pressurization time was 1, 2, 3 minutes, and melt retention time was 1 or 2 minutes to prepare a molded article. Five needles having the highest transfer rate were selected and an average value of the form transfer rate of the molded article was obtained with a 3D laser microscope (LEXT OLS 4000, manufactured by OLYMPUS). In addition, the appearance of the molded needles was also observed using a scanning electron microscope (SEM) (JSM-6510, manufactured by JEOL). Results and discussion When the holding time was 2 minutes and the pressing temperature was 120 ℃, the transfer rate improved (Fig.1(a)) . It is thought that the temperature of the whole film increased with time and as a result the elastic modulus of the film decreased. However, when observing the whole structure by SEM roughly half of the structures caused defective transfer. There are three reasons for this. One is that they are not evenly heated by simultaneous heating both the film and the mold, which has large heat capacity, from the room temperature state. The second is because the film is thick and the resin flows easily. Thirdly the temperature at the bottom of the film is high and the elastic modulus (yield stress) is low, and the resin flows easily. In order to improve the above points, thin film, preheating the mold, lowering the set temperature were performed. As a result, the transfer rate was improved by thinning the film and preheating the mold. When the press temperature was lowered together with preheating the mold, although the form transfer rate was slightly lowered, the overall transfer rate improved to 100% (Fig.1(b)) . Figure 1

Drug-Delivery System Based on Salmon DNA Nano- and Micro-Scale Structures

Microneedles, fabricated by nano-moulding technology show great promise in the field of drug delivery by enabling the painless self-administration of drugs in a patient-friendly manner. In this study, double-stranded salmon DNA (SDNA) was used as both a drug-delivery vehicle and structural material with a microneedle system. SDNA is non-toxic and demonstrates good mechanical robustness, mouldability, biocompatibility, bio-absorbability, and binding affinity with drug molecules for bio-functional applications. Benign fabrication conditions to protect temperature-sensitive biomolecules are used to produce SDNA structures of various sizes with a high aspect ratio (4: 1). Unlike existing dissolving microneedle structure materials, the special binding characteristics of doxorubicin hydrochloride, anti-cancer drug molecules, and SDNA demonstrate the stability of drug-molecule encapsulation via UV-absorption and photoluminescence analyses. Based on COMSOL simulation and in vitro analysis of the stratum corneum of porcine skin, the mechanical functionality of SDNA microneedles was evaluated in vitro by penetrating the stratum corneum of porcine skin. The SDNA microneedle dissolved and drug permeation was assessed using rhodamine, a drug surrogate. Owing to its many beneficial characteristics, we anticipate that the SDNA microneedle platform will serve as an effective alternative for drug delivery.

Continuous minimally-invasive alcohol monitoring using microneedle sensor arrays

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

Minimally Invasive Microneedle Array Electrodes Employing Direct Electron Transfer Type Glucose Dehydrogenase for the Development of Continuous Glucose Monitoring Sensors

Closed loop systems hinge on the accuracy and precision of the continuous glucose monitoring sensors. Most of the commercially available continuous glucose monitoring sensors is implanted subcutaneously for a period of 7-14 days. The subsequent biofouling effects have implications on the performance of the sensors over time especially at low glucose concentrations. In addition, the commercially available sensors are sensitive to the presence of interfering species such as acetaminophen in the skin compartment. We report here on the marriage of minimally invasive, continuous glucose sensors and a direct electron transfer type glucose dehydrogenase enzymatic system. Whilst the microneedles here are designed to sit in the dermal interstitial fluid over a 24-48 hour period to minimize the biofouling effect, the direct electron transfer enzyme allows operation of the electrochemical sensor at lower potentials to minimize the effect of interference. The microneedle structure design also enables the use of compensation electrodes for background subtraction to further nullify the effects of interference.