Silicon Microneedles Research Articles

Design and fabrication of hollow out‐of‐plane silicon microneedles

The design and fabrication of hollow out-of-plane silicon microneedles that mimic the function and dimensions of a mosquito's mouthparts are proposed. Two-step etching and deep reactive ion etching from both sides of the wafer were used to etch the boreholes completely and to ensure the holes have lateral smoothness. Microneedles composed of {411} exterior crystal planes were formed by anisotropic etching in 40% KOH solution at a water-bath temperature of 87°C. Finally, hollow silicon microneedles with a shank height of 100–120 µm and needle borehole diameter of 10–25 µm were fabricated. Flow rate tests using hollow microneedles were performed and demonstrated that the correlation between the flow rate and the inner diameter follows the Hagen-Poiseuille law. Sample tests were performed using pig skin and have shown that the microneedles have sufficient strength to withstand breakup. The microneedles, that the authors fabricated by using the microelectromechanical system, have potential applications in painless transdermal drug delivery systems.

Hepatitis B DNA Vaccine-Polycation Nano-Complexes Enhancing Immune Response by Percutaneous Administration with Microneedle

Percutaneous immune method is becoming an attractive alternative for DNA vaccine as a lot of antigen presenting cells are existed in the viable epidermis. However, due to the barrier function of stratum corneum, it would be hard for DNA vaccine to reach the viable epidermis of the skin. In order to deliver the DNA vaccine successfully cross the stratum corneum, pentagram silicon microneedle array was prepared in this study, and fluorescently labeled nanoparticle was taken as the model to observe the situation inside the skin processed by microneedle. Via microneedle nanoparticles could enter the skin through the micro-channel (diameter about 20-30 µm) and its amount is greatly larger than that enter though the hair follicle of intact skin. A new type of gene vector Pluronic P123-modified polyethyleneimine (P123-PEI) was synthesized by high molecular weight polyethylenimine and Pluronic P123 with the molar ratio of 1 : 1 to take the advantage of P123-PEI as low cytotoxicity and high transfection efficiency. Mice were immunized percutaneously with Hepatitis B DNA vaccine/P123-PEI nano-complexes by microneedle. The humoral and cellular immunity generated in percutaneously immunized mice through microneedle array by Hepatitis B DNA vaccine/P123-PEI nano-complex was significantly higher than that of DNA vaccine intramuscular administration.

Simulation and fabrication of blood filtration system for patients with kidney diseases

Here the authors present the new design of blood filtration system for patients with kidney diseases. The proposed system consists of electronic module, drug delivery part, blood extraction and blood insertion part, blood filtration part, flow sensors and blood pressure sensor. Electronic module provides necessary functionalities and control to other components of system. Using inductively coupled plasma etching technology hollow silicon microneedles have been developed for drug delivery part. Nano porous aluminium membrane has been fabricated for blood filtration part. Ultra-sharp tip polymeric dual radii microneedles have been proposed for blood extraction and insertion part. Using ANSYS, strength modelling, microfluidic static and multifield analyses have been conducted. Water, ethanol and blood have been used as working fluid in microfluidic analysis to foresee the flow rate and viscosity effect through microneedles. Fluidic analysis shows that the proposed design is suitable for blood transport because two different lumens radii in microneedles are useful to avoid the clogging effect because of pressure difference in the lumen regions.

A Flexible Microneedle Electrode Array With Solid Silicon Needles

We propose a novel fabrication process to make flexible microneedle electrode array. The process includes creation of a silicon microneedle electrode array using a silicon-on-insulator substrate followed by its release using parylene films as the support material. The proposed structure provides flexibility of a parylene thin film and rigidity of a silicon structure. Using tissue-penetration tests and impedance spectroscopy, we demonstrate that such a structure is promising in invasive neural electrical stimulation and recording.

Optimization of HNA etching parameters to produce high aspect ratio solid silicon microneedles

High aspect ratio solid silicon microneedles with a concave conic shape were fabricated. Hydrofluoric acid–nitric acid–acetic acid (HNA) etching parameters were characterized and optimized to produce microneedles that have long and narrow bodies with smooth surfaces, suitable for transdermal drug delivery applications. The etching parameters were characterized by varying the HNA composition, the optical mask's window size, the etching temperature and bath agitation. An L9 orthogonal Taguchi experiment with three factors, each having three levels, was utilized to determine the optimal fabrication parameters. Isoetch contours for HNA composition with 0% and 10% acetic acid concentrations were presented and a high nitric acid region was identified to produce microneedles with smooth surfaces. It is observed that an increase in window size indiscriminately increases the etch rate in both the vertical and lateral directions, while an increase in etching temperature beyond 35 °C causes the etching to become rapid and uncontrollable. Bath agitation and sample placement could be manipulated to achieve a higher vertical etch rate compared to its lateral counterpart in order to construct high aspect ratio microneedles. The Taguchi experiment performed suggests that a HNA composition of 2:7:1 (HF:HNO3:CH3COOH), window size of 500 µm and agitation rate of 450 RPM are optimal. Solid silicon microneedles with an average height of 159.4 µm, an average base width of 110.9 µm, an aspect ratio of 1.44, and a tip angle and diameter of 19.2° and 0.38 µm respectively were successfully fabricated.

Microneedle-based electrodes with integrated through-silicon via for biopotential recording

The fabrication of a novel ultrasharp silicon microneedle array for use as a physiological signal monitoring electrode is described. This work uses double-sided silicon wafer patterning and anisotropic potassium hydroxide wet etching to simultaneously create a microneedle on the front side of the wafer, and a through-silicon via from the backside. Metal deposition on both the front and the back of the wafer then establishes electrical contact through this via between both sides of the electrode. This technique eliminates the limitations associated with other approaches that are used to create front-to-back electrical contact and that may be slow or cumbersome. Wearable electrode prototypes have been assembled using these arrays, and electrocardiography (ECG) and electromyography (EMG) recordings have been carried out to verify the functionality of the technique.

Mechanical strengthening of fiberoptic microneedles using an elastomeric support

Microneedles made from silica fiberoptics permit transmission and collection of light, which is an important functional advantage over metal or silicon microneedles. This added functionality may enhance or even enable new percutaneous light-based clinical diagnostic and therapeutic procedures. Micron-diameter fiberoptic microneedles, created from solid fibers capable of light emission and detection, are designed to penetrate several millimeters into tissue while minimizing tissue invasion and disruption. The mechanical strength (critical buckling force) of high aspect ratio (length to diameter) microneedles is a potential problem, which has motivated our invention of an elastomeric support device. In this study, we have tested our hypothesis that embedding the microneedles in an elastomeric support medium may increase microneedle critical buckling force. The critical buckling force of silica microneedles with 55, 70, and 110 µm diameters and 3 mm lengths were measured with and without a surrounding elastomeric support (PDMS, polydimethylsiloxane). These experimental results were compared to theoretical calculations generated by the Rayleigh-Ritz buckling model. The insertion force required to penetrate ex vivo porcine skin was measured for microneedles with 55 and 70 µm diameters. Use of the PDMS support increased critical buckling force for microneedles of 55, 70, and 110 µm diameters by an average of 610%, 290%, and 33%, respectively. Theoretical calculations by the Rayleigh-Ritz model consistently overestimated the experimentally determined strengthening, but correlated highly with the greater enhancement offered to thinner microneedles. Aided by mechanical strengthening, microneedles 55 µm in diameter were able to repeatedly penetrate. The critical buckling force of microneedles can be increased substantially to allow extremely high-aspect ratio microneedles, 55-110 µm in diameter and 3 mm in length, to penetrate ex vivo porcine skin. By this strengthening method, the safety and reliability of microneedles in potential clinical applications can be considerably enhanced.

1A1-R08 蚊の下唇を模倣した穿刺ガイドの作製とその評価(バイオミメティクス・バイオメカトロニクス(1))

The mosquito proboscis is good model for medical painless needle. It consists of 7 parts, which are labrum, two maxillas, two mandibles, pharynx, and labium. Among them, labrum and two maxillas play important role of inserting proboscis to skin. Three paired silicon microneedles are fabricated: one is central straight needle imitating labrum, others are side jagged needles imitating maxillas. However, they are easily buckled and broken due to their fairly thinness. We noticed mosquito's labium, which supports other 6 parts, and prevents them from buckling/breakage. A guide tool for needle insertion is proposed and fabricated, which is made of polydimethylsiloxane (PDMS) rubber sheet and is machined a narrow groove. Through the groove, three needles are inserted to the skin. Even if they are buckled, the sidewall of groove supports them at contact points, preventing them from breakage.

Optimization of Fabrication Process for MEMS Based Microneedles Using ICP Etching Technology

In this paper, optimization of fabrication process for microneedles has been presented. Using inductively coupled plasma (ICP) etching technology, fabrication of out-of-plane hollow silicon microneedles for blood extraction has been carried out. Sharp tip microneedles with length 1100 µm were designed for fabrication. The fabrication of microneedles was not successful because the lumen section was fabricated first and then hole was created for fluid flow. Previously, using same fabrication method successful fabrication of microneedles was done for drug delivery with length 200 µm. This fabrication method is not suitable for long structure. Thus, the alternative microneedle fabrication steps using ICP etching have been developed and presented in this paper. These steps can be more optimized and suitable for sharp tip, long and hollow structure.

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

BackgroundVaccine 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 FindingsRecombinant 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/SignificanceThis 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.

Determination of parameters for successful spray coating of silicon microneedle arrays

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 280 μm 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.

Improve Blood Clotting Feature of Silicon Microneedle by Silver Coating

Microneedles have broad applications in biomedical and neural measurements, drug-delivery systems, and microbiological sample analysis. Blood compatibility is required when microneedle is used in blood related field. We proposed a method to improve the blood clotting feature of silicon microneedle by silver coating. We fabricated the silicon microneedle with and without silver coating by wet etching and metal sputtering and implemented the clotting test. The clotting test results indicated that silver coating plays more important role to improve the blood compatibility of silicon microneedle than surface structure.

Simple and non toxic enzyme immobilization onto platinum electrodes for detection of metabolic molecules in the rat brain using silicon micro-needles

We report the successful fabrication of microelectrode biosensors, onto Pt wires or silicon micro-needles, based on oxidase immobilization by poly(ethylene glycol) diglycidyl ether (PEGDE). We found that biosensors made with PEGDE exhibited high sensitivity and a response time on the order of seconds. Glucose biosensors implanted in the central nervous system of anesthetized rats reliably monitored changes in brain glucose levels induced by sequential administration of insulin and glucose. PEGDE provides a simple, low cost, non-toxic alternative for the preparation of in vivo microelectrode biosensors. This innovative method was applied to functionalize Pt microelectrodes deposited onto silicon microprobes. Their operating parameters were characterized and validated in vivo.

Microneedle-Based Electrodes with Integrated Through-Silicon via for Biopotential Recording

The fabrication of a novel ultrasharp silicon microneedle array for use as a physiological signal monitoring electrode is described. This work uses anisotropic potassium hydroxide wet etching and double-sided wafer patterning to simultaneously create a microneedle on the front side of the wafer, and a through-silicon via from the back side. This technique eliminates the limitations associated with other approaches that are used to create front-to-back electrical contact. Wearable electrode prototypes have been assembled using these arrays, and electrocardiography (ECG) recordings have been carried out to verify the functionality of the technique.

Fabrication of Silicon Needle-Like Structures Suitable for Controlled Gas Permeability

The fabrication of hollow silicon microneedles on silicon membranes is reported. Using high-resolution vertical etching and small angle deposition of a chromium layer allows fabrication of hollow structures without a need to 3D lithography or extra mask alignment. Silicon microneedles with inner diameters of 0.5-3μm and a wall thickness of 100-300nm are realized using hydrogen-assisted deep reactive ion etching (DRIE). Growing carbon nano tubes on top of this structure leads to a cage-like structure, which could have the ability of controlling gas transport across the tiny holes. CNTs serve as the surrounding "bars" for this cage-like structure.

Design, Fabrication and Analysis of Silicon Hollow Microneedles for Transdermal Drug Delivery System for Treatment of Hemodynamic Dysfunctions

In this paper, we present design, fabrication and coupled multifield analysis of hollow out-of-plane silicon microneedles with piezoelectrically actuated microfluidic device for transdermal drug delivery (TDD) system for treatment of cardiovascular or hemodynamic disorders such as hypertension. The mask layout design and fabrication process of silicon microneedles and reservoir involving deep reactive ion etching (DRIE) is first presented. This is followed by actual fabrication of silicon hollow microneedles by a series of combined isotropic and anisotropic etching processes using inductively coupled plasma (ICP) etching technology. Then coupled multifield analysis of a MEMS based piezoelectrically actuated device with integrated silicon microneedles is presented. The coupledfield analysis of hollow silicon microneedle array integrated with piezoelectric micropump has involved structural and fluid field couplings in a sequential structural-fluid analysis on a three-dimensional model of the microfluidic device. The effect of voltage and frequency on silicon membrane deflection and flow rate through the microneedle is investigated in the coupled field analysis using multiple code coupling method. The results of the present study provide valuable benchmark and prediction data to fabricate optimized designs of the silicon hollow microneedle based microfluidic devices for transdermal drug delivery applications.

Design, Simulation and Fabrication of Silicon Microneedles for Bio-Medical Applications

In this paper, design, analysis and fabrication of hollow out-of-plane silicon microneedles for transdermal drug delivery (TDD) have been presented. Combination of isotropic and anisotropic etching process has been used to facilitate the fabrication of microneedles in inductively coupled plasma (ICP) etcher. Using ANSYS, structural and micro°uidic analysis hasbeen performed before the fabrication to insure the microneedle design suitability for TDD. In finite element analysis (FEM), the effect of axial and transverse load on single microneedle has been investigated to envisage the mechanical properties of microneedle. The analysis predicts that the resultant stresses due to applied bending and axial loads are in the safe range. In computational fluid dynamic (CFD) static analysis, the fluid flow rate through 5 x 5 microneedle array has been investigated by applying the pressure 10 kPa to 130 kPa at the inlet to insure that the microneedles are capable for flow of drug up to the desired range for TDD.

In Vivo, In Situ Imaging of Microneedle Insertion into the Skin of Human Volunteers Using Optical Coherence Tomography

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. 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 800nm wavelength and <3µm effective axial resolution was used to visualise the microneedle-treated area during insertion and/or following removal of the device, without any tissue processing. 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. 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.

Axial and shear fracture strength evaluation of silicon microneedles

This research aims to quantify fracture limits of hollow silicon microneedles due to axial and shear forces, and validate their use on human skin. Needle failure due to axial and shear loads may be due to heterogeneous peak stresses within the bulk material. Analytical determination of physical usage limits of microneedles can be misleading, as beam fracture models do not translate well to the micro-scale. In this research, various sizes of hollow silicon microneedles were fabricated. Their point of failure due to fracture was tested via application of axial and shear forces. Axial fracture of 36 gauge silicon microneedles took place at about 740 gram-force. It was determined that the axial force experienced by microneedles during insertion into human cadaver skin, is much lower than this critical limit, and thus needle failure due to breakage can thus be generally attributed to shear forces. Fracture limits of microneedles due to shear forces were quantified; ranging from about 36 gram-force for 36 gauge needles to about 275 gram-force for 33 gauge needles.

Sharpening of hollow silicon microneedles to reduce skin penetration force

In this research, hollow silicon microneedles with sharpened tips have been fabricated without any reduction to the needle shaft diameter. By sharpening the needles only at the tip and not over the entire length of the needle, their mechanical strength is maintained, while reducing the insertion force into skin. The process achieves this geometry by novel use photoresist depletion during DRIE. Microneedles of varying levels of tip sharpness were tested on human cadaver skin to measure their force of penetration. The results show a marked decrease of insertion force with progressive sharpening of microneedle tips, reducing more than 75 times in magnitude for extremely sharp tips. The toughness of human skin was derived to be approximately 24.28 kJ m−2.