Si Microneedle Research Articles

Effect of Triton X-100 surfactant and agitation on tetramethylammonium hydroxide wet etching for microneedle fabrication

Solid silicon (Si) microneedles have many applications such as skin pretreatment to form micrometer-sized holes in the skin surface in transdermal drug delivery systems. Wet etching based on tetramethylammonium hydroxide (TMAH) is an efficient method to fabricate solid microneedles. However, it is challenging to increase the density of microneedle arrays due to the faster lateral etching than the vertical etching that requires a large initial mask size. In this work, we used wet etching based on TMAH to fabricate solid Si microneedles. One kind of nonionic surfactant, Triton X-100, was introduced into the TMAH solution to suppress the lateral etching. When Triton X-100 was added into TMAH for a given etching condition, the maximum height (attained right before the mask fell off) of microneedles could reach ∼230 μm for 600 μm square-shaped mask size and 700 μm array period, compared to microneedles of maximum 152 μm height for the same mask size and period without surfactant addition. Correspondingly, when the target heights of microneedles were the same as ∼230 μm, denser (down to 700 μm period, 600 μm mask size) microneedle arrays were achieved with the help of Triton X-100, in comparison to arrays down to 900 μm period (800 μm mask size) without surfactant addition. Furthermore, agitation by a magnetic stirring bar is important for the fabrication of dense solid Si microneedle arrays based on TMAH. The microneedle structures were rhombic pyramid in shape with Triton X-100 and agitation. But microneedle structures obtained with Triton X-100 yet without agitation were octagonal pyramid in shape with a much less steep side surface.

In-Plane Si Microneedles: Fabrication, Characterization, Modeling and Applications.

Microneedles are getting more and more attention in research and commercialization since their advancement in the 1990s due to the advantages over traditional hypodermic needles such as minimum invasiveness, low material and fabrication cost, and precise needle geometry control, etc. The design and fabrication of microneedles depend on various factors such as the type of materials used, fabrication planes and techniques, needle structures, etc. In the past years, in-plane and out-of-plane microneedle technologies made by silicon (Si), polymer, metal, and other materials have been developed for numerous biomedical applications including drug delivery, sample collections, medical diagnostics, and bio-sensing. Among these microneedle technologies, in-plane Si microneedles excel by the inherent properties of Si such as mechanical strength, wear resistance, biocompatibility, and structural advantages of in-plane configuration such as a wide range of length, readiness of integration with other supporting components, and complementary metal-oxide-semiconductor (CMOS) compatible fabrication. This article aims to provide a review of in-plane Si microneedles with a focus on fabrication techniques, theoretical and numerical analysis, experimental characterization of structural and fluidic behaviors, major applications, potential challenges, and future prospects.

Design and evaluation of in-plane silicon microneedles fabricated with post-CMOS compatible processes

In this paper, a comprehensive study was carried out on in-plane silicon (Si) microneedles, a useful tool for transdermal drug delivery and sample collection. Microneedles with eleven designs were investigated by post-complementary metal-oxide-semiconductor (CMOS) compatible microfabrication processes and characterized via pricking tests by insertion in chicken breast flesh. Mechanical strength of all designs were also evaluated by theoretical calculation and finite element modeling (FEM) for bending and buckling analysis. To efficiently improve the sharpness and insertion, the wedge-shaped needle tips with thickness determined by Si wafer thickness were sharpened by a wet chemical etching process. Insertion forces recorded from pricking tests and bending and buckling from theoretical calculation and FEM analysis before and after etching were compared. The results showed that the insertion force, free bending force and the maximum buckling force were all reduced and the maximum bending stress were improved after tip sharpening. Furthermore, the buckling safety factor of all eleven designs was great than 1 and the maximum bending stress was less than the fracture strength of Si, indicating that our in-plane Si microneedles are robust enough for insertion into human skin.

Fabrication method with high-density, high-height microneedle using microindentation method for drug delivery system

We have developed a microneedle formation method that has high needle height and density by forming indentations on a metal plate using a micro-machined silicon microneedle, called the “microindentation method.” When a silicon microneedle is used as an indenter that is stamped onto a metal plate and the formed indentation has the same shape as the Si microneedle formed by plastic deformation of metal plate, it is possible to fabricate a microneedle mold arranged in an array by repeating indentation formation while changing the position using a single silicon microneedle. In this research, we developed an indentation apparatus that repeatedly forms indentations on lead plates to successfully fabricate a high-density microneedle array that has the height of the silicon microneedle as the indenter.

Fabrication and characterization of gold-coated solid silicon microneedles with improved biocompatibility

In this paper, we discussed biocompatibility improvement and mechanical strength of the solid silicon (Si) microneedles for transdermal drug delivery systems. The pyramidal shape and sharp tip of microneedles are fabricated using an optimized Tetramethylammonium Hydroxide (TMAH) etching factors. The mechanical strength and biocompatibility of the microneedle array are enhanced after coating gold (Au) layer through metal sputtering technique. The needles thus fabricated are suitable for sustained transdermal drug delivery applications with a height of 250 μm and a base width of 52.8 μm, the aspect ratio of 4.73, and tip angle and diameter of 24.5° and 45 μm. The Vickers hardness value of 3800 Hv is obtained for the fabricated Au-coated solid Si microneedles. The attained Vickers hardness value is substantially higher than the skin resistive force. It shows that the capability of drug delivery by piercing these microneedles into the skin becomes readily feasible.

Drug loaded biodegradable polymer microneedles fabricated by hot embossing

This study demonstrates a fast low temperature method for fabrication of drug loaded polymer microneedles (MNs). First, arrays of tapered pillar MNs with a length of 275 ± 3 μm (mean ± SD) and a diameter of 84 ± 1 μm were fabricated in Si with a three-step deep reactive ion etching (DRIE) process. The Si MNs were used as a template for fabrication of polydimethylsiloxane (PDMS) stamps. The stamps were applied for replication of the MNs in spin coated poly‑ε‑caprolactone (PCL) films by hot embossing at 60 °C and a pressure of 1.4 MPa for 3 min. The resulting PCL MNs perfectly resembled the Si MNs and had a length of 270 ± 5 μm and a diameter of 84 ± 3 μm. The MNs had sufficient mechanical strength to penetrate the surface of a 10 w/w% gelatine gel without deformation. Finally, PCL MNs containing 20 w/w% of furosemide were fabricated and drug release by diffusion was demonstrated.

In Vivo Experimental Study of Noninvasive Insulin Microinjection through Hollow Si Microneedle Array.

An experimental study of in vivo insulin delivery through microinjection by using hollow silicon microneedle array is presented. A case study was carried out on a healthy human subject in vivo to determine the influence of delivery parameters on drug transfer efficiency. As a microinjection device, a hollow microneedle array (13 × 13 mm2) having 100 microneedles (220 µm high, 130 µm-outer diameter and 50 µm-inner diameter) was designed and fabricated using classical microfabrication techniques. The efficiency of the delivery process was first characterized using methylene blue and a saline solution. Based on these results, the transfer efficiency was found to be predominantly limited by the inability of viable epidermis to absorb and allow higher drug transport toward the capillary-rich region. Two types of fast-acting insulin were used to provide evidence of efficient delivery by hollow MNA to a human subject. By performing blood analyses, infusion of more-concentrated insulin (200 IU/mL, international units (IU)) exhibited similar blood glucose level drop (5–7%) compared to insulin of standard concentration (100 IU/mL), however, significant increase of serum insulin (40–50%) with respect to the preinfusion values was determined. This was additionally confirmed by a distinctive increase of insulin to C-peptide ratio as compared to preinfusion ratio. Moreover, we noticed that this route of administration mimics a multiple dose regimen, able to get a “steady state” for insulin plasma concentration.

Solid silicon microneedles for drug delivery applications

In this work, solid silicon (Si) microneedles with a higher aspect ratio and sharper tips are fabricated. Tetramethylammonium Hydroxide (TMAH) etching factors have been optimized and used to fabricate long and tapered microneedles. The needles thus fabricated are found to be suitable for transdermal drug delivery applications. The optimized etching factors include varying the concentration of TMAH, etching time, etching rates, temperature, and window size of optical mask. It is found that by increasing the window size, the etch rates in both vertical and lateral directions increase extensively. However, on increasing the temperature beyond 90 °C, etching becomes rapid and uncontrollable. In order to obtain microneedles with high aspect ratio, sample placement in the glass boat of TMAH setup and TMAH concentration should be manipulated to attain a higher etch rate in vertical direction compared to the lateral one. Solid silicon microneedles with an average height of 158 μm, base width of 110.5 μm, aspect ratio of 1.43, tip angle of 19.4° and tip diameter of 0.40 μm are successfully fabricated. A microhardness value of 44.4 (HRC) was obtained for the fabricated Si microneedles. This is 52.2 times higher than the skin Ultimate Tensile Strength (UTS), which makes insertion of microneedles through the skin safer and easier without any breakage.

Comparative study of the effects of phosphorus and boron doping in vapor–liquid–solid growth with fixed flow of silicon gas

This work was carried out to investigate the comparative effects of phosphorus and boron doing in vapor–liquid–solid (VLS) growth. Doped Si microneedles were grown by VLS mechanism at the temperature of 700°C or less using Au as the catalyst. VLS growth using in-situ doping with the mixed gas of Si2H6 and PH3 produced phosphorus doped n-Si microneedles at Au dot sites, whereas, the mixed gas of Si2H6 and B2H6 produced boron doped p-Si microneedles. The variation of growth rate, diameter, resistivity, impurity concentration and carrier (electron, hole) mobility of these n-Si and p-Si microneeedles were investigated and compared with the variation of dopant gas (PH3 or B2H6) flow, with a fixed flow of Si gas (Si2H6). This comparative study shall be helpful while fabricating devices by growing n-Si and p-Si microneedles one above another by multistep (2-step or 3-step) VLS growth.

Characterization of skin penetration efficacy by Au-coated Si microneedle array electrode

Investigation of skin penetration efficacy by a silicon microneedle array is presented. Experiments were performed on porcine and chicken skin samples in vitro and on human skin in vivo. Solid microneedle arrays (13×13mm2), each consisting of 100 microneedles, were designed and fabricated by deep reactive ion etching process. To evaluate the penetration efficacy through the mechanically and electrically resistant upper skin layer of stratum corneum, the electrical skin impedance change with applied force was measured by using Au-coated Si microneedle array as working electrode in 2 and 3 electrode configurations. Skin impedance changes between 2 and 8% were measured when applying incremental force, increased from 1 to 10N on a Au metalized microneedle array electrode. When impact assisted penetration of microneedle array was applied instead of incremental increase of applied force, a significant impedance reduction of up to 50% on animal skin and 95% on human skin was obtained, which is a strong evidence of successful skin penetration. Furthermore, the microneedle array electrode showed consistently lower interface impedance compared to the flat electrode for the samples involved. Analyses of Si microneedle mechanical properties revealed that by proper use a satisfactory safety margin (>60) can be achieved.

28pm3-E-5 マイクロニードルを用いた薬剤投与における定量性向上に関する研究

We proposed two different types microneedles, a two-layers and a tip-separable microneedles, to improve the quantitative of the dosage in drug delivery systems based on the microneedle devices. The medicine is included in a part of needle tip region in the former microneedle. On the other hand, the latter microneedle device is composed of a sharp tip containing medicine and a supporting base. The tips penetrated into the skin surface are separated and placed in the skin inside by removing the supporting base. At first, pyramidal shaped Si microneedles were fabricated by applying a photolithography and anisotropic wet etching of KOH. Then, both microneedles were successfully fabricated using the molding process.

Interface pn junction arrays with high yielded grown p-Si microneedles by vapor–liquid–solid method at low temperature

In this work we report the fabrication and investigation of the properties of interface pn junction arrays formed at the interface of vertically aligned p-Si microneedles and n-Si substrate. Arrays of boron doped p-Si microneedles were grown on n-Si substrate with the maximum yield of 100% by Au-catalysed vapor–liquid–solid (VLS) growth using in-situ doping with the mixed gas of Si2H6 and B2H6 at temperature less than 700°C, which is low as compared to the temperature (1100°C) required by diffusion process to dope Si microneedles after VLS growth. The physical dimension (diameter, length) and position of these p-Si microneedles can be controlled. The variation of growth rate, diameter, conductivity, impurity concentration and hole mobility of these p-Si microneeedles were investigated with the variation of boron doping. The pn junctions, formed with p-Si microneedles having different diameters, were found to exhibit standard diode characteristics. These pn junction embedded Si microneedle arrays might be potential candidate in sensor area applications. Again, low temperature processing would be compatible to integrate these junction arrays with other circuitry on a chip. This work provides one step forward to realize more sophisticated vertical active devices (BJT, MOSFET, etc) with Si microneedles.

Fabrication of a Microneedle/CNT Hierarchical Micro/Nano Surface Electrochemical Sensor and Its In-Vitro Glucose Sensing Characterization

We report fabrication of a microneedle-based three-electrode integrated electrochemical sensor and in-vitro characterization of this sensor for glucose sensing applications. A piece of silicon was sequentially dry and wet etched to form a 15 × 15 array of tall (approximately 380 μm) sharp silicon microneedles. Iron catalyst was deposited through a SU-8 shadow mask to form the working electrode and counter electrode. A multi-walled carbon nanotube forest was grown directly on the silicon microneedle array and platinum nano-particles were electrodeposited. Silver was deposited on the Si microneedle array through another shadow mask and chlorinated to form a Ag/AgCl reference electrode. The 3-electrode electrochemical sensor was tested for various glucose concentrations in the range of 3∼20 mM in 0.01 M phosphate buffered saline (PBS) solution. The sensor's amperometric response to the glucose concentration is linear and its sensitivity was found to be 17.73 ± 3 μA/mM-cm2. This microneedle-based sensor has a potential to be used for painless diabetes testing applications.

Magnetically Guided Nano–Micro Shaping and Slicing of Silicon

Silicon is one of the most important materials for modern electronics, telecom, and photovoltaic (PV) solar cells. With the rapidly expanding use of Si in the global economy, it would be highly desirable to reduce the overall use of Si material, especially to make the PVs more affordable and widely used as a renewable energy source. Here we report the first successful direction-guided, nano/microshaping of silicon, the intended direction of which is dictated by an applied magnetic field. Micrometer thin, massively parallel silicon sheets, very tall Si microneedles, zigzag bent Si nanowires, and tunnel drilling into Si substrates have all been demonstrated. The technique, utilizing narrow array of Au/Fe/Au trilayer etch lines, is particularly effective in producing only micrometer-thick Si sheets by rapid and inexpensive means with only 5 μm level slicing loss of Si material, thus practically eliminating the waste (and also the use) of Si material compared to the ~200 μm kerf loss per slicing and ~200 μm thick wafer in the typical saw-cut Si solar cell preparation. We expect that such nano/microshaping will enable a whole new family of novel Si geometries and exciting applications, including flexible Si circuits and highly antireflective zigzag nanowire coatings.