Integrated Lithographic Molding for Microneedle-Based Devices

This paper presents a new fabrication method consisting of lithographically defining multiple layers of high aspect-ratio photoresist onto preprocessed silicon substrates and release of the polymer by the lost mold or sacrificial layer technique, coined by us as lithographic molding. The process methodology was demonstrated fabricating out-of-plane polymeric hollow microneedles. First, the fabrication of needle tips was demonstrated for polymeric microneedles with an outer diameter of 250 mum, through-hole capillaries of 75-mum diameter and a needle shaft length of 430 mum by lithographic processing of SU-8 onto simple v-grooves. Second, the technique was extended to gain more freedom in tip shape design, needle shaft length and use of filling materials. A novel combination of silicon dry and wet etching is introduced that allows highly accurate and repetitive lithographic molding of a complex shape. Both techniques consent to the lithographic integration of microfluidic back plates forming a patch-type device. These microneedle-integrated patches offer a feasible solution for medical applications that demand an easy to use point-of-care sample collector, for example, in blood diagnostics for lithium therapy. Although microchip capillary electrophoresis glass devices were addressed earlier, here, we show for the first time the complete diagnostic method based on microneedles made from SU-8

Micromachining of buried micro channels in silicon

A new method for the fabrication of micro structures for fluidic applications, such as channels, cavities, and connector holes in the bulk of silicon wafers, called buried channel technology (BCT), is presented in this paper. The micro structures are constructed by trench etching, coating of the sidewalls of the trench, removal of the coating at the bottom of the trench, and etching into the bulk of the silicon substrate. The structures can be sealed by deposition of a suitable layer that closes the trench. BCT is a process that can be used to fabricate complete micro channels in a single wafer with only one lithographic mask and processing on one side of the wafer, without the need for assembly and bonding. The process leaves a substrate surface with little topography, which easily allows further processing, such as the integration of electronic circuits or solid-state sensors. The essential features of the technology, as well as design rules and feasible process schemes, will be demonstrated on examples from the field of ¿-fluidic

3d Self-Aligned Fabrication of Suspended Nanowires by Crystallographic Nanolithography

Known templating procedures mostly create out-of-plane nanowires where individual connections at both ends are complicated. Here we introduce a templating procedure for wafer scale fabrication of in-plane nanowires. The template fabrication process employs two simple interference lithography masking patterns and relies on self-aligned crystallographic processing. In-plane nanowires with diameters down to 10 nm can be fabricated wafer scale through this 3D templating procedure. As a first demonstration arrays of suspended silicon nitride wires have been created.</p

Silicon micromachined hollow microneedles for transdermal liquid transport

This paper presents a novel process for the fabrication of out-of-plane hollow microneedles in silicon. The fabrication method consists of a sequence of deep-reactive ion etching (DRIE), anisotropic wet etching and conformal thin film deposition, and allows needle shapes with different, lithography-defined tip curvature. In this study, the length of the needles varied between 150 and 350 micrometers. The widest dimension of the needle at its base was 250 /spl mu/m. Preliminary application tests of the needle arrays show that they are robust and permit skin penetration without breakage. Transdermal water loss measurements before and after microneedle skin penetration are reported. Drug delivery is increased approximately by a factor of 750 in microneedle patch applications with respect to diffusion alone. The feasibility of using the microneedle array as a blood sampler on a capillary electrophoresis chip is demonstrated

Exploring the surface-enhanced Raman scattering (SERS) activity of gold nanostructures embedded around nanogaps at wafer scale: Simulations and experiments

A unique way of converting free space light into a local electromagnetic field in small spaces is via metallic nanostructuring. In this work fabrication, experimental characterization and simulation of surface-enhanced Raman scattering (SERS) active specimens based on Au nanostructures are discussed. We used displacement Talbot lithography (DTL) to fabricate silicon nano-wedge substrates with Au nanostructures embedded around their apices. After the ion beam etching process, a nanogap is introduced between two Au nanostructures templated over nano-wedges, yielding specimens with SERS characteristics. The Au nanostructures and the nanogaps have symmetric and asymmetric configurations with respect to the wedges. With this nanofabrication method, various wafer-scale specimens were fabricated with highly controllable nanogaps with a size in the order of 6 nm for symmetric gaps and 8 nm for asymmetric gaps. SERS characteristics of these specimens were analyzed experimentally by calculating their analytical enhancement factor (AEF). According to finite-difference time-domain (FDTD) simulations, the Raman enhancement arises at the narrow gap due to plasmonic resonances, yielding a maximum AEF of 6.9 × 106. The results highlight the SERS activity of the nanostructures and ultimately comply with reliable substrates for practical applications

Conformal Electroless Nickel Plating on Silicon Wafers, Convex and Concave Pyramids, and Ultralong Nanowires

Nickel (Ni) plating has garnered great commercial interest, as it provides excellent hardness, corrosion resistance, and electrical conductivity. Though Ni plating on conducting substrates is commonly employed via electrodeposition, plating on semiconductors and insulators often necessitates electroless approaches. Corresponding plating theory for deposition on planar substrates was developed as early as 1946, but for substrates with micro- and nanoscale features, very little is known of the relationships between plating conditions, Ni deposition quality, and substrate morphology. Herein, we describe the general theory and mechanisms of electroless Ni deposition on semiconducting silicon (Si) substrates, detailing plating bath failures and establishing relationships between critical plating bath parameters and the deposited Ni film quality. Through this theory, we develop two different plating recipes: galvanic displacement (GD) and autocatalytic deposition (ACD). Neither recipe requires pretreatment of the Si substrate, and both methods are capable of depositing uniform Ni films on planar Si substrates and convex Si pyramids. In comparison, ACD has better tunability than GD, and it provides a more conformal Ni coating on complex and high-aspect-ratio Si structures, such as inverse fractal Si pyramids and ultralong Si nanowires. Our methodology and theoretical analyses can be leveraged to develop electroless plating processes for other metals and metal alloys and to generally provide direction for the adaptation of electroless deposition to modern applications

The Fast Track for Intestinal Tumor Cell Differentiation and In Vitro Intestinal Models by Inorganic Topographic Surfaces

Three-dimensional (3D) complex in vitro cell systems are well suited to providing mean-ingful and translatable results in drug screening, toxicity measurements, and biological studies. Reliable complex gastrointestinal in vitro models as a testbed for oral drug administration and toxicity are very valuable in achieving predictive results for clinical trials and reducing animal testing. However, producing these models is time-consuming due to the lengthy differentiation of HT29 or other cells into mucus-producing goblet cells or other intestinal cell lineages. In the present work, HT29 cells were grown on an inorganic topographic surface decorated with a periodic pattern of micrometre-sized amorphous SiO2 structures for up to 35 days. HT29 cells on topographic surfaces were compared to undifferentiated HT29 in glucose-containing medium on glass or culture dish and with HT29 cells differentiated for 30 days in the presence of methotrexate (HT29-MTX). The cells were stained with Alcian blue for mucus, antibodies for mucus 2 (goblet cells), villin (enterocytes), lysozyme (Paneth cells), and FITC-labeled lectins to identify different cells, glycomic profiles, and cell features. We observed that HT29 cells on topographic surfaces showed more similarities with the differentiated HT29-MTX than with undifferentiated HT29. They formed islands of cell clusters, as observed for HT29-MTX. Already after 2 days, the first mucus secretion was shown by Alcian blue stain and FITC-wheat germ agglutinin. After 4–6 days, mucus was observed on the cell surface and in the intercellular space. The cell layer was undulated, and in 3D reconstruction, the cells showed a clear polarisation with a strong actin signal to one membrane. The lectins and the antibody-staining confirmed the heterogeneous composition of differentiated HT29 cells on topographic surfaces after 6–8 days, or after 6–8 days following MTX differentiation (30 days)

Complex tumor spheroid formation and one‐step cancer‐ associated fibroblasts purification from hepatocellular carcinoma tissue promoted by inorganic surface topography

In vitro cell models play important roles as testbeds for toxicity studies, drug development, or as replacements in animal experiments. In particular, complex tumor models such as hepatocellular carcinoma (HCC) are needed to predict drug efficacy and facilitate translation into clinical practice. In this work, topographical features of amorphous silicon dioxide (SiO2) are fabricated and tested for cell culture of primary HCC cells and cell lines. The topographies vary from pyramids to octahedrons to structures named fractals, with increased hierarchy and organized in periodic arrays (square or Hexagonal). The pyramids were found to promote complex 2D/3D tissue formation from primary HCC cells. It was found that the 2D layer was mainly composed of cancer‐associated fibroblasts (CAFs), while the 3D spheroids were composed of tumor cells enwrapped by a CAF layer. Compared with conventional protocols for 3D cultures, this novel approach mimics the 2D/3D complexity of the original tumor by invading CAFs and a microtumor. Topographies such as octahedrons and fractals exclude tumor cells and allow one‐step isolation of CAFs even directly from tumor tissue of patients as the CAFs migrate into the structured substrate. Cell lines form spheroids within a short time. The presented inorganic topographical surfaces stimulate complex spheroid formation while avoiding additional biological scaffolds and allowing direct visualization on the substrate