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WIREs Nanomed Nanobiotechnol
Impact Factor: 6.14

Technology modules from micro‐ and nano‐electronics for the life sciences

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The capabilities of modern semiconductor manufacturing offer remarkable possibilities to be applied in life science research as well as for its commercialization. In this review, the technology modules available in micro‐ and nano‐electronics are exemplarily presented for the case of 250 and 130 nm technology nodes. Preparation procedures and the different transistor types as available in complementary metal‐oxide‐silicon devices (CMOS) and BipolarCMOS (BiCMOS) technologies are introduced as key elements of comprehensive chip architectures. Techniques for circuit design and the elements of completely integrated bioelectronics systems are outlined. The possibility for life scientists to make use of these technology modules for their research and development projects via so‐called multi‐project wafer services is emphasized. Various examples from diverse fields such as (1) immobilization of biomolecules and cells on semiconductor surfaces, (2) biosensors operating by different principles such as affinity viscosimetry, impedance spectroscopy, and dielectrophoresis, (3) complete systems for human body implants and monitors for bioreactors, and (4) the combination of microelectronics with microfluidics either by chip‐in‐polymer integration as well as Si‐based microfluidics are demonstrated from joint developments with partners from biotechnology and medicine. WIREs Nanomed Nanobiotechnol 2016, 8:355–377. doi: 10.1002/wnan.1367 This article is categorized under: Diagnostic Tools > Biosensing Therapeutic Approaches and Drug Discovery > Emerging Technologies Nanotechnology Approaches to Biology > Nanoscale Systems in Biology
Affinity–viscosimetric sensor chip. (a) Electrical circuit of affinity sensor chip: the DC voltage introduced is converted to a high‐frequency AC voltage of 3.2 GHz via two ring oscillator circuits. The configuration of beam and ground plate acts as a capacitor C with serial and parallel resistors R (shaded areas). C and R may vary due to beam bending in the measurement circuit, which is indicated by arrows; both quantities remain constant, however, during the measurement in the reference circuit. (b) Chip photograph, from which the measurement and reference MEMS can be recognized on top and at the bottom; also the position of the different components on the chip for the signal transduction cascade are indicated. (c) Transient of the measurement parameter switching time tsw for test solutions with varying glucose concentration cg and temperature T as well
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(a) Measurement set‐up for dielectrophoretic electrode array on a microscope slide (75 × 25 mm). (b) Dielectrophoretic immobilization of anti‐RPE anti‐bodies and subsequent incubation with RPE. An alternating voltage of 100 kHz and 18 Vrms has been applied for 20 min. The figure depicts the superposition of a reflection picture of the array (grey values converted to violet) and a fluorescence picture (grey values converted to yellow).
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(a) Scheme of MEMS concept and operation of an affinity sensor. A cavity is filled by the assay encompassing the receptor (small red balls) and the polymer of the analyte (large blue spheres). The network formed by macromolecular receptors and polymers partially decomposes under inserting the monomeric analyte, which leads to a change in viscosity. (b) Scanning electron microscope (SEM) picture of an assay‐free MEMS with mechanically bendable beam having the shape of an X. Beam and ground plate are prepared from biostable TiN with the beam thickness amounting to 50 nm only. (c) The elastically restoring element in the middle of the beam takes the shape of an open double U. (d) The beam is formed immoveable for a parallel reference measurement by closing the double U.
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Fabrication process of microelectrode array for dielectrophoretic immobilization: (a) metal deposition; (b) SiO2 deposition, CMP and VIA etch; (c) tungsten filling of vias and subsequent CMP; (d) 3D side view; (e) confocal reflection microscopy of a part of the array, scale 50 µm; (f) detail view of part label e, scale 2 µm; (g) Scanning electron microscope (SEM) cross section micrograph of a single tungsten electrode with embedding SiO2 and metal layer beneath, scale bar 500 nm.
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(a) Color‐scale representation of electric potential distribution in and above a doping lattice as calculated by an finite‐element simulation (FEM) simulation for ND = 1020 cm‐3. (b) Course of surface potentials for the different cases of ND = 1016, 1017, 1018, 1019, and 1020 cm‐3. Calculations were performed for the vacuum case, which has to be modified in aqueous solutions due to shielding by electrolyte ions and water dipoles. (c) Scanning electron microscope (SEM) view on a doping lattice upon which MG 63 osteoblasts were cultivated. The orientation of cells along the direction of the lattice (white arrow) can clearly be recognized.
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(a) Optical microscope picture of the surface of a microchip after storing it in electrolyte solution for some days. A top‐most metal layer has been subjected to corrosion as can be recognized by the color change from yellow to green. (b) Scanning electron microscope (SEM) cross section micrograph of the same area shows a penetration of the passivation layer, which turned out to be caused by the topography variation at the edge of TM1‐induced surface protrusion. Such defects can be avoided by usage of an alternative passivation nitride and by a CMP step for planarization.
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(a) Schematic drawing of SG25H1 chip architecture in 0.25 µm technology. Blue areas are formed by inter‐layer dielectric (ILD) layers that have to establish the electrical isolation between electrical connections. Metal layers M1…M3 are horizontally oriented, while vertical currents are transported by VIAs. Active devices such as n‐type and p‐type complementary metal‐oxide‐silicon devices (MOSFETs) as well as HBTs are formed directly on the Si wafer and can be seen at the bottom. The layer stack is terminated on top by a passivation layer of silicon nitride (grey) having openings only in the area of bond pads. (b) Scanning electron microscope (SEM) cross section micrograph of a chip architecture processed until to ILD3. The framing of metal layers M1 to M3 into a top and bottom TiN layer may clearly be recognized as well as the VIAs connecting them.
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(a) Schematic drawing of real and imaginary part ε′ and ε′′ of an aqueous protein solution. The maximum of ε′′ around 108 Hz is due to absorbing proteins, while the absorption maximum above 10 GHz is caused by water molecules. (b) Layout of an impedance measurement chip that can be used for the determination of cell densities. The lower part shows square‐sized bond pads, while sensor elements that will come in contact with the bio‐milieu are arranged on top of the chip. The distance between both was chosen rather large in order to establish a sufficient blocking of the bio‐milieu and protecting the electrical contacts from corrosion. (c) Schematic overview of a test field in a 0.25 µm CMOS/BiCMOS technology occupying an area of 10.7 × 25.9 mm on a 200 mm wafer. There are about 70–120 exemplars of the same test field to be processed on each wafer of a production lot.
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(a) and (b) Transmission electron microscopy (TEM) micrographs of increasing magnification from the cross section of a metal–oxide–semiconductor field‐effect transistor (MOSFET) having a channel length of 130 nm as routinely produced in 0.13 µm complementary metal‐oxide‐silicon devices (CMOS) technologies. Source and drain regions are situated directly below the vertical tungsten plugs (W VIAs). The thin SiO2 film covering the channel exhibits a thickness of 2 nm. (c) TEM cross section micrograph of a most‐recent hetero‐junction bipolar transistor (HBT); the emitter and the base, consisting of 20 nm thin SiGe:C, have been emphasized. The electrical connection to a tungsten VIA and the lowest metal layer M1 can clearly be recognized.
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Scanning electron microscope (SEM) micrograph of an intermediate step during the preparation of a doping lattice. The picture was taken after implantation of n‐doped areas and prior to etching off the photoresist.
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(a) View into IHP clean room. (b) Wafer lot consisting of 24 Si Wafers having a diameter of 200 mm. (c) An almost full‐processed wafer showing the separation of the surface into single dies of the same test field.
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Approach for microfluidics integration into microelectronic chips. (a) Conceptual sketch. (b) finite‐element simulation (FEM) simulation of flow. (c) Cross‐section micrograph of the produced wafer stack. (d) Optical microscope view on HF impedance sensor with microfluidics channel below: unfilled and (e) with fluorescence‐labeled liquid.
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Autonomous sensor capsule for application in photo‐bioreactor with algae cultivation. (a) Outward appearance. (b) configuration of sensor surfaces on equatorially positioned printed circuit board (PCB). (c) photographs of both sides of the PCB: with microcontroller and transceiver (left) and sensor field (right). The semi‐sphere above the sensor field is permeable to the cultivation broth, while the opposite side is impermeable as is the PCB layer.
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(a) General system architecture of a bio‐sensor implant. (b) Printed circuit board (PCB) of with microcontroller μC, radio module (ZL70321), and zero insertion force (ZIF) connector for connecting to sensor chip. The lateral extension of 27 mm fits to that of the battery positioned below. (c) 3D integration scheme for antenna (1), sensor probe (2), flexible cable for connecting to ZIF (3), printed circuit board (4), antenna adapter (5), microcontroller (μC) (6), battery (7), and distance holder (8). (d and e). Top and bottom view of a silicone‐encapsulated biosensor implant. The sensor probe is positioned in the middle of the system in the left figure; in the picture to the right one may recognize the D‐shaped battery through the silicone. The outer dimensions of the implant amount to 38.6 × 49.3 × 15.5 mm.
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Therapeutic Approaches and Drug Discovery > Emerging Technologies
Diagnostic Tools > Biosensing
Nanotechnology Approaches to Biology > Nanoscale Systems in Biology

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