After having reviewed some aspects of microfluidic system preparation in the first part (1), in this second part of the review we will cover a number of standard operations (namely: sample preparation, sample injection, sample manipulation, reaction, separation, and detection) as well as some biological applications of micro total analysis systems (namely: cell culture, polymerase chain reaction, DNA separation, DNA sequencing, and clinical diagnostics). As previously, we will include papers issued from different scientific journals as well as useful abstracts from three conference proceedings: MEMS, Transducers, and μTAS. In this second part, we do not include the period covered by the history section (1975-1997) from part 1 but try to cover the relevant examples of the literature published between January 1998 and March 2002. We briefly describe articles that struck us as needing special attention, while more “standard” papers are dutifully reported in groups of interest. An article might be included in more than one section, depending on the ideas developed in it.

Micro total analysis systems. 2. Analytical standard operations and applications.

Magnetic forces are now being utilised in an amazing variety of microfluidic applications. Magnetohydrodynamic flow has been applied to the pumping of fluids through microchannels. Magnetic materials such as ferrofluids or magnetically doped PDMS have been used as valves. Magnetic microparticles have been employed for mixing of fluid streams. Magnetic particles have also been used as solid supports for bioreactions in microchannels. Trapping and transport of single cells are being investigated and recently, advances have been made towards the detection of magnetic material on-chip. The aim of this review is to introduce and discuss the various developments within the field of magnetism and microfluidics.

Magnetism and microfluidics

Micro total analysis systems. Recent developments.

Rapid and accurate measurement of biomarkers in tissue and fluid samples is a major challenge in medicine. Here we report the development of a new, miniaturized diagnostic magnetic resonance (DMR) system for multiplexed, quantitative and rapid analysis. By using magnetic particles as a proximity sensor to amplify molecular interactions, the handheld DMR system can perform measurements on unprocessed biological samples. We show the capability of the DMR system by using it to detect bacteria with high sensitivity, identify small numbers of cells and analyze them on a molecular level in real time, and measure a series of protein biomarkers in parallel. The DMR technology shows promise as a robust and portable diagnostic device.

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Chip–NMR biosensor for detection and molecular analysis of cells

The use of planar fluidic devices for performing small-volume chemistry was first proposed by analytical chemists, who coined the term "miniaturized total chemical analysis systems" (/spl mu/TAS) for this concept. More recently, the /spl mu/TAS field has begun to encompass other areas of chemistry and biology. To reflect this expanded scope, the broader terms "microfluidics" and "lab-on-a-chip" are now often used in addition to /spl mu/TAS. Most microfluidics researchers rely on micromachining technologies at least to some extent to produce microflow systems based on interconnected micrometer-dimensioned channels. As members of the microelectromechanical systems (MEMS) community know, however, one can do more with these techniques. It is possible to impart higher levels of functionality by making features in different materials and at different levels within a microfluidic device. Increasingly, researchers have considered how to integrate electrical or electrochemical function into chips for purposes as diverse as heating, temperature sensing, electrochemical detection, and pumping. MEMS processes applied to new materials have also resulted in new approaches for fabrication of microchannels. This review paper explores these and other developments that have emerged from the increasing interaction between the MEMS and microfluidics worlds.

Microfluidics meets MEMS

Planar microcoil-based microfluidic NMR probes.

We present the design, fabrication and test of high-Q factor radiofrequency planar microcoils for nuclear magnetic resonance (NMR) spectroscopy in small volume samples. The coils are fabricated on glass wafers using high-aspect ratio SU-8 photoepoxy and copper electroplating. On-wafer electrical characterization shows quality factors up to 40 at 800 MHz. A 500 μm diameter microcoil with a measured quality factor of 24 at 300 MHz is mounted on a printed circuit board and electrically contacted using aluminum wire bonding. This probe is inserted in a 7 T-superconducting magnet, and a 1H-NMR spectrum of 160 nl ethylbenzene contained in a capillary placed over the microcoil is acquired in a single scan. This work is an important step towards the integration of NMR detection into micro-total analysis systems (μTAS).

High-Q factor RF planar microcoils for micro-scale NMR spectroscopy

In this paper, we present a low-power, two-axis fluxgate magnetometer. The planar sensor is integrated in a standard CMOS process, which provides metal layers for the coils and electronics for the signal extraction and processing. The ferromagnetic core is placed diagonally above the four excitation coils by a compatible photolithographic post process, performed on a whole wafer. The sensor works using the single-core principle, with a modulation technique to lower the noise and the offset at the output. In contrast to traditional fluxgate approaches, the sensor features a high degree of integration and minimal power consumption at 2.5 V of supply voltage that makes it suitable for portable applications. A novel digital feedback principle is integrated to linearize the sensor characteristics and to extend the linear working range.

Low-power 2-D fully integrated CMOS fluxgate magnetometer

Nuclear magnetic resonance (NMR) spectroscopy enables non-invasive chemical studies of intact living matter. However, the use of NMR at the volume scale typical of microorganisms is hindered by sensitivity limitations, and experiments on single intact organisms have so far been limited to entities having volumes larger than 5 nL. Here we show NMR spectroscopy experiments conducted on single intact ova of 0.1 and 0.5 nL (i.e. 10 to 50 times smaller than previously achieved), thereby reaching the relevant volume scale where life development begins for a broad variety of organisms, humans included. Performing experiments with inductive ultra-compact (1 mm2) single-chip NMR probes, consisting of a low noise transceiver and a multilayer 150 μm planar microcoil, we demonstrate that the achieved limit of detection (about 5 pmol of 1H nuclei) is sufficient to detect endogenous compounds. Our findings suggest that single-chip probes are promising candidates to enable NMR-based study and selection of microscopic entities at biologically relevant volume scales.

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NMR spectroscopy of single sub-nL ova with inductive ultra-compact single-chip probes

We describe the fabrication and the performance of a microcoil-based probe for electron spin resonance (ESR) spectroscopy on micrometer sized samples. The probe consists of a 100 μm planar microcoil fabricated on a glass substrate, tuned and matched at 1.4 GHz (L band) using miniaturized ceramic capacitors. We performed continuous wave ESR experiments on samples having a volume between (100 μm)3 and (10 μm)3. At 300 K, we achieved a spin sensitivity of about 1010 spins/G Hz1/2, which is comparable to that of commercial ESR spectrometers operating at 9 GHz (X band). The results reported in this article suggest that microcoil-based probes might represent a valid alternative to conventional microwave cavities for ESR studies of sample of the order of (100 μm)3 and smaller.

F. Vincent

Papers

Planar microcoil-based microfluidic NMR probes.

High-Q factor RF planar microcoils for micro-scale NMR spectroscopy

Low-power 2-D fully integrated CMOS fluxgate magnetometer

NMR spectroscopy of single sub-nL ova with inductive ultra-compact single-chip probes

Electron-spin resonance probe based on a 100 μm planar microcoil