Review
Integrated microfluidic devices

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Abstract

“With the fundamentals of microscale flow and species transport well developed, the recent trend in microfluidics has been to work towards the development of integrated devices which incorporate multiple fluidic, electronic and mechanical components or chemical processes onto a single chip sized substrate. Along with this has been a major push towards portability and therefore a decreased reliance on external infrastructure (such as detection sensors, heaters or voltage sources).” In this review we provide an in-depth look at the “state-of-the-art” in integrated microfludic devices for a broad range of application areas from on-chip DNA analysis, immunoassays and cytometry to advances in integrated detection technologies for and miniaturized fuel processing devices. In each area a few representative devices are examined with the intent of introducing the operating procedure, construction materials and manufacturing technique, as well as any unique and interesting features.

Introduction

Modern microfluidics [1] can be traced back to the development of a silicon chip based gas chromatograph at Stanford University [2] and the ink-jet printer at IBM [3], [4]. Though both these devices were quite remarkable, the concept of the integrated microfluidic device (which often fall under the broad categories of labs-on-a-chip or miniaturized total analysis systems) as it is known today was not developed until the early 1990s by Manz et al. [5]. Since that time the field has blossomed and branched off into many different areas, for which a number of excellent general reviews are available (e.g. biological and chemical analysis [6], [7], [8], point-of-care testing [9], clinical and forensic analysis [10], molecular diagnostics [11] and medical diagnostics [12]).

An integrated microfluidic device incorporates many of the necessary components and functionality of a typical room-sized laboratory on to a small chip. An example is presented in Fig. 1, which shows a device with on-chip temperature control and gradient generation for use with heterogeneous DNA hybridization assays [13]. Originally it was thought that the most significant benefit of these lab-on-a-chip devices would be the analytical improvements associated with the scaling down of the size [5]. Further development revealed other significant advantages including: minimized consumption of reagents, increased automation, and reduced manufacturing costs [14]. The latter of these has been perhaps the most important advancement as the field drifts from the relatively complex silicon and glass based micromachining originally developed in the electronics industry, to much simpler techniques and other materials [15], [16], [17], [18]. As these manufacturing technologies are further and further advanced (both in terms of the potential complexity of an integrated device and the ease with which a simple prototype can be made) in parallel with analytical needs, the development of future integrated devices will inevitably be less expensive and faster than ever before.

In this work we review the “state-of-the-art” in integrated microfluidic technology from the beginning of the year 2000 to present (for earlier microfluidic devices or historical details, readers are referred to the comprehensive set of reviews written by Reyes et al. [19] and Auroux et al. [20]). For the most part we will focus on application-based devices and prototypes (as opposed to works which simply demonstrate an integrated technology or platform) for which significant details on the operation and construction of the device are available in journal publications (as opposed to overviews in conference abstracts). These devices are grouped by specific application areas.

Section snippets

Integrated microfluidic devices for DNA analysis

Driven largely by huge potential markets and thanks in no small part to the Human Genome Project, of all the areas into which microfluidics has been introduced, the general field of DNA analysis has produced the most highly integrated procedure chips [21]. Some of the first devices concentrated on rapid and low power polymerase chain reaction (PCR) through either a continuous flow procedure (for example, the three temperature zone flow through device presented by Martin et al. [22]) or batch

Devices for separation based detection

As mentioned above, due to the shorter analysis times and potential for more theoretical plates [5], one of the first major applications of modern microfluidics was separation based on electrokinetic processes. An excellent, all encompassing paper covering the fundamentals of capillary electrophoresis and the progress to that time was written in 1996 by St. Claire [65]. More recently some excellent reviews focusing on microchip based separations have been published [10], [66] as well as several

Devices for cell handling, sorting and general analysis

In addition to on-chip DNA analysis and capillary electrophoresis, there has been a large amount of research directed towards the integration of microfluidic technologies with different aspects of cellular analysis [6], [20]. Recent reviews have discussed these directions in the context of single cell analysis by capillary electrophoresis [113], drug development [114], tissue engineering [115], sample preparation for molecular diagnostics [11] and biosensors [116]. Here, we review some of the

Devices for protein based applications

In general the development integrated microfluidic devices that are specifically designed for protein analysis, beyond traditional CE chips, is less mature than some of the applications already listed. Such work has however been addressed in some reviews [20], [136], and more specifically by Sanders and Manz [137], and Figeys and Pinto [138]. These latter two authors provide a good review of chip based devices for proteomics. As before, we present some examples of the more highly integrated

Integrated microfluidic devices for immunoassay

Generally a large number of repetitive steps are involved in an immunoassay analysis, resulting in high time and labor costs. As such the advantages in automation and reaction rates offered by microfluidics are particularly well suited to this application. Currently, the development of integrated devices for immunoassay is significantly less advanced than that for DNA analysis. A few reviews have focused immunoassays using microfluidics [155], [156]. Here we review both surface and solution

Integrated microreactors

Microreactors form an integral component of many microfluidic devices and have been reviewed by a number of authors, most notably by Haswell et al. [167], [168], [169]. These authors have written a number of excellent reviews on some of the promising advantages that microreactors have to offer in terms of synthetic chemistry. Here we examine just a few devices to provide an overview of the field.

Losey et al. [170] presented a highly integrated microfluidic device for two-phase mixing, and for

Integrated optical sensing elements

The integration of high resolution optical sensing elements into microfluidic devices is one of the inevitable requirements of constructing truly portable lab on-chip devices. Adams et al. [198] developed a technique for integrating replica molded microchannels systems with a complementary metal oxide semiconductor (CMOS) imaging chip to develop an on-chip adsorption or fluorescence microspectrometer. They were able to obtain absorption signatures for dilute (<100 μM) dye solutions. Camou et al.

Conclusions and outlook

In this work we have reviewed a sampling of recently reported (between 2000 and mid 2003) integrated microfluidic devices, otherwise known as lab-on-a-chip. The objective was to present devices from a broad spectrum of application areas, in order to provide a glimpse into the current state-of-the-art in each of these fields. As we have stated, the majority of microfluidics research has been concentrated in those areas that have the highest potential for short-term commercial success. In

Acknowledgements

The authors are thankful for the financial support of the Natural Sciences and Engineering Research Council through a scholarship to D. Erickson and through a research grants to D. Li. The financial support from Glynn Williams, through a scholarships to D. Erickson, is also acknowledged.

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