I first discovered the promised potential of lab-on-a-chip (LOC) technology at a Gordon Conference in the mid-1970s, when gas chromatography (GC) columns were reported on glass microscope slides. Since then, the technology's potential has fueled much innovation and product development. Yet this potential has not for the most part transmuted into practical, commercially available products. Although the widespread appeal of LOC generates much publicity and excitement, manufacturing a robust, reliable, and user-friendly device that is as good as or, ideally, better than established technologies has proven elusive. The technology's challenge, it seems, is twofold. One factor is technical: the difficulty (so far) to efficiently transfer "real-world" samples to the chip or miniature device. The other factor is human: our inborn resistance to accepting change, particularly when the perceived advantages of doing so are but minimal.

Certain separation techniques, including capillary electrophoresis (CE) and nano high performance liquid chromatography (HPLC), have been performed on a chip. These techniques use both on-chip and off-chip detection. However, when a mass spectrometer serves as the detector, additional practical challenges arise. It is relatively easy to focus a laser through a glass-microfabricated channel for on-chip, laser-induced, fluorescence detection (1). But it is quite another matter to remove the sample from the chip and thereafter ionize and transport the sample for mass spectrometry (MS) detection. Nevertheless, despite this difficulty, reports continue to suggest a future for chip-based analytical devices (2–4). The actual measure of the technology's success, however, will take the form of commercial LOC products that customers choose and use because they work better than established techniques.

Why microchips appear to make sense: To those who grapple daily with the challenges of conventional laboratory methods, the concept of integrated chemical and analytical processes that share a common substrate free of sample transfers and associated plumbing has much to recommend it. You can discard an LOC device after a single or otherwise limited use. Doing so obviates the need to wash glassware and frees you from concern about sample-to-sample carryover. It also makes possible low-cost, easy-to-follow procedures. Moreover, from the LOC–MS point of view (5), the volume of liquid handled is nicely compatible with mass spectrometer operation. For both electrospray ionization (ESI) and matrix-assisted laser desorption ionization (MALDI)-MS, the lower the flow, the better the analysis. Thus, MS, an easily scalable technique, exhibits an enhanced response when you decrease the sample size (5). Unfortunately, some chip-based commercial products currently fail to impart such advantages.

The dream for LOC–MS is a fully integrated device that integrates sample handling, sample preparation, and separation science (CE, HPLC, and so forth) coupled to a mass spectrometer as a sensitive, selective detector. Additional promises include the ability to handle toxic chemicals safely, economically, and in an environmentally responsible way. Low sample and reagent quantities and improved detection limits for concentration-sensitive detectors make these promises worth pursuing, as does the reduced requirement for operator intervention and the need to connect tubes, fittings, or accessories.

In principle, the LOC device should be inexpensive, portable, disposable, and amenable to productive use by unskilled operators. Regrettably, LOC analytical devices do not couple well with much larger instruments such as mass spectrometers. So the promise implied by the devices is difficult to deliver on. Yet progress is ongoing, and hope remains for the future of LOC–MS and related technologies.