IBM researchers develop a versatile new diagnostic device that could significantly contribute to the study of cancerous and nerve cells

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Zurich, Switzerland, 2 August 2005 — Scientists at IBM Research - Zurich have developed a ground-breaking device that opens new possibilities for biochemical analysis and diagnostics on the micrometer scale, as reported in the August 1 issue of Nature Materials. The device's major breakthrough is its ability to manipulate biomolecules and single cells in their native cell-culture environment, which holds great promise for cell research in medicine and biology.

The fields of medicine and biology are being revolutionized by so-called biochips and microfluidic devices such as DNA chips, protein microarrays or "lab-on-a-chip" systems that operate on the micrometer scale (one thousandth of a millimeter). These devices, some of which are no larger than a fingernail, are miniature laboratories that consist of a large array of micrometer-sized capture spots—tiny test sites where the concentration of various proteins in cells and biofluids are analyzed. At the same time, the devices also permit a wide range of other tests, thus achieving much higher throughput and speed than conventional diagnostic devices. In addition, they are much more economical and efficient thanks to their use of as little as a few nanoliters (one millionth of a milliliter) of sample material. Yet, currently existing technologies have major limitations, including poor quality of the capture spots and the inability to allow tests to be conducted directly on individual selected cells in the native cell-culture environment.

IBM researchers David Juncker, Heinz Schmid, and Emmanuel Delamarche have overcome these limitations by developing a novel technology that offers unprecedented functionality and, most notably, the ability to manipulate single cells. The device is called a "microfluidic probe" (MFP) in reference to the fact that it is moved over a surface like a scanning probe, similar to scanning tunneling (STM) or atomic force microscopes (AFM), both invented by researchers at IBM Research - Zurich.

The basic operating principle of the MFP is straightforward and comparable to that of a high-pressure cleaner. A jet of solution is directed onto a surface, but because the MFP operates on the micrometer scale, it dispenses only nanoliter amounts of solution. To prevent the microjet from spraying neighboring areas, the scientists designed a "micro-vacuum cleaner" next to the nozzle of the microjet, which aspirates the solution immediately after it has impinged on the surface. Like a pair of micropipettes, this injection-aspiration configuration allows the MFP to harvest tiny amounts of sample material—even individual cells—and deposit them on a surface without direct contact between the device and the surface. "The contact-free design is crucial because it allows us to scan the device along the surface and process randomly selected spots," explains Emmanuel Delamarche.

The MFP can be used, for example, to select individual cells that exhibit a particular response or pathology and either expose them to various chemical solutions or remove them so that they can be studied individually. Moreover, the MFP's operation requires a liquid environment, which is a key advantage because liquid solutions are the native environment of biomolecules and cells. "This device closes a gap in cell biology research. Despite the fundamental significance of a cell's extracellular environment, there have so far been no practical devices or means to define and tailor this environment at the resolution of a single cell," states David Juncker, who led the basic research project that culminated in the MFP. In one experiment, the team of IBM scientists used a special staining solution to dye selected cells to produce the word CELLS. They also demonstrated the ability to remove a single cell from a surface while leaving its neighbors intact. Such an approach holds particular promise for the study of cancerous or nerve cells. One possible scenario is drug screening: The MFP could be used to expose cancerous cells to various drug therapies. The efficacy of a potential drug could be assessed in greater detail by selecting individual cells and exposing them to additional chemicals, or by removing a single cell and depositing it on a sensor area for further investigation.

Other possible applications include protein microarrays, which can detect the presence of multiple target proteins in a cell, thus revealing the cell's "fingerprint". This fingerprint can provide information about various diseases and, even more intriguingly, about the causes of a given disease. The MFP can be used to form such protein microarrays. In lab demonstrations, it took IBM researchers less than half an hour using a single MFP to produce arrays having more than one thousand capture spots. Most importantly, because the device operates in liquid solutions, which is the native environment of proteins, it prevents their dehydration and denaturation—the major causes of imperfect spots and irreproducible results. Lacking alternatives, conventional spotting techniques, which operate in air and suffer from these problems, have nevertheless been used until now to produce protein microarrays. The MFP constitutes a serious alternative for the formation of high-quality protein microarrays.

These first demonstrations have already shown the remarkable versatility of the tool and its potential benefits, in particular for applications in the fields of biology and medicine. Still, the technology is only in its infancy. "Recalling the development of AFM and its great variety of subsequent applications, one might be tempted to predict a comparable career for the MFP. Whereas STM and AFM made novel inroads to atomic-scale research by providing the unprecedented ability to image and manipulate atoms, the microfluidic probe promises to introduce several of these advantages to cell biology by enabling in vitro manipulation of single cells within their native cell-culture environment," says David Juncker and adds, "We are already thinking about how to expand this technology for in vivo analyses, for example to mark and excise cancerous cells locally, or to excite selected nerve cells."

The scientific paper entitled "A Multipurpose Microfluidic Probe" by David Juncker, Heinz Schmid and Emmanuel Delamarche, was published in Nature Materials Vol.4, No. 8, pp 622-628 (2005).

Supplemental information can also be found under Nature Materials.