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  • Prodding cells with a nanoprobe may improve cancer detection

Feb 2008
Michael A. Greenwood

Determining whether a cell is cancerous is not as straightforward as it might seem.

Current methods, including morphological analyses and the use of antibodies to label specific markers on the cancerous tissue, generally are accurate, but they are far from foolproof. A misdiagnosis is the last thing that a patient -- or a physician -- wants.

Researchers from the University of California, Los Angeles, recently reported that they had developed a possible alternative detection method that relies on a cell’s elasticity to detect the deadly disease. Although it has been known that cells with highly elastic membranes probably are metastatic cancer cells (a property that likely facilitates their spread throughout the circulatory system), this criterion has not been used to diagnose cancer. Cells that are firmer, meanwhile, are probably healthy. Both types are generally similar in shape and appearance under a microscope.

To gauge cell elasticity, the research team led by James K. Gimzewski recently used an atomic force microscope (AFM) to control a nanomechanical probe (Figure 1). The procedure is delicate, with the probe’s sharp point exerting pressure on the cell’s exterior to make a nanoindentation. It is akin to probing an inflated balloon with the sharpened tip of a pencil. Too much pressure will result in a rupture.


Figure 1. This schematic shows an AFM tip interacting with a cell surface. The AFM tip, as it approaches the surface (a), first indents into the cell (b) and then retracts from it (c). The central inset shows a force-displacement curve (a-c correspond to the positions described above), which is recorded as the “approach” and “retract” curves of the cantilever as it moves toward and away from the surface. Mechanical properties such as cell stiffness can be calculated from force curves using a hertz model. Images courtesy of Sarah E. Cross and James K. Gimzewski.

The researchers analyzed fluid samples taken from cavities surrounding the lungs, chest and abdomen of patients with suspected metastatic cancer. The samples contained both cancerous and noncancerous cells, which served as a built-in control.

Experiments were conducted with a Veeco Digital Instruments AFM coupled with a Nikon inverted optical microscope. This setup allowed the researchers to position the probe, located at the end of a cantilever, over the nuclear region of a cell with micrometer precision. The motion of the AFM cantilever is measured by monitoring the reflection of a laser spot off the top of the cantilever via a position-sensitive detector as the tip is brought into contact with the cell membrane with nanonewton force. The tip had a radius of <20 nm (Figure 2).

Figure 2. An AFM tip probed a cell’s exterior to gauge its flexibility.

Force-displacement curves were recorded at 1 Hz. To avoid damaging the cell surface and to limit any possible effects from the substrate, the researchers made only shallow indentations in the cell, <400 nm deep.

They determined that cancerous cells have an average stiffness of 0.56 ±0.09 kPa. The average stiffness for cancer-free cells, by comparison, is 2.10 ±0.79 kPa. The cancerous cells were ~73 ±11 percent less stiff than benign cells in the same sample and also when compared with samples collected from other patients. Various cancer types also were found to exhibit a common stiffness.

The researchers said that, when the nanoprobe method is used in conjunction with other techniques, it could help to improve the diagnosis of cancerous cells in bodily fluids. The team’s plans are to extend the technique to cancerous tissue. Gimzewski said that he wants to refine the procedure so that eventually it can be used for cancer detection in clinical settings.

Nature Nanotechnology, December 2007, pp. 780-783.

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