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Laser-activated bubbles mitigate toil and troubles

BioPhotonics
May 2006
Gary Boas

A number of biomedical applications take advantage of laser light interactions with tissue that are accompanied by absorption of light by tissue. As the absorbed energy converts into heat, it produces transient nonuniform thermal fields in cells, and this can be exploited for a variety of diagnostic and therapeutic purposes.

At the same time, laser light can create local vapor bubbles in single cells in the areas of absorption. Although these bubbles can damage the cells in which they appear, they also offer a highly visible nonfluorescent target for optical monitoring. They could be particularly helpful in cytometry and cell-level therapy, said Dmitri O. Lapotko, head of the Laser Cytotechnology Lab at the Lykov Heat and Mass Transfer Institute in Minsk, Belarus. However, this and other applications of the bubbles have yet to be fully realized.

Lapotko cited several reasons for this. First, there are no widely available instruments for analysis of such short-lived thermal events in single cells and at nanometer and micron levels. Also, the extent to which basic properties of laser-activated bubbles — including size, lifetime generation probability and threshold — are dependent on cell properties is not well understood. For this reason, he and colleagues recently explored and characterized these events. This ultimately led them to propose new biomedical applications for the bubbles as cell-level photothermal phenomena.


Researchers have developed a photothermal microscope that takes advantage of vapor bubbles created by laser light in the area of light absorption. This could help advance optical monitoring by allowing nonfluorescent imaging at the cellular level.


A laser photothermal microscope that the researchers developed at the institute uses nanosecond pulses of visible laser light to excite thermal phenomena and induce bubbles in individual living cells. Two collinear probe laser beams register the phenomena as a time-resolved photothermal image and as an integrated photothermal response.

Lotis TII, also of Minsk, developed the device’s pulsed triple-laser system, based on a solid-state Nd:YAG laser. A standard optical microscope images the bubbles and measures their generation probability and threshold at a specific wavelength and fluence.

Bubble generation

The experiments showed that the size and lifetime of the laser-activated bubbles ranged from 0.44 to 100 μm and 0.02 to 10 ms, respectively. The bubbles can be generated in vivo or in vitro in living cells of any type. The probability and threshold depended on the physiological state of the cells.

Application of the nano- and microbubbles requires control of these and other parameters, however; for example, if investigators wanted to generate 3- to 10-μm bubbles in cells of type A but not in cells of type B. To address this, the researchers collaborated with Alexander Oraevsky of Fairway Medical Technologies Inc. in Houston, to develop exogenous nanostructures with clusters of light-absorbing gold nanoparticles, which attach to cell membranes using cell-specific antibodies and then concentrate into clusters.


The team controlled the bubbles’ parameters by using clusters of light-absorbing gold nanoparticles attached to cell membranes with cell-specific antibodies. Because the nanoparticles offer much higher absorption than natural components of cells, the scientists could target specific cells and use lower laser fluences, allowing a greater degree of control.


Light absorption is several orders of magnitude higher with gold nanoparticles than with any natural component of cells, Lapotko explained. Using the nanoclusters therefore allowed them to reduce the laser fluence to levels at which bubbles were generated only in cells to which they were attached, providing the necessary degree of control. At the same time, no bubbles emerged in the surrounding cells and tissues (those without nanoclusters), suggesting that the mechanism has single-cell precision and provides a safety level that matches clinical standards.

The technique could be used for a variety of biomedical applications. Lapotko describes two of these: laser-activated bubble cytometry and laser-activated nanothermolysis as cell elimination technology, or Lantcet. The former would allow studies of physiological processes in single, intact living cells, he said, as bubble generation probability and threshold characterize parameters and processes such as oxygenation in red blood cells, and apoptosis/necrosis and redox state in various cells. No fluorescence is needed, and a standard optical microscope or flow cytometer is sufficient for these measurements.

Lantcet could enable users to selectively target and destroy specific cells, such as tumor cells, without damaging the surrounding normal cells or tissue. With the laser-activated bubble technique, a single pulse would be enough to damage the cells. Thus, the method may be more efficacious (and safer) than photodynamic therapy, in which laser-induced chemical reactions in dyes destroy the cells, and photothermolysis, in which laser-induced heating destroys the cells.

Lapotko is developing a Lantcet-based technique specifically for cleaning bone marrow and blood transplants used for treatment of leukemia. To this end, he is collaborating with researchers from Fair-way Medical Technologies as well as from M.D. Anderson Cancer Center and Rice University, both also in Houston.

Finally, he noted that the bubbles may help to “see” nano objects that often cannot be seen with optical devices because of the diffraction limit. “We use a pulsed laser to generate the bubble around such nano objects,” he said. “This bubble expands to micrometer size and, thus, [the nano object] becomes visible.”

Lasers in Surgery and Medicine, March 2006, pp. 240-248.


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