slash and burn

The December 2007 issue of Physics Today is out, and among other interesting articles, it contains one by yours truly describing emerging medical applications for cold plasmas. I stumbled on the topic quite by accident while browsing abstracts for the APS-sponsored 2007 Gaseous Electronics Conference back in October, and it turned out to be a pretty rich subject. Sure, I have a soft spot for plasma science in general (along with materials science, acoustics, and the occasional quirky little fringe item). Plasmas, cold or otherwise, are so versatile, they're used in all manner of practical real-world applications. But it turns out that perhaps we've only scratched the surface thus far. According to the folks I interviewed for the article, with a bit more development work, cold plasmas could be used to kill bacteria,remove dental plaque, loosen the connections between cells that make up biological tissue, help coagulate blood and reduce bleeding following a wound, or during surgery, and perhaps even remove cancerous tumors.

The term "cold" is a bit misleading, like scientific terminology tends to be. (Eg, "high-temperature superconductivity" takes place at temperatures common to liquid nitrogen.) They're cold compared to, say, the sun, but many so-called cold plasmas are still pretty hot: on the order of 70 to 100 degrees Celsius. Apply that to living human tissue, and it's gonna burn. Badly. Still, they're useful for things like sterilizing drinking water and decontaminating industrial surfaces. That's because they kill ("inactivate") bacteria by destroying the bacterial cell membrane via a lethal combination of charged particles, free radicals and UV radiation. They work fast, too: the Air Force has an active cold plasma research program, using them to break down the chemicals found in toxins like anthrax in mere minutes, compared to several hours for other methods.

Sometime in the late 1990s, researchers figured out how to create truly room-temperature cold plasmas in the laboratory, so for the first time, they could be tested on biological tissue. Needless to say, those decontamination properties are incredibly useful in helping accelerate wound healing. Wound healing has roughly three stages, although they tend to overlap here and there. There's an inflammatory stage, where everything is red and/or swollen and painful, in which it might seem like little healing is actually taking place -- in fact, it's easy to confuse with actual infection. But in fact, there's all kinds of things going on to prompt the body into the second stage: producing collagen to strengthen the wound. This can take several weeks, depending on the severity of the injury, and thick scars can develop. The final stage is called the remodeling phase, in which the body gets rid of the excess scar tissue. Sometimes a heavy raised (keloid) scar still remains, if the wound was especially deep and nasty.

Being able to kill bacteria reduces the chance of infection, and being able to remove dead cells and replace them with healthy ones can significantly speed up this weeks-long process. Eva Stoffels-Adamowicz of Eindhoven University of Technology in the Netherlands is one of several researchers interested in exploiting the ability of cold plasmas to cause biological cells to temporarily detach from each other. She's developed a handy little device called a plasma needle -- basically a thin tungsten wire about 50 millimeters long, inside a gas-filled quartz tube -- that enables her to precisely remove or manipulate biological cells. She calls it "surgery without cutting." Just drive a voltage through the needle and voila! A small plasma spark is generated at the tip.

Then there's the helium-filled plasma pencil developed by Mounir Laroussi, currently director of Old Dominion University's Laser and Plasma Engineering Institute. (ODU also opened a brand-new Center for Bioelectrics in 2003, devoted to investigating how electromagnetic fields and ionizes gases interact with biological cells.) It's a little different from the EUT device, which generates small plasma sparks. Laroussi's tool creates a long plasma plume of 2 to 3 inches, which can kill bacteria on the delicate surface of human skin without damaging the surrounding tissue. Laroussi has used it on e coli bacteria. Other groups working with cold plasma "jet guns" have demonstrated the destruction of salmonella and even a few viruses. (One day, similar devices might be used in dentistry to remove plaque; it can't be any worse than the ultrasonic tool my dentist uses these days.)

Neither the plasma needle nor the plasma pencil are actually using a cold plasma to do actual cutting. But a company called Peak Surgical has a prototype device called the Plasma Blade that actually uses cold plasmas to cut biological tissue. Surgical scalpels have served us well for a very long time, but while they cut very precisely, they can't control bleeding. There are alternative electrosurgical devices that can do both, but there's usually some accompanying thermal damage to surrounding tissue. The Plasma Blade cuts, cauterizes, and doesn't burn surrounding tissue, plus you've got those built-in decontamination attributes to fight infection and reduce inflammation, thereby accelerating the healing process. Peak has tested their Plasma Blade on both retinal tissue and on pig skin.

Pretty nifty, right? We think cold plasmas are cool. But cold plasmas aren't the only physical mechanism under investigation as an alternative surgical tool: in fact, they're relative newcomers. Many researchers have spent the last decade or more looking into how sound -- particularly ultrasound -- can be used therapeutically in medicine. I wrote about this topic way back in 1998 for The Industrial Physicist magazine, and it continues to be an active and innovative field.  For instance, Zhen Xu and colleagues at the University of Michigan are interested in creating acoustical "mini-scalpels" for non-invasive surgery, using pulses of high-intensity ultrasound. Xu's team thinks it might be possible to use those pulses to make surgical incisions inside the body without ever opening up or puncturing the skin in any way.

Apparently it's possible to deliver enough power without heating to tissues deep within the body using a concave transducer that focuses the acoustical waves onto one small spot of intense energy. In the case of the acoustic mini-scalpels, the energy from the ultrasonic pulses cause microbubbles to form at the focal point, which expand and collapse, in the process fragmenting tissues. Xu thinks it's because the individual cell membranes can't withstand the pressure caused by the bubbles. The Michigan researchers, reporting at the recent Acoustical Society of America meeting in New Orleans (which we sadly missed this year) have managed to focus the acoustical beams into a bundle of tiny scalpels roughly the size of a singe cell, manipulating them with a computer mouse or joystick. It's not entirely clear to me how all that acoustical power can conveniently bypass the outer layers of skin, but sound has some pretty amazing physical properties, so it wouldn't surprise me. It's a nifty idea if they can ever get it to work in a practical clinical setting.

Combine that acoustical scalpel with a bit of therapeutic ultrasound, and you can reduce bleeding as well.  Essentially, the heat from the ultrasonic pulses "cook" the proteins in the blood, causing it to coagulate, or clot, much more quickly. This is especially useful when someone is bleeding in delicate internal organs, like the liver, spleen, or kidneys, where many tiny capillaries can burst all at once. More often than not, car accident victims perish from this uncontrollable bleeding, not from the more obvious injuries they sustain. There's lots of groups working in this area, but at the New Orleans meeting, the focus was on Vesna Zedric (George Washington University) and his University of Washington collaborator, Shahram Vaezy, who reported on their latest work. They tested a range of ultrasound frequencies and found they blood would coagulate faster at energies that produce microbubbles at the focal point.

Yes, we're back to microbubbles! (Bubbles are another longstanding fascination.) The same effect that helps control bleeding can also be used to aid in drug delivery. In this application, the ultrasound energies need to be lower to avoid thermal damage to the tissue (translation: big, nasty burns). Instead of heating the tissue, applying the ultrasonic pulse produces microbubbles pinpointed in the target area, and this gives rise to temporary holes in the cell membranes, allowing drugs placed there to diffuse more easily. Right now Zedric and Vaezy are conducting preclinical studies in the cornea, in hopes that the microbubbles produced will more efficiently deliver antibiotics and anti-inflammatory compounds to treat serious eye infections.

Not even cancer is safe from the power of sound. It's tough to remove brain tumors completely, for reasons scientists don't fully understand, although they suspect it might be that cancerous cells migrate too quickly for the timed-delivery chemotherapy drugs that are usually implanted in the affected area in wafer form after a tumor is removed. Ideally, it would be nice if the brain was a bit quicker on the uptake when it comes to absorbing those life-saving drugs. George Lewis Jr. of Cornell University, also at the ASA meeting, has been testing the effectiveness of acoustic pulses to do just that. It's ultrasound again -- a damned useful frequency range -- and Lewis found that focused ultrasound agitates the tissue matrices in such a way that they become more permeable to the chemotherapy drugs. (Can you say "microbubbles"?) So the drugs spread further and faster into the brain tissue.

Lewis likens the effect (and the brain) to a damp sponge. (Now there's some vivid imagery for you: SpongeBob reimagined as a pinkish, squishy brain, instead of a bright yellow cheese-like square wearing funny pants.) If you hold the sponge under a dripping faucet, it gradually absorbs more and more water until it becomes saturated. Typical sponge-like behavior. But, says, Lewis, "If you move the sponge and squeeze it in your hand while it is under the water faucet, the sponge would absorb more water and become saturated more quickly." He's not the only researcher working in this area, either. Sham Sokka of Phillips Medical Systems is developing an MRI-guided therapeutic ultrasound system designed to treat cancerous tumors, among other clinical applications. Again, it's the formation of microbubbles at the targeted area that is the key, enabling doctors to "remove" tumors without ever piercing the skin. And once again, it can also be used to generate just enough heat to speed effective drug delivery, rather than causing the cavitation that gives rise to microbubbles.

Even a relatively old use of ultrasound -- for imaging and diagnostics -- still has a few innovative tricks up its sleeve, according to Azra Alizad of Mayo Clinic College, who presented data at the ASA meeting on his novel non-invasive imaging technique called vibro-acoustography. Ultrasound is a very sensitive means of detecting thyroid nodules, but it's not very good at figuring out whether they are malignant or benign; a biopsy is usually required to do that. But biopsies can be painful, so ideally, it would be nice to have a way to figure out the difference without the need for biopsies. Enter vibro-acoustography. Alizad's method uses ultrasound to vibrate the tissue at low frequencies, then detects those vibrations with a sensitive microphone. Harder tissues have different acoustical signatures than softer ones, and since malignant lesions tend to be stiffer than their benign counterparts, this might turn out to be a useful method for telling the difference between the two. Right now Alizad is testing the technique for detection of breast cancer lesions.

I should probably note that almost none of these techniques are yet routinely used in clinical settings -- although the cold plasma jet guns are being used in European clinics, so we should be seeing them here in the US within five years or so, depending on how quickly regulatory approval proceeds. What works beautifully in the laboratory doesn't always easily transfer to the harsher, less predictable (and controllable) real-world clinical environment. But it's fun to hear about them, plus, it's just nice to know that there are people out there looking for new tools, even brand new paradigms, for medical treatments. Because human health is pretty darn important.

Comments

[Carol Oman]

The link to your article doesn't work. Here's the current one:

http://ptonline.aip.org/journals/doc/PHTOAD-ft/vol_60/iss_12/23_1.shtml

[bilard]

You have very interesting site.Thanks for all.

[D]

The high concentration of ultrasonic energy within - in this case - the human body or - more generally - any matter that does not exhibit such anisotropic characteristics as to propagate ultrasound in a non-linear direction is achieved by utilisation of a principle known in the industry as "phased array" and more commonly in medicine as ecography. Assume that you have a square rigid sheet of piezoelectric crystal of such a thickness that, when excited by a voltage spike, will vibrate at its resonant frequency - in this case within the frequency range known as ultrasound. Assume you now split this sheet into a grid arrangement, and you provide each single piezoelectric part with a separate electrical connection with means of creating an individual voltage spike per part, completely independent from the others.

If you apply an equal voltage spike to all parts together, each part will produce a theoretically equivalent wavefront that, summed to the others, will produce an overall ultrasonic wavefront approximately equal to that you would have obtained if you had not split the piezoelectric crystal in the first place. The smaller the parts you divide your crystal into, the more this equality is correct.

Now assume you want to concentrate a certain amount of energy at a specific point inside a body. As the piezoelectric crystal is normally not on the surface of a probe, but embedded inside some sort of casing and coupling plastic, your ultrasound will have to travel through two different media to get to that point: the coupling plastic and the body. For the purpose of this explanation, let's assume that the body is a fully homogeneus mass. Assume that each piezoelectric part into which you have divided your original crystal is small enough to be considered an ultrasonic point source, hence producing a wave travelling away from the crystal and expanding in a spherical manner. This wave will travel through the coupling plastic and refract into the body according to Snell's law, and reach the desired point within the body in a time T. This is valid for all your piezoelectric parts since, according to our assumption that the wavefront is spherical, the wavefront will always reach the point within the body sooner or later. The only difference between the various parts into which you have divided your crystal is the time T that it will take for that front to reach the desired point.

Once all the wave trajectories have been calculated according to Snell's law, you must find which part of the crystal exhibits the shortest path to the desired point (in terms of travelling time) and compute the paths of all the other parts (always in terms of travelling time) wrt that first one, in terms of a time difference or delay Delta T, which is specific to each different part of the crystal. It follows that, if the "closest" part of the crystal is excited first (by means of a voltage peak) and all the others are excited with a time delay wrt the first one which is equal to the specific DeltaT previously calculated, all the wavefronts produced by all the parts of the crystal will reach that desired point in space at the same time.

If the system that manages the voltage peaks is precise enough (generally speaking with a time precision which is equivalent to much less than a wavelength within the matter of the body) then all the wavefronts will combine at the desired point following the principle of constructive interference, and the total energy at that point will be roughly the energy of a single wavefront at that point multiplied by the number of wavefronts, or parts of the crystal.

The energy input into the system is not sufficient for a single wavefront to interact with the matter of the body in a destructive way, but becomes sufficient once the wavefronts of all the parts of the crystal are combined together by constructive interference. The same effect can in fact be achieved by using a single-piece piezoelectric crystal coupled with an ultrasonic lens shaped according to a Fermat's surface, however in this case the point where one wants to concentrate the energy is fixed in space and determined by the geometry of the crystal and the lens. Instead, in a phased array system you create a virtual Fermat's lens by applying time delays to the parts of the crystal and gain the ability to fully control the energy distribution and the position of the point in space exhibiting the highest energy distribution.

Phased array in a nutshell.

[gwen]

a friend of mine drinks a lot of tequila, she also has no plaque on her teeth and doesn't floss much at all - same with her husband. she had the idea that maybe the tequila is keeping her teeth free from plaque - any truth to this?