'Shock' Engineers for Better Medical Treatment

Pei ZhongPei Zhong’s tireless efforts to technologically fine-tune the shock wave therapy used to pulverize kidney stones are not only leading to better treatment for that painful condition but also opening up surprising new avenues for medical advances, such as by manipulating genes and unleashing genetic assaults against tumors.

These are all different applications of therapeutic ultrasound, an emerging field at the interface of engineering, biology and clinical medicine, said Zhong, who is an associate professor of mechanical engineering and material science and urologic surgery.

While ultrasound is well known and widely used in diagnostic imaging, its potential in therapeutic applications such as molecular and gene therapy and fighting cancer could be even more promising, he added.

"I'm just very excited to have the opportunity to work in these areas," said Zhong, who likes to "push the envelope" in separate laboratories at Pratt and the Duke Medical Center. "Hopefully, we will be able to generate results that can be directly translated into clinical treatment, benefit patient care and advance medical technology," he said.

For years, Zhong has collaborated with Glenn Preminger, a professor of urologic surgery at the Duke Medical Center, and Hadley Cocks, a professor of mechanical engineering and materials science at Pratt, on ways to improve the efficiency and safety of lithotripters, machines that use shock waves to demolish kidney stones. "The clinical criterion for success is to reduce the whole stone mass down to a collection of fine powders that can be excreted after the treatment," he said.

He continues to explore lingering uncertainties about how the treatment works and is also trying to understand why the latest version of lithotripters seem to under-perform the old one.

While more cumbersome, the first generation lithotripters "are still considered the gold standard of performance," Zhong said. "They work extremely well in breaking up stones and the recurrence rate of new stones is very low. But the device is bulky -- a huge bathtub filled with warm de-gassed water that patients have to lie inside."

The older apparatus uses a sparking electrical discharge to create a shock wave that travels through the water and is focused on the patient's kidneys. In the new version, an alternative loudspeaker-like shock wave source is embedded in a water-filled cushion. That cushion's surface is held next to the patient's skin so that the shock wave energy can pass inside through a contact gel.

The newer form "is much more user-friendly, but it definitely comes with its own problems," said Zhong, who has examples of both the old and new versions in his labs.

Some of Zhong's earlier experiments using high speed photography revealed that the shock wave's pressure creates tiny bubbles in the fluid, a process called acoustic cavitation. The collapse of those bubbles generates a secondary shock wave which is "an important mechanism for stone fragmentation," he said.

"We don't completely understand the interplay between various mechanisms in stone comminution (pulverization) yet," he said. What they do understand, so far, is that collapsing cavitation bubbles produce "microjets" of fluid that smash into the surfaces of kidney stones.

But recent research shows that bubbles generated by the newer devices are smaller, and may thus collapse less effectively, he said. To compensate, the new device operates at higher energy levels. But that energy boost itself "can cause problems too, because it increases the risk for tissue injury," Zhong added.

In a research collaboration with Siemens, a leading lithotripter manufacturer, he and co-researchers are now evaluating possible ways to overcome the newer technology's deficits by modifying the shapes of the initial shock waves, and by changing the timing, sequence and energy levels for delivering those shocks.

For instance, tests in animals have shown that shock wave treatments can reduce blood flow to the kidneys. And that seems to help shield the organs from damage. So pretreating the kidneys by starting out with lower energy shocks can condition them for higher energy shocks later.

To improve the reduction of stones to powder, Zhong and co-researchers have been investigating a new “microsecond tandem pulse” technology that can boost the collapse of cavitation bubbles near the stone surface through shock wave and bubble interactions.

In studies published in the July 15, 2005 issue of Physical Review Letters and the October, 2006 issue of Physical Review E, Zhong and co-researchers described a unique experimental system in which a single bubble can be generated by an infrared laser. That bubble then interacts with a shock wave produced by a piezoelectric device. They have found that this shock wave-bubble interaction, at the optimal phase of bubble oscillation and size, produces more powerful microjets.

"The laser provides two advantages over lithotripter generated bubbles," Zhong said. "With it I can very precisely create a bubble of desirable size at the location I want." These fine-tuning approaches could lead to improved lithotripsy procedures, he said.

The collapse of finer bubbles might also be able to push large molecules and genes into living cells in a pinpoint way, like a microscopic version of a syringe.

"For example, doctors could have drugs circulating in the bloodstream," he said. "They could then focus the shock waves to a specific region of the body and microinject the drugs into a targeted tissue there."

Zhong and his research team are also evaluating a different kind of shock treatment based on high intensity focused ultrasound (HIFU) that could cook and kill cancer cells.

HIFU holds great promise as a noninvasive treatment for a variety of solid tumors, Zhong and colleagues from Pratt and the medical center wrote in the September, 2005 issue of the journal Biochemical and Biophysical Research Communications.

Already in use in Europe and Asia and currently being evaluated by the U.S. Food and Drug Administration, HIFU focuses high frequency ultrasound waves through the skin to heat up and destroy tumor tissues.

“You can increase the temperature of such tissue almost instantaneously to above 65 degrees Celsius (149 Fahrenheit), enough to denature its protein and coagulate it,” Zhong said. “Doctors can create damage sites the size of rice grains, moving line by line and layer by layer to summarily vaporize the primary tumor.”

But after these primary tumors are obliterated, in many cases a few stray cancer cells will inevitably survive and spread to other body regions through the process called metastasis. “The primary failure of HIFU and other cancer therapy methods is their inability to treat metastatic cancer cells,” he said.

So Zhong’s group has been collaborating with Timothy Clay and H. Kim Lyerly at Duke’s Comprehensive Cancer Center on advanced strategies that might be called “HIFU-plus.”

“We thought that, rather than simply evaporating tumor cells, we might be able to also ‘prime’ the tumor with an ultrasound beam to enhance the body’s own anti-tumor response and affect metastatic cancer cells as well,” he said.

His cancer center colleagues are using a technique that removes, cultures and processes cancer cells from patients and then re-injects them into the body, alerting the immune system to launches a stronger counterattack on the cells.

“But this process is very time consuming and very expensive,” Zhong said. “So we thought if we could do everything inside the patient with HIFU that would be a significant advantage over current therapy.”

The method proposed in the Biochemical and Biophysical Research Communications report draws on the “danger model” theory developed by National Institutes of Health scientist Polly Matzinger.

According to that theory, distressed or injured cells send out danger signals that in turn can activate components of the immune system -- called antigen-presenting cells (APCs) -- to initiate an immune response.

Working with cell cultures, Zhong's group evaluated different forms of HIFU-treatment that can either vibrate cancer cells apart or evaporate them with pinpoint heat. They found that damaging the cells by either method activates APCs, but that the vibration method was much more potent for APC activation.

"We have done some animal experiments that have essentially confirmed our observations in cell cultures," Zhong added. "We are also exploring adding other immunotherapeutic agents to boost the anti-tumor immune response."

"So we have really expanded significantly from our initial research in lithotripsy," he said. "We are looking at innovative ways that can improve the potential for all these approaches to achieve maximum therapeutic gain with minimal damage to surrounding healthy tissues."