By Juan Miguel Pedraza

The surgical blade has cut its way through ages of medical history, evolving, fortunately, from the barely modified wood saws and various crude chopping tools to exotic metal scalpels so small you've got to use them with a microscope. And, yes, even with all the high-tech laser gadgets that can cut a single cell from diseased retinal

Working across boundaries, Timothy Bigelow, assistant professor of electrical engineering, does a lot of his research in a lab within UND's School of Medicine and Health Sciences. 

"There is no more science in surgery than in butchering," proclaimed Edward Lord Thurlow - active in British politics at the time of the American Revolution - in an 1811 public debate about setting up the Royal College of Surgeons. That opinion echoes through malpractice lawsuits to this day. But a handful of scientists at UND are delving into a hot new technology that may put a happy end to that dismal assessment.

Electrical engineer Timothy Bigelow, biologists Diane Darland and Dane Crossley, and UND School of Medicine and Health Sciences surgical chief Robert Sticca, M.D., are among a handful of pioneers developing a new surgical technology that uses bubbles to thermally ablate, or “burn” away, diseased or injured tissue.

In essence, they’re using a tool that’s a distant cousin of the process for carbonating your typical soft drink. This technology, dubbed noninvasive cavitational ultrasound histotripsy, also could be used to deliver drugs directly to specific sites in the body and to remediate certain genetic deficiencies with precisely oriented gene therapy. Bigelow explains that this process is similar to surgery. However, where surgeons now slice away diseased areas, this bubble process removes the cancer without traumatizing surrounding tissue. This ultrasound technique points to better rates of patient recovery because there are no surgical openings to disinfect, no wounds to suture.

Bigelow, who completed his Ph.D. in acoustic physics in 2004 at the University of Illinois, Champaign-Urbana, says this is a keenly exciting area of inquiry, especially because it aims to enhance human health and because it crosses a lot of academic boundaries.

“The long-term goal of our ultrasound research here at UND is to develop the scientific basis for the development of surgical tools that will be dramatically more accurate and significantly safer,” said Bigelow, who is researching both the theoretical and computational underpinnings for this technology as well as the actual hardware that will deliver the therapy.

“That’s also what’s so interesting about this project,” he said. “I get to do both theory and application, and hopefully, we’ll end up with a technology that will actually be used by surgeons in the future.” But getting there, he adds, requires a lot of cross-disciplinary research.

The core of this ultrasound surgical technology is a lipid encapsulated microbubble on the order of a few microns in diameter, Bigelow explains. Focused ultrasound energy — sound waves at frequencies above 20 kHz, beyond the hearing limits of the human ear — can pass through several layers of skin, muscle, fat, and other soft tissues. Low-intensity ultrasound already is familiar to anyone who’s had a baby; it’s what health practitioners use to create real-time images of babies in the womb.

At higher intensities, Bigelow explains, surgically focused ultrasound energy heats targeted tissue enough to destroy it, sort of like how a magnifying glass can light up a piece of paper by focusing sunlight on it. That’s thermal ablation.

“Such microbubble-enhanced surgical techniques have been used successfully for human cardiac and blood flow imaging for years,” Bigelow said. But Bigelow, his research team, and Dr. Sticca are looking to take that to the next level, specifically on noninvasive cancer surgery. A parallel research effort is looking at how to develop this technology as a way to deliver surgical intervention on babies, both before and right after birth.

“We’re building on research that’s already demonstrated that ultrasound contrast agents have shown great potential in animal experiments for enhancing drug delivery to cells, performing gene therapy, and enhancing heating and subsequent cell death when performing ultrasound thermal ablation —

basically, killing cancer cells with heat,” said Bigelow.

Thermal ablation, he points out, is one of several very promising outcomes: ultrasound “bubble” surgery potentially will eliminate cancerous tissue without collateral damage to other tissue. And, Bigelow emphasizes, here’s the big benefit: You can do all this cancer therapy without or with only minimal drug use. In other words, future patients with cancers that can be appropriately treated with ultrasound histotripsy and related technologies won’t have to endure the often nasty side effects of chemotherapy.

That’s among the big promises that lie behind this area of research. But, Bigelow cautions, there are many obstacles to clear before you’ll see this in your surgeon’s operating room.

Enter Dane Crossley, a UND developmental vertebrate physiologist and assistant professor of biology. Crossley, whogot his Ph.D. in biology from the University of North Texas in 1999 and also lectures at the UND School of Medicine and Health Sciences, is an expert microsurgeon whose skill set is vital to Bigelow’s research project.

“I focus on understanding developmental physiology in vertebrates,” said Crossley, who is able to tackle the singularly detailed and potentially nerve-wracking task of successfully doing surgery on the cardiovascular system of a bird embryo still in its egg. “I use a comparative approach, investigating several vertebrate groups including amphibians, reptiles, and birds.”

Ultimately, with the help of Crossley’s insight into developing fetuses, Bigelow figures on working out how to use microbubbles for surgical interventions on unborn babies, such as repairing vascular damage, doing brain surgery, or delivering gene therapy, all without damaging a single cell that shouldn’t be disturbed. The goal, of course, is to enhance baby’s development into a fit, healthy person.

To get there, Bigelow has to figure a way around a major challenge: in its current state of development, ultrasound surgery still has problems with collateral damage. So he has engaged Diane Darland and her team of student researchers to measure such tissue damage. Darland, a UND assistant professor of biology, spent several years as a post-doc researcher and instructor at the prestigious Schepens Eye Research Institute at Harvard Medical School.

Darland’s lab includes a MicroBrightfield, Inc. (MBF) stereology microscope system and workstation equipped with the Neurolucida™ and StereoInvestigator™ software analysis and data management modules required for the quantitative analyses of tissue damage. The precise quantification of tissue damage is essential to discovering ways to mitigate that damage, Bigelow notes.

Ultrasound surgery has undergone radical improvements since it was first discovered in 1926. It’s used routinely in a variety of applications, but it’s still relatively dangerous when you’re talking babies and fetuses, said Bigelow.

“So this ultrasound research we’re doing here at UND includes figuring out exactly what’s happening — what tissues are being damaged and why — before we can figure out what to modify or change” with the ultrasound surgery at the microlevel of fetal tissue, he said.

Bigelow’s work with cavitational ultrasound histotripsy earned him a prestigious $400,000, five-year National Science Foundation (NSF) CAREER grant. Bigelow’s NSF CAREER grant also includes funding to teach North Dakota and rural Minnesota high school math and science educators about the process of hands-on biomedical research and its ethical implications.

“This is really exciting research because of its potential surgical applications in curing cancer and other diseases,” said Bigelow.