Histotripsy sets its sights on cancer

Not many researchers would consider bursting bubbles a successful day in the laboratory. 

But in Eli Vlaisavljevich’s Therapeutic Ultrasound and Noninvasive Therapies Laboratory at Virginia Tech, an innovative technology called histotripsy generates cavitation bubbles in tissue that, when popped, have the ability to destroy targeted tumors in what could soon be a game-changing therapy for a variety of cancers. The platform technology has proved to be a versatile tool and has even inspired the development of new ultrasound technologies for environmental conservation that allow for the efficient extraction of DNA from tough tissues like timber.

Histotripsy’s adaptability makes it a prime test case for collaborative research, and Vlaisavljevich’s effervescent personality has established him as a highly motivated colleague both within and outside of his academic home in the Department of Biomedical Engineering and Mechanics since he arrived in 2017.

He believes that histotripsy will fundamentally change the way we handle cancer therapy. In 25 to 30 years, he said with a wry but earnest smile, his researchers hope that surgery could even be considered medical malpractice.

“Noninvasive therapies and the ability to noninvasively remove tumors is hopefully where we see the future going,” he said.

A technology for the future

Histotripsy is a focused ultrasound technology that can be used to precisely and noninvasively ablate tissues, particularly cancerous tumors. Researchers at the University of Michigan invented the technology in the early 2000s, coining the term by combining the Greek roots “histo,” for soft tissue, and “tripsy,” for breakdown.

Most people are familiar with ultrasound in the context of imaging, which uses low-pressure pulses to receive echoes back to create an image. However, histotripsy uses very high-pressure sound waves emitted through a transducer. Its short pulses lower pressure in the targeted area and extract gas naturally found in tissues, thus generating cavitation bubbles. These bubbles expand and then collapse very rapidly, mechanically liquefying the diseased tissue.

The technology appeals to both the scientific and medical communities for several reasons: It’s noninvasive, nonthermal, safe, effective, and efficient, and it provides real-time image guidance. Normal cancer treatments such as chemotherapy aren’t suitable to treat tumors in some regions of the body because the tumor can't be targeted without damaging other tissues and inducing significant side effects. But histotripsy can predictably ablate incredibly small areas of tissue, which opens a large range of applications, said Coy Allen, an associate professor of inflammatory disease at the Virginia-Maryland College of Veterinary Medicine who frequently collaborates with Vlaisavlejevich. 

“He’s working on technologies that clinicians are already somewhat familiar with,” said Allen. “Being able to image the tumor, and then being able to treat the tumor without having any invasive surgeries, I felt was a very impressive technology.”

Histotripsy may also trigger the abscopal effect, a phenomenon in which localized tumor therapy stimulates the body’s immune system to attack nontargeted tumors.

“By engaging the immune system better, it really gives us hope that we can be looking at cures instead of just palliative care,” said Allen.

Focused and inspired

When histotripsy was in its infancy at the University of Michigan, Vlaisavljevich was studying biomedical engineering as an undergraduate at nearby Michigan Tech. He had chosen the field because it allowed him to explore a variety of research paths.

“I always say Da Vinci would be a biomedical engineer,” said Vlaisavljevich. “Because he’d see all these options – autopsies! engineering! – and want to do a bit of everything.”

But Vlaisavljevich narrowed his own focus when University of Michigan researcher Zhen Xu visited his classroom for a seminar on histotripsy. She had just completed the first-ever histotripsy treatment, successfully using the technology to bore a hole into cardiac tissue inside a water tank, he said. Upon seeing the impressive footage, Vlaisavljevich was hooked. He applied to the University of Michigan’s grad school and began working in Xu’s lab. His primary project was developing histotripsy for the treatment of liver cancer, but he was also working on side projects about basic physics studies and innovating new technologies for tissue-selective ablation approaches.

After earning his doctoral degree in biomedical engineering in 2015, he worked for two years in a joint position between the University of Michigan and HistoSonics, a private medical device company created by fellow Michigan researchers that had completed one initial human safety study for treating benign prostatic hyperplasia. But the company hadn’t done anything yet related to cancer.

Vlaisavljevich brought his expertise in liver cancer research to HistoSonics, as well as a personal connection to the disease. His mother, Theresa, died of liver cancer in 1990 when he was 4 years old.

“It was a motivation for me to work in cancer, and more particularly, to work on translational research, like medical devices that we can get into the clinic,” Vlaisavljevich said.

At HistoSonics, Vlaisavljevich created the first prototype histotripsy system for treating liver cancer, which the company continued to use after he arrived at Virginia Tech. In September, the company announced the promising results of its first clinical trial for liver cancer patients, which was conducted in 2018-19 in Barcelona, Spain. The trial brings the company one step closer to advancing histotripsy into a commercial device that can be used to treat liver tumors, possibly as early as 2023, Vlaisavljevich said. 

HistoSonics is now completing the #HopeforLiver Trial, a much larger clinical trial in the United States and Europe, which builds on the success of the 2018-19 THERESA study, named in honor of Vlaisavljevich’s mom.

Riding the waves of discovery

Vlaisavljevich and his veterinary school collaborators – including Allen, Shawna Klahn, Joanne Tuohy, John Rossmeisl, and Nick Dervisis – currently have grants exploring uterine fibroids, breast cancer, pancreatic cancer, soft tissue sarcoma, osteosarcoma, and brain cancer. But histotripsy’s versatility can be both an opportunity and a struggle. The research team recognizes that histotripsy’s features will not scale directly in every application without technological advancements.

“Every time we go into a new organ, it poses different challenges,” said Vlaisavljevich.

Pancreatic cancer and osteosarcoma each create unique obstacles for typical ultrasound image guidance. Therapy transducers have an ultrasound imaging probe in the center that allows surgeons and radiologists to see exactly where they’re treating. The liver is fairly easy to image, Vlaisavljevich said. However, the pancreas is obscured by bowels and intestines, often filled with gas. With osteosarcoma, or bone tumors, ultrasound doesn’t propagate through bone. Vlaisavljevich hopes to find synergistic approaches to solve these problems.

Because air and ultrasound also don’t mix well, lung cancer has been another hard nut – one that Vlaisavljevich hopes to eventually crack. German researcher Frank Wolfram and others have developed a lung-filling technique that has Vlaisavljevich excited, but his research team still needs to find the bandwidth for such a complex undertaking.

These big-picture clinical challenges can give a sense of purpose to laboratory problem-solvers. Vlaisavljevich said his team prioritizes the urgent need for improved therapies to treat cancers.

“We constantly have this clinical goal in mind guiding our projects. How do we develop technologies to treat cancer safer, less invasively, and more effectively?” Vlaisavljevich said.

But these noble goals often have messy, indefinite timelines. Much more tangible are the incremental platform advancements that the researchers see every day in the lab. Sometimes a day’s work is motivated by better understanding the basic physics of a technology, characterizing a transducer, or setting a pulsing regime. Researchers on a project may bounce between clinical and technological goals, or even find that one feeds the other.

“When you have a scientific breakthrough, all of a sudden, the amount of tools in our toolbox changes, and an application we couldn’t go after previously, we now have the tools to do that,” Vlaisavljevich said.

Following the research

Vlaisavljevich’s lab has grown significantly in the past couple of years, adding an array of doctoral, master’s, medical school, and undergraduate students, but graduate student Jessica Gannon said Vlaisavljevich still takes time to make each researcher feel like a valued member of the team. Rather than fear or disappointment driving their discoveries, it’s enthusiasm.

“There’s something about his excitement that’s contagious,” said Gannon. “He’s somebody that you want to match the energy of so it creates such a positive environment for everyone.”

Vlaisavljevich cultivates a relaxed environment and encourages students in his laboratory to organically explore their interests. When students follow the research, he said, their natural dispositions come to the forefront, thus opening themselves to the wonders of pure scientific curiosity.

“Sometimes the research selects you as much as you’re selecting the direction of the research,” Vlaisavljevich said.

Gannon joined Vlaisavljevich’s lab in 2019 as a sophomore majoring in mechanical engineering after receiving the Clare Boothe Luce Fellowship. At the time, their paths seemed destined to merge. Gannon was mourning the recent death of her father from pancreatic cancer. Vlaisavljevich and Allen were looking to develop histotripsy for the treatment of that same disease.

Though Gannon’s personal experience with cancer did infuse her research with purpose, she has welcomed the freedom to explore. She has appreciated that Vlaisavljevich – who called her a “true engineer” – has always supported her pursuit of other research projects, such as fundamental physics and device development. In her daily work with histotripsy, she has developed a fascination with the technology itself.

“I honestly fell in love with the fact that you can monitor the treatment in real-time with regular ultrasound. You can actually see the bubble cloud ablating,” Gannon said. “It’s so beautiful and elegant even though it’s causing so much destruction to a tumor.”

Vlaisavljevich’s lab recruitment efforts have benefited from interdisciplinary programs such as the Translational Biology, Medicine, and Health graduate program and the Virginia Tech – Wake Forest University School of Biomedical Engineering and Sciences. Collaboration across the university and beyond campus has proved vital to histotripsy’s fast-paced development. 

“I really view us in some sense as stewards of the technology, and not that we have any ownership over it,” said Vlaisavljevich. “In order to get a technology like this into the clinic properly, and fully study it from all directions, you really need teams of experts across colleges and across divisions.”

Built for success 

When Vlaisavljevich arrived at Virginia Tech five years ago, he found an interdisciplinary environment tailor-made for his brand of research.

Rafael Davalos, a professor of biomedical engineering and mechanics in the College of Engineering, had already established key collaborators around the university for tumor ablation research, which helped Vlaisavljevich immediately see a clear pathway for his own work. Because the two researchers work on different technologies, they don’t often have direct collaboration, but Davalos helped establish the infrastructure that makes Vlaisavljevich’s work possible.

Virginia Tech’s institutional framework has also been a boon to histotripsy research. Having access to the Virginia-Maryland College of Veterinary Medicine allows the research team to conduct veterinary clinical trials, essential for translational technologies that aren’t yet ready for human application. The university’s unique setup enables teams to seamlessly move projects “from bench to kennel to bedside,” said Allen.

“It’s a translational pipeline that a lot of universities just don’t have,” he said. “We can take ideas that engineers come up with and then, working with people like Eli, turn those ideas into functional products, test those products in the lab, and then implement them in human and veterinary patients. There is often a direct translation from veterinary patients to human clinical subjects and trials.”

Histotripsy projects at the university have received funding support through Destination Areas, the Carilion Research Accelerator Program, and the Center for Engineered Health at the Institute for Critical Technology and Applied Science. Pilot grants give researchers a chance to propose smaller studies, gather preliminary data, and then grow them into bigger projects, which is particularly helpful when considering histotripsy’s ever-emerging applications.

The research lab has also maintained a close working relationship with HistoSonics. Vlaisavljevich remains a consultant and research partner for the company as they continue their translation efforts. HistoSonics has supported studies in Virginia Tech labs through technical support and clinical prototype systems for large animal studies, both in pancreatic research and veterinary clinical trials.

Virginia Tech benefits from a proximity to Charlottesville, home of the Focused Ultrasound Foundation, a vital supporter of Vlaisavljevich’s research, he said. Rather than lobbying on a disease platform, the nonprofit, which was created in 2006, raises money for “accelerating the development and adoption of focused ultrasound” in multiple applications, according to its website.

Can histotripsy work on trees?

Because histotripsy has shown such promise in cancer research, that application dominates most headlines, but Vlaisavljevich is always looking for new paths to highlight the technology.

“I’ve joked with a lot of people that our lab should be called the unfocused focused ultrasound lab,” said Vlaisavljevich.

Nonetheless, his openness to following the research has helped jumpstart another promising line of study: environmental conservation. 

Timber is the most illegal trafficked wildlife commodity, said Hal Holmes, chief engineer at Conservation X Labs in Washington, D.C. Although DNA testing could help identify illegally harvested timber, the wood has only a small amount of extractable DNA tightly encapsulated in dense tissue, said Holmes. Regular extraction techniques can be time-consuming and complex.

Holmes, who attended Michigan Tech with Vlaisavljevich, gave his former research partner a congratulatory phone call when he joined Virginia Tech’s faculty. As their talk moved to histotripsy, Holmes realized that the properties Vlaisavljevich was describing could also work for timber tissue. 

“When I asked him on that call if he had ever tried it on trees, I’m sure he thought I was setting him up for a punchline,” said Holmes.

But the colleagues decided the application showed promise. When Holmes came to Virginia Tech to work as a postdoc in Vlaisavljevich’s lab, the researchers discovered that histotripsy’s collapsing bubble clouds can rapidly break down tough tissues like timber into extremely small particles, making the entrapped DNA much more accessible to reagents that isolate and then extract the genetic material. Holmes envisions that their new Focused Ultrasound Extraction (FUSE) technology could be extended to other tough tissues, such as ivory or pangolin scales, and even speculates whether histotripsy could be used to break up plastics lodged in the stomachs of turtles or other marine animals.

In another application beneficial to wildlife, Vlaisavljevich hopes to initiate a research collaboration with wildlife ecologists in Tasmania studying devil facial tumor disease. Discovered in the 1990s, the highly contagious disease, thought to be spread via bites between Tasmanian devils, has ravaged the animal’s population. 

Helping histotripsy make a global impact is high on Vlaisavljevich’s research wish list. He wants to share the technology’s benefits as widely as possible, particularly to low-resource countries that could benefit from noninvasive, cost-effective treatments. He is currently working with the TEAM Malawi initiative started by Andy Muelenaer, a professor of practice in the Department of Biomedical Engineering and Mechanics, to establish a focused ultrasound program in Malawi, which would serve as a flagship program for bringing focused ultrasound therapies to Malawi and other countries in Africa. 

Photos by Peter Means, video by Spencer Roberts