Key Takeaways

• Histotripsy is a non-invasive focused ultrasound technology that mechanically destroys targeted tissue. Unlike HIFU, which uses heat, histotripsy uses high-amplitude ultrasound pulses to generate cavitation and liquefy tissue, which is then naturally absorbed by the body.
• HistoSonics is building a new treatment category rather than simply competing with one existing procedure.
• The path was not linear. The company pivoted from an unsuccessful BPH program to liver tumors and had to overcome skepticism around regulatory feasibility, adoption, and market size.
• Commercial use has surfaced applications that were difficult to anticipate during development, including palliation and repeat treatment.
• Hannes Holste sees HistoSonics as a broader medtech lesson: breakthrough companies may require investors to look beyond conventional market models and milestone-driven thinking.

At LSI USA ’26, Hannes Holste, Director, Life Science Investments & Data Science at Thiel Capital, joined Michael Blue, Chairman and CEO of HistoSonics, for a keynote to discuss the origins of histotripsy, the skepticism surrounding the technology, and what its trajectory could teach the medtech industry about building new categories.

From Discovery to a New Category

Histotripsy originated at the University of Michigan, where ultrasound researchers were looking for a way to non-invasively create a small opening in the cardiac septum. Because thermal energy was unsuitable, they began experimenting with extremely high-amplitude, short-duration ultrasound pulses that could mechanically destroy targeted tissue.

“They ultimately created the way to liquefy targeted tissue and then coined the phrase in 2002, histotripsy,” Blue said. “We’re mechanically destroying and ultimately creating a liquefaction that then gets naturally absorbed by the body.”

The technology was explored across applications ranging from blood clots and tumors to gallbladder stones, but its commercial path was far from straightforward.

HistoSonics initially focused on benign prostatic hyperplasia (BPH), conducting a 28-patient U.S. IDE study that failed to meet its primary endpoint. When Blue joined in 2017, the company faced a fatigued investor syndicate and growing skepticism over whether histotripsy could be delivered safely and effectively in the body.

The company pivoted to tumors in the abdomen and ultimately chose the liver.

Rather than defining HistoSonics by the liver procedures it could replace, including surgery, microwave ablation, or transarterial delivery of chemotherapy or Yttrium-90 radiation therapy, Blue saw the company as creating something broader.

“We’re developing a new category we don’t quite yet know,” Blue said. “We think that we can be used in early-stage patients and replace everything that was just mentioned, including, at some point, when we have enough clinical evidence, surgery. I don’t know why you wouldn’t want to replace surgery, especially if you’re a patient and start with something that’s non-invasive, non-toxic, and without any side effects.”

Building a Market for Histotripsy

That uncertainty became part of Holste’s investment thesis.

In medtech, markets are often modeled from patient incidence, procedure volume, and price. Holste argued that this can also limit how investors think about technologies capable of creating markets larger than existing categories suggest.

“If you’re thinking about building potentially a generational company, where in life science do markets turn out to be far larger than this modeling assumed?” Holste asked. “I think the clues to that sometimes lay within qualitative, non-obvious insights.”

For HistoSonics, some of those insights emerged only after commercialization.

Blue highlighted patients with large tumors, multiple tumors, and tumors near critical anatomy, including those treated for palliation. Those cases challenged the idea that the technology should be evaluated only by how much of an existing procedural market it could replace.

“I said to our company many, many times, if all we ever did was palliation, sign me up for that,” Blue said.

The company also changed how it presented itself to investors. Rather than framing HistoSonics solely around an unfamiliar therapeutic modality, Blue began describing it as a non-invasive surgical robotics company.

“We were going to complete the evolution of surgery from open to laparoscopic to minimally invasive robotic to single port to completely non-invasive robotics,” Blue said. “We did that through the foundation of our company, which is histotripsy.”

Evidence, Adoption, and the Bigger Medtech Lesson

Regulatory clearance solved one challenge, but not the broader question of clinical evidence.

Blue acknowledged that medical oncologists are accustomed to extensive long-term data, while HistoSonics reached the market through a Class II De Novo pathway and a more focused safety and effectiveness study.

The company is now investing in the evidence needed to support broader adoption.

“We are committed,” Blue said. “We’ve got an incredible group of investors who are very committed and convicted to building the clinical evidence we need to create a paradigm-changing new category in healthcare.”

Holste sees a larger lesson in that journey. More data can be important, but entrepreneurs should not assume another clinical study will automatically solve funding, adoption, or commercialization.

“We’ve forgotten as an industry as well that we’re in the business of building businesses, not crafting assets to be packaged up and to be sold for a predictable multiple,” Holste said.

HistoSonics still has significant clinical evidence to generate and new applications to validate. But its evolution from an experimental ultrasound technology into a commercial platform shows what can happen when a company refuses to define its opportunity solely by the market that already exists. If histotripsy continues to expand across indications, its impact may ultimately be measured less by what it replaces and more by the category it creates.