Man Makes PACT

Lihong Wang fell in love with light-based science during his high school years, when he saw a laser being used in a sci-fi movie. "I watched that laser and thought, ‘Wow, this is really powerful,'" recalls Wang. "There's nothing in nature that collimates so well, projects so far. I thought, ‘This has to be really useful.' Think about it: a man-made, purified light source that, even then, I assumed could be broadly used. I was fascinated by it." He decided then and there to study laser physics.

Wang, an SPIE Fellow, winner of the 2015 SPIE Britton Chance Biomedical Optical Award, former editor of the SPIE Journal of Biomedical Optics, and the Bren Professor of Medical Engineering and Electrical Engineering at Caltech's Andrew and Peggy Cherng Department of Medical Engineering, has pursued that fascination to groundbreaking ends: his team has developed a photoacoustic breast-imaging system fast enough to complete a scan of an entire breast within a single breath hold. It's an innovative, noninvasive, fast, painless, affordable system for screening breasts and other biological tissue, one that Wang has described as a "dream machine." The team's work was described in a paper published in Nature Communications earlier this year.

Wang's photoacoustic computed tomography (PACT) uses light, sound, and math to achieve high-resolution optical imaging in deep tissues on multiple levels: structural, functional, and molecular. This technique, notes Wang, could prove to be better than other current modalities in terms of efficiency, clarity, and safety. "In detecting the functional changes, sometimes you can do better than just looking at a structure," he says. "MRI and x-ray mammography can see structures; we can see functions as well. It's important to see the function because sometimes the structure alone is misleading. Our system offers fine spatial resolution as well."

Sound + Light

X-rays, ultrasound, and MRI don't detect molecules, whereas light does, but using light on its own results in poor spatial resolution and blurry images when the desired penetration is beyond one millimeter. Utilizing photoacoustics, Wang points out, addresses that issue. A physical phenomenon initially introduced by Alexander Graham Bell, photoacoustics was used for sensing molecules after the laser was invented; Wang's team, initially experimenting with a combination of microwave and ultrasound technologies, was the first to create functional photoacoustic images, as well as in vivo photoacoustic images.

"Bell was too far ahead of his time. We now have laser, state-of-the-art ultrasound detection techniques, computers, and the concept of tomography," says Wang. "So we're combining Bell's old physical concept with this set of modern technologies to create photoacoustic tomography. The idea is that ultrasound actually propagates in tissue in a well-behaved way. The analogy I use is that tissue to ultrasound is like water to light: when we see through a cup of water we have no trouble seeing any object in there-a spoon, a sugar cube-and ultrasound behaves very similarly in biological tissue. But if you use ultrasound alone, you're not going to see molecules, you're not going to see the color of blood, and you're not going to see smaller blood vessels. So we combine light and sound synergistically in a single modality. We fire a light pulse and the light spreads into tissue-actually the photons or light particles will dive into tissue-and when the light gets absorbed, it will generate minute transient heating and a photoacoustic wave: it will expand tissue and that will cause an acoustic wave emission. Those are ultrasound waves. We pick up the ultrasound signals outside the tissue, and, using math, we form an image. So now we're combining an optical contrast that is sensitive to molecules with ultrasonic resolution and at great depths-we're talking about multiple centimeters, up to four centimeters one way."

Faster, cheaper, and safer

Wang expects that PACT will be sensitive and affordable enough to be an improved option over current gold-standard digital mammography techniques, useful for screening as well as for other applications. While the physical system itself means an initial investment in capital equipment, ultimately the per-patient cost should be low. "This system will be cheaper than an MRI but more expensive than an x-ray mammography system. But our throughput is an order of magnitude higher than that of MRI. The MRI throughput is about 45 minutes per session; we can image a breast within as short as 15 seconds. So that's more than an order of magnitude faster."

In addition, MRI requires injecting a heavy-metal, gadolinium-based contrast agent in order to see smaller vessels. "We can resolve four times finer blood vessels without injecting any exogenous or extrinsic contrast agents," says Wang. "Gadolinium has side effects. People can be allergic to it; it can deposit into the brain. People with kidney failure face an increased risk of developing a rare but serious disease called nephrogenic systemic fibrosis with a gadolinium injection. So there are a number of issues that we can't really ignore. This technology offers an optional workaround to those challenges."

In addition to its optimal use for screening, PACT promises to be a viable option for diagnosis, as well as for the monitoring of certain therapies such as neoadjuvant chemotherapy. Other potential applications include human brain imaging. While this is a challenging project for adults because the skull is in the way, for new babies it is simpler because the fontanelle is open. "Fontanelles give a little window for light delivery and for ultrasound detection," notes Wang, "and the skull is softer so it's more friendly for ultrasound transmission." Then there's whole-body neonatal imaging: "For NICU, for example, instead of using an MRI machine where, because of the long imaging time, you have to sedate the babies in order to image them, we can potentially build a radiation-free bedside device that can be used to monitor sick neonates."

Yet another application target is addressing diabetes, which, alongside breast cancer, is a huge health problem. "With our technique," Wang explains, "we might be able to provide routine monitoring of blood vessels and proactively manage diabetic foot. A lot of people lose their feet because of poor management. So monitoring for diabetic patients is another option, as well as monitoring any therapies for those patients."

As to how soon his "dream machine" might become a mainstream option, Wang is cautiously optimistic. Investors have already licensed the IP and created two companies-of which Wang is a founder and shareholder-one in the US, one in China. The goal is for an initial system to be ready in the next few months, image a reasonably large group of patients in China, and get through the Chinese FDA system of approval. The hope, says Wang, is that within a few years PACT will be commercially available.

Meanwhile, he remains an annual mainstay at the SPIE Photonics West Symposium where he has co-chaired the Photons Plus Ultrasound Conference since 2004: "Before 2003, the Photonics West conference on photoacoustics was one of the smallest ones. It just grew exponentially after that. In 2010 that conference became the largest at Photonics West." Photonics West, he says, is a tradition for him, akin to Thanksgiving. "I never stopped attending," Wang laughs. "There's no other conference I've been to every year: everybody is there, you see the latest results, you interact with the top leaders of the field, and it's intellectually stimulating. Being privy to new results is exciting. And it's a platform for us as a team to show our best. It's just a great platform." Watch Wang's presentation on his single-breath-hold PACT system at Photonics West 2018: doi.org/10.1117/12.2290987

Mentoring the next generation

It was his post-doctoral adviser Steve Jacques, then at University of Texas MD Anderson Cancer Center, who introduced Wang to his first Photonics West conference in 1993. "I've been really fortunate to have been advised by a number of world-class scientists starting with my doctoral advisors at Rice University, Robert Curl, Richard Smalley, and Frank Tittle, who discovered the buckyball (C60)," says Wang. "I learned a lot about how to pursue first-rate research. After graduation, I decided to switch to something more applied. I'd used laser light for basic science in my doctoral research, but then I was using it for a very different purpose-for sensing and imaging biological tissue." Jacques proved to be the icing on the mentoring cake. "He's very much hands-off," Wang says. "He lets you have ideas and implement them. He supports you. He's also one of the most intuitive scientists I've ever met. While I learned a lot from my doctoral advisers, all that I learned with them was reinforced through working with Steve."

Wang points to Jacques' generosity as a colleague: "My first project in Steve's lab was to build a software package to simulate photon transfer in biological tissue and share it, for free, with the rest of the field." Jacques' invaluable tutelage in grant writing "turned out to be super beneficial. We all know how important it is to be able to support our own research. That training was critical to my independent career," notes the one-time mentee. "He prepares people well."

The student has now become the master. Wang has mentored more than 50 doctoral students and 70 post-doctorates. His Caltech Optical Imaging Laboratory is working on compressed ultrafast photography (the world's fastest camera), microwave-induced thermoacoustic tomography, time-reversal wavefront shaping, and ultrasound-modulated optical tomography in addition to PACT. And, at the site of his lab's annual reunion, many of his current and former lab members will be on hand at "Thanksgiving" to present at Photonics West in February 2019.