By Deborah Borfitz
August 24, 2021 | Thanks to photoacoustics, a blend of modern-day ultrasound machines and lasers, physicians in the next decade could be using a routine imaging test to “hear” the sound signal of a future heart attack. As envisioned, photoacoustic imaging would likely serve as a complement to intravascular ultrasound (IVUS) or standard ultrasound by reporting on the whereabouts and inflammatory status of atherosclerotic plaque, according to Bryan Smith, associate professor in Michigan State University’s College of Engineering.
Traditional, less specific diagnostic imaging using CT or MRI could be deployed as a screening tool, funneling at-risk individuals to follow-up photoacoustic imaging scans focused on immune cells in the plaque—specifically, monocytes and macrophages—critical to the pathogenesis of plaques that lead to acute myocardial infarction, Smith says. Those particular cells can be targeted with nanoparticles, developed by an MSU-led research team, which would serve as a contrast agent.
With plaque-seeking nanoparticles in the mix, the same instrument used to do IVUS can be used for photoacoustic imaging with the addition of a laser, says Smith, yielding a multipurpose multimodality imaging device.
The technique, detailed in a research article recently published by Advanced Functional Materials (DOI: 10.1002/adfm.202101005), is premised on the idea that not all plaques are created equal. Current medical understanding is that heart attacks are driven by inflammatory plaque that is prone to rupture, while angina is associated with another (not necessarily mutually exclusive) type that thickens over time to constrict a major artery, Smith explains.
Monocytes and macrophages are useful in identifying threats (e.g., a splinter), and work as needed to clear an initial pathogen invasion and prompt a response from the body’s adaptive immune system. However, they are also the “most responsible” cells for making inflammatory plaque susceptible to rupturing and blocking blood vessels, he continues. “In this case, your body is responding to an intrinsic process that is… not completely understood but doesn’t go away and produces increasingly dangerous chronic inflammation.”
Scientists in multiple fields are looking to derail chronic inflammation, Smith notes. When it comes to heart disease, the interesting part is that the process is localized in plaque where macrophages and monocytes congregate.
The nanoparticles can be used to detect those immune cells via photoacoustic imaging. “Virtually no other cell types take up the nanoparticles,” he says.
When used diagnostically in mice, the nanoparticles absorbed the laser light researchers shone into the arteries only when inflammatory plaque was present. “As a product of the release of that energy, they can literally shout back at us in ways that we can detect and use to create 3D images,” says Smith. That is, the acoustic signal could be used to locate and visualize the plaque.
Long History
The idea behind coupling light and sound, the so-called photoacoustic effect, has been around for more than a century, Smith says. The credit goes to Alexander Graham Bell in the late 1800s as he was exploring different forms of communication. “He found that sound waves could be stimulated within solid materials when exposed to intermittent light.”
Creating clinically useful images from the discovery required ultrasonic transducers to detect the waves and lasers that could stimulate their induction in a highly controlled fashion, says Smith. With the invention of those technologies, together with computational reconstruction algorithms to model light-tissue interactions, the field of photoacoustics has been “really heating up over the last 15 to 20 years.”
It was only earlier this year that the U.S. Food and Drug Administration (FDA) approved a photoacoustic imaging machine developed by Seno Medical Instruments for detecting breast cancer. Researchers in Europe have also been using vascular photoacoustic technology in recent clinical trials, Smith notes. “I definitely think people are going to be hearing more and more about it and may see it in a doctor’s office near [them] in the coming years.”
Anything that absorbs light well could potentially serve as a contrast agent for photoacoustic imaging provided it also efficiently dissipates heat, he adds. The physical interaction of interest is the conversion of light energy into heat, which is why it is also possible to image vessels without any contrast agent whatsoever.
Hemoglobin is a particularly good absorber of light and responds to the interaction “by shouting back in ultrasonic waves, so we can detect that,” Smith says. The photoacoustic technique can even distinguish between oxygenated and deoxygenated hemoglobin to differentiate between arteries and veins.
As discussed in a 2014 paper in Nature Nanotechnology (DOI: 10.1038/nnano.2014.62), the novel nanoparticles targeting immune cells are “exquisitely selective” for inflammatory monocytes, says Smith. “That means that 99% of monocytes in the blood take up these particles and less than 3% of any other cell type takes them up.” On top of their natural affinity, the physical chemistry of the particles was nanoengineered to promote their specific uptake by both monocytes and macrophages, he adds.
Design Principles
Collaborating researchers hail from Stanford and Emory universities. Smith is the director of the Translational NanoImmunoEngineering Lab located at MSU’s Institute for Quantitative Health Science and Engineering (IQ). He is also the director of BioDesignIQ, a new program at MSU based around the Biodesign paradigm popularized at Stanford where he was formerly an instructor.
MSU’s BioDesignIQ program “trains students to delve deeply into and characterize the clinical need before they ever start prototyping on a project,” says Smith. “It essentially turns typical innovation on its head.”
One project originating in a BioDesignIQ class MSU is already spinning out into an independent entity, says Smith. At Stanford, the BioDesign process over the past two decades has helped launch over 50 startup companies impacting over 3 million patients.
To get the new imaging from mice to market will require a “careful, robust process to ensure the nanoparticles are efficacious and non-toxic in multiple animal models,” he continues, a process that could easily take eight years given the relative novelty of the underlying technology. “We’re pretty satisfied that it works in mice and have also done extensive toxicological studies in mice to ensure [the nanoparticles] aren’t toxic… and we now have a joint grant to study the nanoparticles in pigs” whose cardiovascular system in many ways resembles that of humans.
In another paper published in Nature Nanotechnology (DOI: 10.1038/s41565-019-0619-3) last year, the research team reported on a treatment using the same nanoparticles to reduce plaque burden in mice. Additional studies focused on diagnosing those plaques are planned, says Smith.
The researchers are now in the process of making nanoparticles and injecting them into pigs, he adds, and will also look at immunotoxicology and toxicological processes of the tiny tubules in various animal models. The efficacy and safety data will be used in discussions with the FDA as the technology moves closer to first-in-human trials.
Patent applications on the technology are all owned by Stanford, where Smith initiated work on the project.
Physician training should be straightforward, Smith notes. For anyone who already knows how to read an ultrasound scan, learning to read and analyze photoacoustic scans may only take about an hour or two.
By the time the nanoparticle-aided technique hits the clinic, photoacoustic instruments will likely already be commonplace, he adds, in and outside of traditional healthcare settings. At Stanford University, where Smith did his postdoctoral training and began his independent career, one group for instance recently submitted a patent application for a photoacoustic bra designed to provide ongoing breast cancer surveillance.