Seeing Sound: UCSD Researchers Study Biology in a Whole New Light

LZ250

Jesse V. Jokerst, Ph.D.
Assistant Professor, Department of NanoEngineering
Affiliate Faculty, Materials Science Program
Adjunct Faculty, Department of Radiology
University of California, San Diego

When most people think of ultrasound, their first thought might be monitoring a fetus in utero. However, ultrasound has many applications in medicine beyond obstetrics, including oncology, cardiology, and orthopedics. Ultrasound imaging is perhaps the most widespread imaging modality with a wide range of device sizes and applications. Ultrasound is a fast, accurate, and affordable method to diagnose disease and monitor a disease’s response to treatment: There are handheld scanners for remote clinics and research prototypes for advanced therapeutic monitoring applications.

One of the biggest limitations to even broader use of ultrasound is low contrast—it can be difficult to identify the specific cells, proteins, or anatomic structures of interest in the image. One tool to increase the contrast of specific features in an image is called photoacoustic imaging. The photoacoustic effect was first described by Alexander Graham Bell in 1880 but has only been used for medical imaging in the last 20 years.

The photoacoustic effect generates sound via light. Conventional ultrasound imaging is “sound in/sound out”: The contrast is generated by differences in the reflection of the incident acoustic pressure waves off structures in the body. Photoacoustic ultrasound is “light in/sound out.” When the target tissue absorbs light, there is a spatially confined thermal expansion and thus no bulk heating of the tissue. This rapid thermal expansion creates a pressure difference that can be detected acoustically. That is, the light causes the tissue itself to generate sound rather than bouncing sound off of the tissue.

Photoacoustics has several advantages over both purely optical and purely acoustic approaches. First, it can dramatically increase the contrast of the images. This is because differences in light absorption between tissue types are often larger than differences in acoustic impedance between tissue types. Second, it is easier to see multiple channels of data. Traditional ultrasound is largely monochromatic. Because photoacoustics can use different wavelengths to excite the tissue, it can generate ultrasound in different color channels and thus offer greater insight into biological processes. Third, photoacoustics has a much higher resolution than optical techniques for deep tissue imaging because acoustic waves are not scattered by tissue nearly as much as light. Finally, photoacoustics can image both endogenous and exogenous targets: hemoglobin, deoxyhemoglobin, and melanin are all excellent absorbers and can report tissue oxygenation. Alternatively, chemists can synthesize contrast agents that report a specific biological process via the photoacoustic signal.

There are various designs to photoacoustic imaging equipment. One of the more popular designs is the VisualSonics Vevo LAZR (Figure 1). This system combines photoacoustic capabilities with high frequency imaging. In both ultrasound and photoacoustics, the spatial resolution is a function of the frequency used for imaging: This resolution increases as the frequency increases but with a loss of penetration depth. Most hospitals and clinics use 5 -12 MHz. The Vevo LAZR system offers a range of transducers from 12 – 70 MHz to facilitate a range of custom applications in both ultrasound and photoacoustics.

Figure 1
Figure 1. VisualSonics Vevo LAZR. The system contains a traditional ultrasound console, tunable laser, and light tight box for small animal imaging.

 

A team at the University of California, San Diego (UCSD), led by Dr. David Hall installed a Vevo LAZR system in 2016 with support from the NIH’s Office of Research Infrastructure Program’s S10 mechanism. Although housed in Moores Cancer Center on the UCSD campus, this tool has been used for several other applications beyond cancer imaging.

Dr. Jesse Jokerst’s group at UCSD is using photoacoustic imaging for acoustics-based stem cell imaging. Stem cell therapy is a powerful tool to treat disease, but there are a number of questions that can arise when the cells are administered: How many cells are there? Where are the cells located? Are they alive or dead? Are they interacting with the diseased tissue? These are all questions that imaging is ideally suited to answer.

Magnetic resonance imaging is perhaps the gold-standard in this field, but it is very expensive and has a long temporal resolution (i.e., it is like taking a picture). In contrast, acoustic imaging is incredibly fast and is like making a movie. This fast temporal resolution is important because it allows real-time guidance of the cell implantation event to ensure that a sufficient number of cells are administered to the target tissue. Dr. Jokerst’s group has created nanoparticle contrast agents that allow physicians to image cells in real-time.1-3 This group also invented nanoparticle contrast agents with multimodality imaging capabilities or combined therapeutic and diagnostic tools into nanoparticles to improve stem cell viability.4 As part of this focus on nanoparticle-based contrast agents, ORIP also has recently supported next-generation nanoparticle tracking analysis (NTA) tools for UCSD via the S10 program (MANTA Viewsizer). The MANTA Viewsizer is a very accurate tool to measure the size, charge, and monodispersity of nanoparticle contrast agents—these are critical steps to clinical translation.

UCSD also has a very active research program in dental and periodontal photoacoustic imaging to characterize the gingiva and gingival disorders. The immediate goal is an improved approach to taking periodontal pocket depth measurements. This depth measurement is conventionally done with a metallic probe (Figure 2A), but this gives highly variable values; it is painful to the patient and time-consuming for the provider. Thus, Dr. Jokerst and colleagues developed an approach to measuring this non-invasively using photoacoustics (Figure 2B) in both swine models5 and human subjects.6

Figure 2
Figure 2. Dental Imaging. UCSD’s photoacoustic dental work is reinventing the pocket depth measurements currently done with a metallic probe (A). Sagittal section (B) and en face view (C) show that this technique generates a signal for plaque (blue) and maps the contours of the periodontal pocket (red; yellow line). Green dashed line: gingival margin. Greyscale data is ultrasound and color is photoacoustics.

 

A third diverse application is monitoring heparin anticoagulation therapy. Heparin is a common anticoagulant but is very difficult to manage—particularly in high-dose scenarios such as the operating suite or extracorporeal membrane oxygenation. Dr. Jokerst’s group is supported by an NIH New Innovator Award to build an intravenous catheter that will be used to deliver and monitor heparin7 (Figure 3). This device has a heparin-sensitive cladding that produces an increased photoacoustic signal in response to heparin. A prototype of this device was recently used to study a cohort of human samples with good correlation to gold standard monitoring methods that require invasive blood samples.8

Future efforts in this space will include imaging of the retina9 as well as tools to improve wound care.10 All projects harness the specific signal of photoacoustics to report a molecular phenotype, and these studies would be impossible without the support of the ORIP program.

Figure 3
Figure 3. Real-time monitoring of heparin with the drug-selective catheter.

 

References

1. Kim T, Lemaster JE, Chen F, Li J, Jokerst JV. Photoacoustic imaging of human mesenchymal stem cells labeled with Prussian blue-poly(l-lysine) nanocomplexes. ACS Nano. 2017;11(9):9022-9032.

2. Lemaster JE, Wang Z, Hariri A, Chen F, Hu Z, Huang Y, Barback CV, Cochran R, Gianneschi NC, Jokerst JV. Gadolinium doping enhances the photoacoustic signal of synthetic melanin nanoparticles: a dual modality contrast agent for stem cell imaging. Chemistry of Materials. 2018;31:251-259.

3. Chen F, Ma M, Wang J, Wang F, Chern S-X, Zhao ER, Jhunjhunwala A, Darmadi S, Chen H, Jokerst JV. Exosome-like silica nanoparticles: a novel ultrasound contrast agent for stem cell imaging. Nanoscale. 2017;9:402-411.

4. Lemaster JE, Chen F, Kim T, Hariri A, Jokerst JV. Development of a trimodal contrast agent for acoustic and magnetic particle imaging of stem cells. ACS Applied Nano Materials. 2018;1:1321-1331.

5. Lin CY, Chen F, Hariri A, Chen CJ, Wilder-Smith P, Takesh T, Jokerst JV. Photoacoustic imaging for noninvasive periodontal probing depth measurements. Journal of Dental Research. 2018;97:23-30.

6. Moore C, Bai Y, Hariri A, Sanchez JB, Lin C-Y, Koka S, Sedghizadeh P, Chen C, Jokerst JV. Photoacoustic imaging for monitoring periodontal health: A first human study. Photoacoustics. 2018;12:67-64.

7. Wang J, Chen F, Arconada-Alvarez SJ, Hartanto J, Yap L-P, Park R, Wang F, Vorobyova I, Dagliyan G, Conti PS. A nanoscale tool for photoacoustic-based measurements of clotting time and therapeutic drug monitoring of heparin. Nano Letters. 2016;16:6265-6271.

8. Jeevarathinam AS, Pai N, Huang K, Hariri A, Wang J, Bai Y, Wang L, Hancock T, Keys S, Penny W. A cellulose-based photoacoustic sensor to measure heparin concentration and activity in human blood samples. Biosensors and Bioelectronics. 2019;126:831-837.

9. Hariri A, Wang J, Kim Y, Jhunjhunwala A, Chao DL, Jokerst JV. In vivo photoacoustic imaging of chorioretinal oxygen gradients. Journal of Biomedical Optics. 2018;23:036005.

10. Kim T, Zhang Q, Li J, Zhang L, Jokerst JV. A gold/silver hybrid nanoparticle for treatment and photoacoustic imaging of bacterial infection. ACS Nano. 2018;12:5615-5625.