Photoacoustic Imaging in Oncology: Translational Preclinical and Early Clinical Experience

Abstract

Photoacoustic imaging has evolved into a clinically translatable platform with the potential to complement existing imaging techniques for the management of cancer, including detection, characterization, prognosis, and treatment monitoring. In photoacoustic imaging, tissue is optically excited to produce ultrasonographic images that represent a spatial map of optical absorption of endogenous constituents such as hemoglobin, fat, melanin, and water or exogenous contrast agents such as dyes and nanoparticles. It can therefore provide functional and molecular information that allows noninvasive soft-tissue characterization. Photoacoustic imaging has matured over the years and is currently being translated into the clinic with various clinical studies underway. In this review, the current state of photoacoustic imaging is presented, including techniques and instrumentation, followed by a discussion of potential clinical applications of this technique for the detection and management of cancer. (©) RSNA, 2016.

Figure 1:

Top: Illustration of the photoacoustic effect. Pulsed laser irradiation is absorbed by either a contrast agent or endogenous tissue chromophore. Energy deposition is sufficiently fast to prevent diffusion and allow for a localized and rapid thermal expansion of the environment immediately surrounding the chromophore. With the cooling and contraction of the environment, high-frequency and broadband acoustic transients are released. These transients can be detected with a standard US transducer. Bottom left: Absorption spectra of endogenous chromophores in near-infrared region are shown including melanin (limited to skin) and oxygenated (HbO2) and deoxygenated hemoglobin (Hb) (the primary chromophores in tissue); water and lipid have significantly lower absorption coefficients in the near-infrared range. Bottom right: An example of a coregistered US and photoacoustic image showing a map of optical absorption primarily from hemoglobin in a mouse tumor. Brighter signals in photoacoustic image correspond to stronger optical absorption and are not correlated with the intensity of the anatomic image provided with B-mode US.

Figure 2:

Schematic of photoacoustic imaging instrumentation. When a tissue is exposed to pulsed near-infrared (NIR) laser, the pressure transients produced from tissue chromophores are collected by a US transducer scanned over the surface. An internal clock synchronizes the transducer acquisition time to laser firing. The pressure transients are converted by the transducer to time-dependent voltage signals (photoacoustic signals) and are fed into front-end acquisition module where the signals are channeled through a low-noise preamplifier (20–30 dB), followed by a variable gain amplifier (20–50 dB) to achieve a cumulative gain (40–80 dB). The amplified signals are filtered for high-frequency noise components and digitized by using analog-to-digital converters. These digitized signals are further handled by a back-end processing module, which performs a multitude of signal processing and image reconstruction tasks after which the images are appropriately stored and displayed.

Figure 3:

Commercially available preclinical photoacoustic imaging systems. A, Vevo LAZR (Fujifilm VisualSonics) uses handheld transducers for laser delivery and photoacoustic signal detection. B, Nexus 128 (Endra) uses an animal holder inserted in an aperture consisting of a rotating hemispherical transducer with laser delivered from the bottom. The animal holder is shown outside for illustration purpose.

Figure 4:

Photoacoustic imaging systems currently used in clinical trials for breast cancer detection. A, Imagio (Seno Medical Instruments) uses handheld transducer for breast imaging. Laser is delivered via optical fibers that are attached on either side of the transducer (131). B, Photoacoustic mammoscope developed at the University of Twente uses a patient bed with an aperture to insert the breast. Laser is delivered from the cranial side onto the breast, and a planar circular array of US detectors acquires images from the caudal side (132). 2D = two-dimensional. C, Photoacoustic tomography system (Optosonics) consists of a patient bed with an aperture. Laser is delivered from beneath the breast, and a rotating hemispherical array of US transducers acquires photoacoustic images (64). D, Laser optoacoustic imaging system (LOIS-64) developed by Ermilov et al consists of a setup similar to the Optosonics system, with a hemispherical array of annular US detectors (60). E, Photoacoustic imaging system (Canon) consists of a setup similar to the Twente photoacoustic mammoscope, with laser delivered through both plates and detector coupled to caudal plate (133).

Figure 5:

Clinical photoacoustic images overlaid on US images show endogenous photoacoustic signals corresponding to oxygenated and deoxygenated hemoglobin in breast lesions. A, Solid lesion with high oxygenated hemoglobin concentration. Lesion was confirmed at biopsy as benign fibroadenoma. B, Solid lesion with high deoxygenated hemoglobin concentration. Lesion was confirmed at biopsy as phyllodes tumor. (Reprinted, with permission, from reference .)

Figure 6:

Visualization of coated brachytherapy seeds in canine prostate in vivo. A, Postoperative CT scan shows location of seeds (arrows) with respect to the intraoperative transrectal US (TRUS) probe. B, Combined photoacoustic and gray-scale US image. Two of the three implanted brachytherapy seeds were visualized on the photoacoustic image. Red arrow = photoacoustic response from the location of the fiber, white unlabeled arrow = signal of unknown origin. (Adapted and reprinted, with permission, from reference .)

Figure 7a:

A, Photograph of a melanocytic nevus located on the forearm of a healthy volunteer. B, Photoacoustic B-mode image taken along the blue dashed line in, C. Notable features include the nevus, epidermal–dermal junction, and subpapillary blood vessels (all labeled). C, Maximum amplitude projected photoacoustic image of the nevus acquired at 570-nm wavelength. The nevus is clearly shown in green scale, and blood vessels are shown in red. D, Photoacoustic image acquired at 700-nm laser excitation wavelength shows nevus only without any blood vessels. (Adapted and reprinted, with permission, from reference .)

Figure 7b:

A, Photograph of a melanocytic nevus located on the forearm of a healthy volunteer. B, Photoacoustic B-mode image taken along the blue dashed line in, C. Notable features include the nevus, epidermal–dermal junction, and subpapillary blood vessels (all labeled). C, Maximum amplitude projected photoacoustic image of the nevus acquired at 570-nm wavelength. The nevus is clearly shown in green scale, and blood vessels are shown in red. D, Photoacoustic image acquired at 700-nm laser excitation wavelength shows nevus only without any blood vessels. (Adapted and reprinted, with permission, from reference .)

Figure 7c:

A, Photograph of a melanocytic nevus located on the forearm of a healthy volunteer. B, Photoacoustic B-mode image taken along the blue dashed line in, C. Notable features include the nevus, epidermal–dermal junction, and subpapillary blood vessels (all labeled). C, Maximum amplitude projected photoacoustic image of the nevus acquired at 570-nm wavelength. The nevus is clearly shown in green scale, and blood vessels are shown in red. D, Photoacoustic image acquired at 700-nm laser excitation wavelength shows nevus only without any blood vessels. (Adapted and reprinted, with permission, from reference .)

Figure 7d:

A, Photograph of a melanocytic nevus located on the forearm of a healthy volunteer. B, Photoacoustic B-mode image taken along the blue dashed line in, C. Notable features include the nevus, epidermal–dermal junction, and subpapillary blood vessels (all labeled). C, Maximum amplitude projected photoacoustic image of the nevus acquired at 570-nm wavelength. The nevus is clearly shown in green scale, and blood vessels are shown in red. D, Photoacoustic image acquired at 700-nm laser excitation wavelength shows nevus only without any blood vessels. (Adapted and reprinted, with permission, from reference .)

Figure 8:

Molecular photoacoustic imaging of thyroid cancer using a photoacoustic contrast agent B-APP-A that specifically binds to follicular thyroid cancer biomarkers MMP-2 and MMP-9. Mice bearing follicular thyroid cancers in the hind legs underwent photoacoustic imaging at 680 and 750 nm before and after intravenous injection of 4.8 nmol of the activatable probe B-APP-A and a noncleavable control probe. A, The subtraction photoacoustic signal at 140 minutes after injection was approximately 1.7-fold higher than the preinjection signal for the active probe. The subtraction signal for the control probe did not change over time. At early time points, the difference in subtraction signal was not significantly different for the two probes. Over time, the signal for the activatable probe steadily increased, becoming significantly different at 100 minutes. MMP = matrix metalloproteinase, B-APP-A = Alexa750-CXeeeeXPLGLAGrrrrrXK-BHQ3. B, Graph shows that subtraction photoacoustic (PA) signal was normalized by the preinjection subtraction photoacoustic signal: (PA_{680 nm} − PA_{750 nm}) after injection/(PA_{680 nm} − PA_{750 nm}) before injection. Error bars = standard error (n = 5 for B-APP-A, n = 4 for control probe). * = P < .05. Scale bar = 0.25 cm. (Reprinted, with permission, from reference .)

Figure 9:

Photoacoustic imaging of surgical ovarian specimen from a 58-year-old postmenopausal patient with bilateral ovarian cancers at stage IIIC. A, Malignant ovary imaged at two locations (* and ◆). B, Coregistered US and photoacoustic image of location *. E, Coregistered US and photoacoustic image of location ◆. Highly vascularized intraepithelial areas compared with the surrounding tissue are observed on photoacoustic images of both locations. C, F, Hematoxylin-eosin–stained images (original magnification, ×40) of the corresponding areas show extensive high-grade tumors. D, G, CD31-stained images (original magnification, ×100) of the corresponding areas show extensive thin-walled microvessels. White bar = 5 mm. (Reprinted, with permission, from reference .).