Photoacoustic ultrasound bimodal imaging assisted sentinel lymph node surgery for breast cancer

Photoacoustic/ultrasound bimodal imaging assisted sentinel lymph node surgery for breast cancer

Original author：HandiDeng1, Liujie Gu1,Yizhou Bai,Cheng Ma,BinLuo*

“This article introduces the clinical research on the precise positioning of sentinel lymph nodes of breast cancer using PA/US bimodal imaging technology. The technology uses carbon nano-particles (CNPs) as a tracer to clearly visualize the lymphatic vessels for the first time, thus verifying the effectiveness of bimodal imaging in lymph node localization research, which shows that multispectral PA imaging has the ability to distinguish deep lymph nodes from other tissue characteristics. Compared with using only ultrasound imaging, the method of combining bimodal imaging and tracers has shown higher accuracy in lymph node identification. Therefore, by integrating the advantages of PA and US imaging, or further exploring more specific tracers, it is expected to effectively determine the lymphatic metastasis of breast cancer. These directions provide an important exploration path for future research. ”

01

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Design and principle of acoustic probe

Photoacoustic (PA) imaging is an emerging imaging method that can image endogenous and exogenous pigments non-radioactively, in real time, and with high resolution, and perform functional imaging through spectral scanning. At present, a variety of exogenous contrast agents have been used to combine PA imaging to locate sentinel lymph nodes. Toluene blue (MB), indocyanine green (ICG) and carbon nano particles (CNPs) have been approved for clinical application by the State Drug Administration of China. Due to the large particles of CNPs, it can be retained in sentinel lymph nodes for a longer time than small molecule tracers, and it has been successfully used to locate lymph nodes in gastric cancer and thyroid cancer. Our team started a clinical trial based on 11 patients, using PA/ultrasound (US) bimodal positioning staining CNPs, and preliminarily summarized the effectiveness of combining CNPs tracer with PA/US bimodal imaging for sentinel lymph node positioning. This paper discusses in depth the method of using PA/US bimodal imaging combined with CNPs to locate sentinel lymph nodes. First, the PA signal strength of various tracers at different wavelengths was carefully tested, and the best imaging wavelength was selected. A new type of ultrasonic transducer design is also proposed to improve the sensitivity of PA detection. In the end, two pilot clinical trials were conducted based on the established system, which verified the resolution and accuracy of PA imaging, and observed the excellent staining ability of CNPs on lymphatic vessels.

PA signals are less intense than normal ultrasound signals, so the sensitivity of the probe needs to be maximized. Conventional silicone acoustic lens probes have high acoustic attenuation (30 dB/cm, 5 MHz) and are not suitable for PA imaging. This study presents a new probe design based on self-focusing array elements and polystyrene wedges. The probe design is shown in Fig. 1(a). It is based on a curved piezoelectric chip with a self-focusing array element design, polystyrene with lower acoustic attenuation (2 dB/cm, 5 MHz) and stronger adhesion of the gold film. With the use of the wedge, a better acoustic coupling between the probe and the body contact surface can be achieved.

In order to verify the effectiveness of the probe for signal reception, the sensitivity of the designed probe and the conventional ultrasound probe were first simulated using the Krimholtz-Leedom-Matthaei (KLM) model, which is a commonly used one-dimensional simulation model for efficiently calculating the sensitivity and the received waveforms of the probe. The results are shown in Fig. 1(b), where the dashed line represents the simulation results of the conventional silicone acoustic lens probe and the solid line represents the results of the self-focusing and polystyrene wedge probes. During the moving process, we recorded the voltages received by both probes with a data acquisition system (DAQ).

Figure 1

Probe design diagram and simulation results. (a) Design plan of the probe equipped with a self-focusing transducer and a polystyrene wedge. (b) Simulation results of the probe equipped with a self-focusing transducer and a polystyrene wedge versus the probe equipped with a silicone acoustic lens. Black line: probe equipped with a self-focusing transducer and a polystyrene wedge; red line: probe equipped with a silicone acoustic lens.

02

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System sensitivity calibration

In order to ensure the accuracy of the detection of the experimental results, the sensitivity and precision of the tracer detection need to be ensured. Figure 2 illustrates the results of the variation response of several tracers calibrated with CuSO4 solution in the spectral range from 700 nm to 900 nm. The accuracy of this measurement was confirmed by a validation performed by evaluating the optical absorption coefficient of bovine blood. Since the tracers had different light absorption coefficients, they were diluted at different ratios in order to represent them uniformly in the same figure. Carbon nanoparticles (CNP) exhibited significant light absorption in the 700 nm to 900 nm spectral band. At 1064 nm, the absorption of bovine blood is approximately 4.44 cm^-1 , while the absorption of CNP diluted 1:1000 is 1.46 cm^-1. In contrast, MB and MH show minimal absorption, and even at a dilution ratio of 1:10, only a very weak signal is observed, at a dilution of approximately 0.05 cm^-1. CNPs commonly used for photoacoustic imaging at the wavelengths maintains a high optical absorption. Remarkably, their light absorption coefficients remain similar to those of oxygenated blood even after thousand-fold dilution, making them suitable tracers for photoacoustic imaging.

Figure 2

The light absorption coefficients of various tracers in the wavelength range of 700nm~900nm are measured by photoacoustic imaging.

The probe sensitivity calibration results are shown in Figure 3. In this figure, the blue dots represent the probes with the self-focusing transducer and polystyrene wedge, while the orange dots represent the probes with the silicone acoustic lens. As shown, the probe equipped with the self-focusing transducer and polystyrene wedge displayed twice the signal strength of its silicone acoustic lens counterpart. This result indicates that the sensitivity of the probe equipped with a self-focusing transducer and a polystyrene wedge is twice as high as that of the probe with a silicone acoustic lens. The experimental results are consistent with the simulation results and confirm the higher sensitivity of the new probe.

Figure 3
Probe sensitivity calibration. Blue dot: the sensitivity of the probe with a self-focusing transducer and a polystyrene wedge. Orange dot: The sensitivity of the probe with a silicone acoustic lens.

03

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Clinical imaging and surgical methods

First, photoacoustic imaging is used to locate the darkened lymph nodes. The probe was aligned perpendicular to the long axis of the body, and an axial scan was performed starting from the mammary gland to mark the suspicious location. In Figure 4(a), arrows point to two distinct signals representing the darkened lymph nodes. Subsequent surgical exposure of the two darkened lymph nodes at the corresponding locations provided initial verification of localization accuracy. Figure 4(c) demonstrates the lymph nodes identified during surgery. Figure 4(d) shows all lymph nodes removed during surgery. Preoperatively, "vessel-like" photoacoustic imaging features (indicated by red arrows) were identified, which had a stronger signal than normal blood vessels (blue arrows), were located between the two lymph node features, and were extremely similar to lymphatic vessels in terms of signal intensity and physiology. The tissue was extracted intraoperatively and verified that it was indeed a darkened lymphatic vessel, as indicated by the black arrow in Figure 4(d). The discovery of physiological structures that are difficult to recognize with conventional examination techniques through innovative imaging techniques highlights the importance of such methods.

Fig. 4 Photoacoustic imaging results and intraoperative photo documentation of Patient 1. (a) Preoperative photoacoustic imaging results with black arrows pointing to the sentinel lymph nodes. (b) Determination of lymph node surface markings and surgical incision, black arrow indicates surface markings. (c) Intraoperative photographic documentation with black arrow pointing to the darkened lymph node. (d) Photographs of the retrieved darkened lymph nodes, with 1, 2, and 3 designating lymph node 1, lymph node 2, and lymph node 3, respectively.(e) Preoperative photoacoustic imaging findings, with red arrows pointing to darkened lymphatic vessels and blue arrows indicating blood vessels. (f) Intraoperative photographic documentation with black arrows pointing to stained lymphatic vessels.

Dual-modality imaging localization and surgical procedures are the same as described above. Ultrasound imaging is unable to clearly demonstrate the lymphatic system, so combining photoacoustic imaging with tracers has better application prospects for visualizing the lymphatic system. Thus, after localization of lymph nodes with the synergistic application of photoacoustic imaging and tracers, careful observation of the staining pattern and ultrasound features can reveal more details, thereby increasing the likelihood of a more comprehensive diagnosis, such as the detection of breast cancer that has metastasized through the lymphatic system.

Figure 5

The bimodal imaging results of patient 2, (a) photoacoustic imaging, (b) ultrasound imaging. The blue arrows point to the lymphatic vessels and the black arrows point to the lymph nodes.

In this study, C-PIIP, a comprehensive clinical photoacoustic imaging platform developed by Beijing Qingpai Technology, was used. The device has a photoacoustic (PA)/ultrasound (US) bimodal imaging system, which provides a new perspective for the treatment of breast cancer and shows great potential in clinical research.

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Summary

This paper provides an in-depth study on the precise localization of sentinel lymph nodes by combining photoacoustic (PA) and ultrasound (US) dual-modality imaging techniques and contrast-enhanced nanoparticles (CNPs). The study first tested the photoacoustic signal intensity of different tracers at different wavelengths to determine the most suitable imaging wavelength and thus optimize the imaging effect. Meanwhile, a novel ultrasound transducer was proposed and designed to improve the detection sensitivity of photoacoustic imaging. Through this series of technological innovations, the overall performance of the system was enhanced. After establishing the optimal imaging parameters, we also conducted two pilot clinical trials based on the system, and the results verified the significant advantages of photoacoustic imaging in terms of resolution and accuracy, while demonstrating the efficient staining ability of contrast-enhanced nanoparticles in the localization of sentinel lymph nodes. The results of these studies provide novel techniques and methods for intraoperative imaging and surgical guidance, which are expected to greatly improve the success and safety of surgery.

C-PIIP (Clinical Photoacoustic Integrated Imaging Platform) is an optical-acoustic integrated imaging platform tailored for clinical research workloads, which combines the high resolution of optical imaging and the high penetration of ultrasound imaging, with a maximum observation depth of up to 40mm and a spatial resolution of up to 120μm. C-PIIP comes with both photoacoustic and ultrasound scanning modes, combining the molecular specificity of optical imaging with the depth and spatial and temporal resolution of ultrasound: it is able to identify and quantify disease-related biomarkers by recognizing endogenous absorbers and injected contrast agents, and at the same time, it is able to acquire real-time in vivo tissue images with sub-millimetre spatial resolution.

Figure 6

Qingpai Technology clinical photoacoustic imaging integrated platform C-PIIP and Half-loop probe

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