Review of Photoacoustic Imaging for Imaging-Guided Spinal Surgery
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Abstract
This review introduces the current technique of photoacoustic imaging as it is applied in imaging-guided surgery (IGS), which provides the surgeon with image visualization and analysis capabilities during surgery. Numerous imaging techniques have been developed to help surgeons perform complex operations more safely and quickly. Although surgeons typically use these kinds of images to visualize targets hidden by bone and other tissues, it is nonetheless more difficult to perform surgery with static reference images (e.g., computed tomography scans and magnetic resonance images) of internal structures. Photoacoustic imaging could enable real-time visualization of regions of interest during surgery. Several researchers have shown that photoacoustic imaging has potential for the noninvasive diagnosis of various types of tissues, including bone. Previous studies of the surgical application of photoacoustic imaging have focused on cancer surgery, but photoacoustic imaging has also recently attracted interest for spinal surgery, because it could be useful for avoiding pedicle breaches and for choosing an appropriate starting point before drilling or pedicle probe insertion. This review describes the current instruments and clinical applications of photoacoustic imaging. Its primary objective is to provide a comprehensive overview of photoacoustic IGS in spinal surgery.
INTRODUCTION
Imaging-guided surgery (IGS) is classified within the broader category of computer-assisted surgery [1]. Through IGS, the spine surgeon is able to see the procedure as it is performed in real time. The technique of IGS has been developing since the early 1990s, and it is now used on a daily basis in the field of spinal surgery, including cancer surgery. Numerous imaging techniques have been developed to help surgeons perform complex operations more safely and quickly; however, it is more difficult to perform surgery with static reference images (e.g., computed tomography scans and magnetic resonance images) of internal structures. Photoacoustic imaging could enable the real-time visualization of regions of interest during surgery [2]. The photoacoustic imaging technique detects optical contrasts at the spatial resolution of ultrasound using a short-pulse laser as the light source and a conventional ultrasound transducer as the imaging sensor. Furthermore, it is nonionizing and noninvasive; as such, it is the fastest-growing new method of biomedical imaging, with clinical applications under further development. The ultimate goal of this article is to review the current status of photoacoustic imaging technology and its applicability to IGS in the field of spinal surgery and cancer.
HISTORY OF PHOTOACOUSTIC IMAGING
Photoacoustic imaging, also known as optoacoustic imaging, is a truly fused multi-imaging modality. It has emerged over the last decade, and is based on the use of laser-generated ultrasound. Fig. 1 shows the history of photoacoustic imaging technology since 1980. The photoacoustic effect was first observed in 1880 by Alexander Graham Bell, the scientist credited with inventing the first practical telephone. Bell is considered to have discovered the photoacoustic effect by observing that sound was generated by the absorption of modulated sunlight [3]. In the 1990s, photoacoustic imaging began to be more seriously researched for medical applications due to advances in both laser light sources and acoustic detection equipment [4].
PRINCIPLES OF PHOTOACOUSTIC IMAGING
In the photoacoustic effect, ultrasound waves are generated by a light-absorbing material following the absorption of modulated light, usually pulsed laser light on a nanosecond timescale. The absorbed light energy causes localized heating, which in turn produces a temperature rise, well below the amount that would produce physical damage or a phase change inside the object. This temperature increment gives rise to an initial pressure increase due to rapid thermal expansion. The pressure increase is followed by relaxation, generating broadband low-amplitude ultrasound waves. These ultrasound waves, better known as photoacoustic waves, are emitted from the object and can be captured by ultrasound transducers in different configurations depending upon the mode of imaging to produce a sequence of A-line signals [5]. An A-line signal is simply the display of the time-dependent response of the transducer generated by the ultrasound wave [6]. A-line signals are suitably processed and combined to produce 2-dimensional photoacoustic images of the materials. Fig. 2 shows the basic principles of photoacoustic imaging.
Photoacoustic imaging can be divided into 2 geometries, as shown in Fig. 3. For a handheld device, a linear transducer is used, which can only measure the ultrasound signal from a limited point of view, resulting in the limited view problem (Fig. 3A). Fig. 3B shows a more advantageous geometry, in which the transducers surround the tissue and a 360° scan is used to measure the signal [7]. In photoacoustic imaging, both the resolution and the penetration depth correlate with the ultrasound frequency. Therefore, a higher ultrasound frequency of the photoacoustic signal results in better spatial resolution because the relative value decreases. The maximum penetration depth simultaneously decreases as well, because higher ultrasonic frequencies are more attenuated than lower frequencies. Thus, there is a trade-off between resolution and penetration depth. It should be kept in mind that this is only valid within the tissue area in which sufficient optical power is obtained for generating the optical sound waves. Its size may vary depending on the wavelength of radiation used. Near-infrared light can usually penetrate the tissue well, and the following relationship holds [4]:
This definition is characteristic of high-resolution imaging modalities, which means that photoacoustic imaging can be considered such a modality. A microscopy system utilizing photoacoustic imaging was found to achieve a relative spatial resolution of roughly 200. Table 1 shows a comparison of the imaging technologies discussed above and summarizes their function.
INSTRUMENTS FOR PHOTOACOUSTIC IMAGING
Photoacoustic imaging systems typically include a pulsed nearinfrared laser (532- to 1,100-nm wavelengths, 1- to 100-ns pulse width, and 10- to 50-Hz pulse repetition rate), an ultrasound transducer, and a data acquisition and display unit (Fig. 4). Photoacoustic imaging instruments can be categorized as preclinical and clinical imaging systems. Preclinical imaging systems typically use a small animal placement platform (with a selective heating pad to keep the animal warm during the procedure and respiratory gating to compensate for heart rate monitoring and motion artifacts) and high-frequency transducers for highresolution imaging. Fig. 5 shows 2 commercially available preclinical photoacoustic imaging system used currently.
VisualSonics first developed the Vevo LAZR-X (Fujifilm VisualSonics, Toronto, Canada; technology licensed from Seno Medical Instruments, San Antonio, TX, USA) photoacoustic platform for small-animal preclinical imaging, based on an ultrasound imaging system. Endra Life Sciences also manufactured the Nexus 128 (Ann Arbor, MI, USA; technology licensed from OptoSonics, Oriental, NC, USA) platform for small-animal photoacoustic imaging of cancers for preclinical use. Clinical photoacoustic imaging systems are a logical extension of preclinical imaging systems and use transducers with clinically relevant frequencies (1–10 MHz). Clinical photoacoustic imaging systems are often region-specific because different laser-detector configurations are preferred for different applications (e.g., tomography is suitable for the breast; low-frequency handheld transducer arrays, for internal abdominal organs; high-frequency transducers, for superficial organs such as the skin and thyroid; endocavitary arrays, for prostate or ovary imaging). Aiming at clinical applications, TomoWave Lab Inc. (Houston, TX, USA) developed the LOUISA-3D photoacoustic imaging instrument (Fig. 6). Additionally, the Twente Group, in collaboration with ESAOTE Europe BV, developed a dual-imaging modality in which an ultrasound transducer array and a diode stack laser are combined in a single ultrasound probe connected to a commercially available ultrasound system. The new modality combines the benefits of ultrasonography and photoacoustic imaging by providing anatomic details through ultrasonography and functional information through the photoacoustic imaging [8]. Photoacoustic imaging scanners have been applied in clinics as a prototype for augmenting ultrasound through techniques such as sentinel lymph node (SLN) dye injection. Table 2 shows typical commercial photoacoustic imaging instruments for preclinical and clinical applications [9].
CLINICAL APPLICATIONS OF PHOTOACOUSTIC IMAGING
The applications of photoacoustic imaging are being intensively studied in fundamental, preclinical, and clinical studies. Many research groups are studying clinical photoacoustic imaging systems. Fig. 7 presents an overview of possible clinical applications of photoacoustic imaging. Several photoacoustic platforms for clinical use already exist or are under development, including handheld probes and photoacoustic computed tomography.
1. Cancer Detection
Photoacoustic imaging is highly promising for cancer monitoring, assessing tumor margins, and screening for tumor metastasis. Several studies have explored photoacoustic breast imaging as a possible alternative to X-ray mammography. Typically, photoacoustic mammography systems include a patient examination table that contains an aperture through which the patient’s breast is suspended while lying in prone position. A laser and detector are arranged underneath the examination table, and imaging is conducted with the breast mildly compressed. An example of such a system is the photoacoustic mammoscope, which was developed at the University of Twente (Enschede, The Netherlands) as a clinical prototype [10]. This system utilizes a 2-dimensional circular ultrasound detector array (80-mm diameter, 590 elements, 1-MHz center frequency) on one side of the compressed breast with laser exposure (1,064 nm, 10 mJ/cm2) from the other side to facilitate 3-dimensional imaging. A clinical study was recently conducted (Fig. 8) of 43 patients, who had 31 malignant lesions, 2 fibroadenomas, 1 area of chronic inflammation, 5 cysts, and 2 invalid measurements. The tumors were visualized with high contrast in 30 of the 31 breast cancer patients (Breast Imaging Reporting and Data System density: low [1 or 2] in 23 patients and high [3 or 4] in 8 patients). On the basis of these findings, it was concluded that the photoacoustic image contrast was independent of the breast density estimated on mammography, unlike X-ray mammography [11]. The average scan time with the photoacoustic mammoscope was 10 minutes for a field of view of 90×80 mm [2].
In addition to detecting primary tumors, screening for metastasis is another important application of clinical imaging. Early-stage metastasis always occurs in the SLNs, which comprise a tumor bed that receives lymphatic drainage from cancerous tissues [12,13]. By using an exogenous agent, such as methylene blue or indocyanine green (ICG), photoacoustic imaging has been used to detect SLNs deep in tissues. The absence of endogenous photosensitive molecules in lymph nodes has led researchers to use exogenous photoacoustic imaging contrast agents. In an in vivo rat study, Song et al. [14] successfully imaged SLNs with a photoacoustic imaging system using methylene blue, an optically absorbing contrast agent. Fig. 9 presents an ICG-stained SLN photoacoustic image [15].
Some researchers have studied photoacoustic imaging of prostate cancer in vivo using animal models [16-20]. Levi et al. developed a photoacoustic contrast agent labeled AA3G-740 that binds to gastrin-releasing peptide receptor, which has been reported to be highly overexpressed in prostate cancer [21,22]. In vivo molecular photoacoustic imaging of mice (n=6) bearing PC3 human prostate cancer cells was performed 30 and 60 minutes after contrast agent injection using the Nexus 128 photoacoustic computed tomography system (Endra Life Sciences). AA3G-740 was able to bind to gastrin-releasing peptide receptor in mice, even in poorly vascularized tumors, leading to a nearly twofold increase in the photoacoustic signal relative to a control contrast agent [22]. It was also reported that the smallest number of AA3G-740–labeled PC3 cells required to produce a background-differentiable photoacoustic signal was only 0.5 million (whereas a 1-cm3 tumor may have up to 100 million cells), which demonstrates the potential of molecular photoacoustic imaging to detect prostate cancer, even in small tumors.
Aguirre et al. [23] developed a coregistered photoacoustic and ultrasound imaging system suitable for ex vivo ovarian imaging. This system uses a tunable laser (740 nm, 12 ns, 15 Hz) and a custom-developed 1.75-dimensional transducer array (5 MHz). With this system, an ex vivo study was performed on 33 human ovaries that were extracted from patients who underwent oophorectomy. This system showed the capability to differentiate normal postmenopausal versus malignant postmenopausal ovaries (p=0.0237) (sensitivity, 83%; specificity, 83%). In contrast, no significant differences were found between normal premenopausal versus normal postmenopausal ovaries (p=0.2361) (Fig. 10). The same research group [24,25] later reported an upgraded system built specifically for clinical use that employed a laser (750 nm, 20 ns, 15 Hz) and a modified commercial transvaginal ultrasound probe (6 MHz), around which an array of 36 optical fibers was mounted to facilitate in vivo photoacoustic imaging.
2. Imaging-guided Surgery
IGS refers to real-time correlation of the operative field with preoperative imaging data in order to determine the precise location of a selected surgical instrument relative to the surrounding anatomic structures. IGS has become recognized as a way for surgeons to perform safer, less invasive surgery in the fields of intracranial otolaryngology, spine, orthopedics and cardiovascular disease. Some researchers have shown that photoacoustic imaging enables real-time visualization of areas of interest during surgery. This is significant because it is more difficult to perform surgery with static reference images (e.g., computed tomography scans and magnetic resonance images) of internal structures, although surgeons typically use such images to visualize targets hidden by bone and other tissues [2]. Studies of intraoperative photoacoustic imaging remain in their early stages. Xi et al. [26] reported a microelectromechanical system using intraoperative photoacoustic tomography and examined the capability of this system to map tumors accurately in 3 dimensions and to inspect the completeness of tumor resection during surgery in a tumor-bearing mouse model.
IGS can help surgeons perform minimally invasive percutaneous, laparoscopic, or robotic-aided treatment more precisely and safely, to achieve complete tumor removal, and to preserve of the function of critical organs. Recently, with the advent of minimally invasive treatment procedures, surgical procedures have tended to shift from large-scale exploration to approaches with limited access and limited visibility. These new applications increase the need for image guidance and mandate the use of the most advanced imaging methods. Some research groups are exploring systems for delivering light surrounding surgical tools, with applications to minimally invasive surgery, such as neurosurgical procedures to remove pituitary tumors using the endonasal transsphenoidal approach. In this approach, the light delivery system would be attached to the surgical tool, which is inserted in the nose, and would transmit light across the sphenoid bone. The internal carotid arteries hidden behind the bone would absorb the light, undergo thermal expansion, and generate an acoustic response to be detected by an external transcranial ultrasound probe placed on the patient’s temple [27]. The Photoacoustic & Ultrasonic Systems Engineering (PULSE) Lab at Johns Hopkins University has been investigating the use of photoacoustic imaging for minimally invasive IGS [2,27]. Bell and colleagues [2,27-29] have reported the application of photoacoustic imaging for real-time surgical guidance. They provided an overview of the combination of photoacoustic imaging with the da Vinci surgical robot, which is often used to perform teleoperated hysterectomies (i.e., surgical removal of the uterus) [30]. A concerning complication of hysterectomies is accidental injury of the ureters, which are located within millimeters of the uterine arteries that are severed and cauterized to hinder blood flow and enable full removal of the uterus. The researchers explored the possibility that photoacoustic imaging could visualize the uterine arteries (and potentially the ureters) during hysterectomy. Photoacoustic images were obtained while sweeping the tool across a custom 3-dimensional uterine vessel model covered in ex vivo bovine tissue that was placed between the 3-dimensional model and the light delivery system, as well as between the ultrasound probe and the 3-dimensional model (to introduce optical and acoustic scattering). Fig. 11 shows how the photoacoustic imaging system was interfaced with the da Vinci Robot surgical system for teleoperation of the imaging system components, facilitated by the da Vinci research toolkit [31].
3. Other Applications
Most recently, photoacoustic imaging been broadly applied in fields ranging from functional brain mapping and cancer diagnosis to tissue engineering, surgery, drug delivery, and cell biology, as has been reviewed in depth elsewhere [32]. In addition to the above-discussed applications of cancer diagnosis and surgery, we will introduce the application of photoacoustic imaging for related to brain and bone imaging in neuroscience. Photoacoustic tomography provides important information about the cerebral vasculature by enabling functional and metabolic brain imaging on both the microscopic and macroscopic scales [32], yielding information about oxygenation (Fig. 12) [33], the metabolism of oxygen and glucose [34], resting-state connectivity [35], and how the brain responds to various physiological and pathological challenges [36-38]. Photoacoustic tomography can be used for neuronal imaging, using either exogenous contrast from dyes or endogenous contrast from lipids [39]. In addition, photoacoustic tomography has been increasingly used to study small-animal models of brain diseases, including stroke [40], epilepsy [41], and edema [42]. Recently, head-mounted photoacoustic computed tomography systems have been developed, which is an important step toward functional photoacoustic imaging of the brain in free-moving animals [43]. Van den Berg et al. [44] developed a dualmodality photoacoustic imaging system with a handheld probe for assessing synovitis in patients with rheumatoid arthritis. As shown in Fig. 13, the probe contains a fully assembled ultrasound transducer and a compact diode laser module in a size comparable to that of commercially-available ultrasound imaging probes used in current clinical practice [45]. The photoacoustic images in Fig. 14A show a superficial blood vessel in both the inflamed and non-inflamed joints, with additional photoacoustic findings on the bone surface. The inflamed joint shows larger amplitudes and more confluent features, as can be further observed in Fig. 14B, where only high amplitudes (18-dB dynamic range) are plotted. With this threshold, almost no photoacoustic features are visible for the noninflamed joint [44].
APPLICATIONS OF PHOTOACOUSTIC IMAGING FOR SPINAL SURGERY
Thella et al. [46] demonstrated that photoacoustic imaging shows potential for the noninvasive diagnosis of various bone types, including bones containing cancer. In addition, photoacoustic technology has been found to be sensitive to minor variations in cortical bone density [47]. Quantitative photoacoustic imaging has been further used to determine differences in bone mineral density and bone composition [48,49], which could be useful for preventing spinal injury and choosing a suitable starting point prior to drilling or insertion of a spinal probe. However, to the best of the authors’ knowledge, photoacoustic images of the pedicles in a human vertebra have never been published, meaning that a clinically viable photoacoustic imaging approach to guide spinal fusion surgery has never been explored. In 2018, Shubert and Lediju Bell [50] published a paper about spinal surgery using photoacoustic imaging, exploring the possibility of using photoacoustic imaging to differentiate between cortical and cancellous bone, with implications for possible use for guidance in spinal fusion surgery. For deployment as a viable clinical system, the optical fiber carrying the laser light can be detached or attached to surgical instruments (e.g., a burr, drill, awl, or spinal probe). Next, a standard clinical ultrasound probe would be placed on the vertebra of interest with acoustic coupling gel. They have shown that it was possible to use photoacoustic imaging to differentiate cancellous and cortical bone without drilling or otherwise disrupting the pedicle. This finding suggests that photoacoustic imaging has the clinical potential to generate signals from the cancellous core of the pedicle prior to the removal of any surface cortical bone. With photoacoustic imaging used to determine the starting point, the findings presented in Figs. 15 and 16 indicate that a smaller probefiber pair that fits inside a predrilled hole may also be used as a real-time indicator of the optimal trajectory of the drill or pedicle probe. Their study was the first to show that 3-dimensional photoacoustic imaging could be used as a noninvasive technique to reveal differences between cancellous and cortical bone, indicating that this modality is promising for spinal fusion surgery.
CONCLUSION
Photoacoustic imaging is a promising imaging modality used for cancer diagnosis, surgery, drug delivery, brain imaging, and inflammatory arthritis, as a complement to existing imaging modalities. In this review, we presented several instruments used for photoacoustic imaging and described selected clinical applications, including spinal surgery. Although photoacoustic imaging has many potential applications, several challenges remain, as we discussed. In the field of spinal surgery, the first steps have been taken in studying the use of photoacoustic imaging for IGS. This initial work generally shows promise for the potential of photoacoustic imaging systems to overcome a wide range of longstanding challenges in spinal surgery, including the occurrence of bone breaches due to misplaced pedicle screws. To surmount these challenges, many institutions and researchers are developing novel approaches regarding laser sources, ultrasound transducers, multimodal platforms, and detector geometry, and are exploring potential applications.
Notes
The author has nothing to disclose.
Acknowledgements
The author acknowledges helpful discussions with and contributions from members of Brian Wilson’s Bio-photonics Group in the University Health Network.