Niche preclinical and clinical applications of photoacoustic imaging with endogenous contrast.

In the past decade, photoacoustic (PA) imaging has attracted a great deal of popularity as an emergent diagnostic technology owing to its successful demonstration in both preclinical and clinical arenas by various academic and industrial research groups. Such steady growth of PA imaging can mainly be attributed to its salient features, including being non-ionizing, cost-effective, easily deployable, and having sufficient axial, lateral, and temporal resolutions for resolving various tissue characteristics and assessing the therapeutic efficacy. In addition, PA imaging can easily be integrated with the ultrasound imaging systems, the combination of which confers the ability to co-register and cross-reference various features in the structural, functional, and molecular imaging regimes. PA imaging relies on either an endogenous source of contrast (e.g., hemoglobin) or those of an exogenous nature such as nano-sized tunable optical absorbers or dyes that may boost imaging contrast beyond that provided by the endogenous sources. In this review, we discuss the applications of PA imaging with endogenous contrast as they pertain to clinically relevant niches, including tissue characterization, cancer diagnostics/therapies (termed as theranostics), cardiovascular applications, and surgical applications. We believe that PA imaging's role as a facile indicator of several disease-relevant states will continue to expand and evolve as it is adopted by an increasing number of research laboratories and clinics worldwide.

Integrated Ultrasound and Photoacoustic-Guided Laser Ablation Theranostic Endoscopic System.

Advancements in ablation techniques have paved the way towards the development of safer and more effective clinical procedures for treating various maladies such as atrial fibrillation (AF). AF is characterized by rapid, chaotic atrial activation and is commonly treated using radiofrequency applicators or laser ablation catheters. However, the lack of thermal lesion formation and temperature monitoring capabilities in these devices prevents them from measuring the treatment outcome directly. In addition, poor differentiation between healthy and ablated tissues leads to incomplete ablation, which reduces safety and causes complications in patients. Hence, a novel photoacoustic (PA)-guided laser ablation theranostic device was developed around a traditional phased-array endoscope. The proposed technology provides lesion formation, tissue distinguishing, and temperature monitoring capabilities. Our results have validated the lesion monitoring capability of the proposed technology through PA correlation maps. The tissue distinguishing capability of the theranostic device was verified by the measurable differences in the PA signal between pre-and post-ablated mice myocardial tissue. The increase in the PA signal with temperature variations caused by the ablation laser confirmed the ability of the proposed device to provide temperature feedback.

Photoacoustic-MR Image Registration Based on a Co-Sparse Analysis Model to Compensate for Brain Shift.

Brain shift is an important obstacle to the application of image guidance during neurosurgical interventions. There has been a growing interest in intra-operative imaging to update the image-guided surgery systems. However, due to the innate limitations of the current imaging modalities, accurate brain shift compensation continues to be a challenging task. In this study, the application of intra-operative photoacoustic imaging and registration of the intra-operative photoacoustic with pre-operative MR images are proposed to compensate for brain deformation. Finding a satisfactory registration method is challenging due to the unpredictable nature of brain deformation. In this study, the co-sparse analysis model is proposed for photoacoustic-MR image registration, which can capture the interdependency of the two modalities. The proposed algorithm works based on the minimization of mapping transform via a pair of analysis operators that are learned by the alternating direction method of multipliers. The method was evaluated using an experimental phantom and ex vivo data obtained from a mouse brain. The results of the phantom data show about 63% improvement in target registration error in comparison with the commonly used normalized mutual information method. The results proved that intra-operative photoacoustic images could become a promising tool when the brain shift invalidates pre-operative MRI.

The role of noninvasive diagnostic imaging in monitoring pregnancy and detecting patients at risk for preterm birth: a review of quantitative approaches.

Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality worldwide. The ability to predict patients at risk for preterm birth remains a major health challenge. The currently available clinical diagnostics such as cervical length and fetal fibronectin may detect only up to 30% of patients who eventually experience a spontaneous preterm birth. This paper reviews ongoing efforts to improve the ability to conduct a risk assessment for preterm birth. In particular, this work focuses on quantitative methods of imaging using ultrasound-based techniques, magnetic resonance imaging, and optical imaging modalities. While ultrasound imaging is the major modality for preterm birth risk assessment, a summary of efforts to adopt other imaging modalities is also discussed to identify the technical and diagnostic limits associated with adopting them in clinical settings. We conclude the review by proposing a new approach using combined photoacoustic, ultrasound, and elastography as a potential means to better assess cervical tissue remodeling, and thus improve the detection of patients at-risk of PTB.

Endocavity ultrasound and photoacoustic system for fetal and maternal imaging: design, implementation, and ex-vivo validation.

Purpose: Transvaginal ultrasound (TVUS) is a widely used real-time and non-invasive imaging technique for fetal and maternal care. It can provide structural and functional measurements about the fetal brain, such as blood vessel diameter and blood flow. However, it lacks certain biochemical estimations, such as hemoglobin oxygen saturation ( SO 2 ), which limits its ability to indicate a fetus at risk of birth asphyxia. Photoacoustic (PA) imaging has been steadily growing in recognition as a complement to ultrasound (US). Studies have shown PA imaging is capable of providing such biochemical estimations as SO 2 at relatively high penetration depth (up to 30 mm). Approach: In this study, we have designed and developed a multi-modal (US, PA, and Doppler) endocavity imaging system (ECUSPA) around a commercialized TVUS probe (Philips ATL C9-5). Results: The integrated system was evaluated through a set of in-vitro, ex-vivo, and in-vivo studies. Imaging of excised sheep brain tissue demonstrated the system's utility and penetration depth in transfontanelle imaging conditions. The accuracy of using the spectroscopic PA imaging (sPA) method to estimate SO 2 was validated by comparing sPA oximetry results with the gold standard measurements indicated by a blood gas analyzer. The ability of US and Doppler to measure moving blood volume was evaluated in-vivo. Spectral unmixing capabilities were tested using fluorophores within sheep brains. Conclusion: The developed system is a high resolution (about 200 µ m at 30 mm depth), real-time (at 30 Hz), and quantitative ( SO 2 estimation error < 10 % ) imaging tool with a total diameter less than 30 mm, making it suitable for intrapartum applications such as fetal and maternal diagnostics.

Dual-Illumination Ultrasound/ Photoacoustic System for Cervical Cancer imaging.

Early stage cancer detection technologies can provide functional information and potentially decrease the mortality rate caused by cervical cancer. In our previous work, a miniaturized ultrasound and photoacoustic endoscopic system has been developed to image the cervical tissue through the cervical canal to fulfills the need for a safe, low-cost, and high-resolution functional diagnostic system. However, the miniaturized size of endoscope and American National Standards Institute safety limits cause constraints of using high-intensity illumination during imaging. In addition, the strong light scattering of tissues limits the light penetration depth. Fortunately, the cervix anatomy allows for the delivery of additional light from the ectocervix by using an external illumination system. Here we propose a dual, co-planar illumination system, which can provide adequate illumination to the cervical tissue via combined internal and external light delivery strategies. Therefore, an increase in the area of light-tissue interaction allows us to raise the laser light energy while keeping fluence under safety limits. Thus, a reliable PA imaging can be obtained for the whole cervical tissue thickness. The system performance was tested using a Monte Carlo simulation, and laser-light fluence was calculated and compared at different depths within a simulated cervical-tissue model. The results indicated a higher and more uniform fluence in the Monte Carlo simulations. In addition, the photoacoustic imaging of the proposed system was evaluated by two cervical tissue-mimicking phantoms with human blood and graphite rods as inclusions inside it. In accordance with the simulations, the phantom study revealed a more reliable photoacoustic signal for the entire depth of the phantoms with an improved contrast to noise ratio and signal to noise ratio, and a higher coverage ratio of the imaging field of view. In summary, the dual-mode illumination system can provide more realistic information of inclusions within the tissue while considering safety limits, which can lead to more accuracy in biomarker detection for cervical cancer diagnostics.

Spectroscopic photoacoustic imaging of cervical tissue composition in excised human samples.

OBJECTIVE: Cervical remodeling is an important component in determining the pathway of parturition; therefore, assessing changes in cervical tissue composition may provide information about the cervix's status beyond the measurement of cervical length. Photoacoustic imaging is a non-invasive ultrasound-based technology that captures acoustic signals emitted by tissue components in response to laser pulses. This optical information allows for the determination of the collagen-to-water ratio (CWR). The purpose of this study was to compare the CWR evaluated by using spectroscopic photoacoustic (sPA) imaging in cervical samples obtained from pregnant and non-pregnant women. METHODS: This cross-sectional study comprised cervical biopsies obtained at the time of hysterectomy (n = 8) and at the scheduled cesarean delivery in pregnant women at term who were not in labor (n = 8). The cervical CWR was analyzed using a fiber-optic light-delivery system integrated to an ultrasound probe. The photoacoustic signals were acquired within the range of wavelengths that cover the peak absorption of collagen and water. Differences in the CWR between cervical samples from pregnant and non-pregnant women were analyzed. Hematoxylin and eosin and Sirius Red stains were used to compare the collagen content of cervical samples in these two groups. RESULTS: Eight cervix samples were obtained after hysterectomy, four from women ≤41 years of age and four from women ≥43 years of age; all cervical samples (n = 8) from pregnant women were obtained after 37 weeks of gestation at the time of cesarean section. The average CWR in cervical tissue samples from pregnant women was 18.7% (SD 7.5%), while in samples from non-pregnant women, it was 55.0% (SD 20.3%). There was a significantly higher CWR in the non-pregnant group compared to the pregnant group with a p-value <0.001. A subgroup analysis that compared the CWR in cervical samples from pregnant women and non-pregnant women ≤41 years of age (mean 46.3%, SD 23.1%) also showed a significantly higher CWR (p <0.01). Lower collagen content in the pregnancy group was confirmed by histological analysis, which revealed the loss of tissue composition, increased water content, and collagen degradation. CONCLUSION: The proposed bimodal ultrasound and sPA imaging system can provide information on the biochemical composition of cervical tissue in pregnant and non-pregnant women. Photoacoustic imaging showed a higher collagen content in cervical samples from non-pregnant women as compared to those from pregnant women, which matched with the histological analysis. This novel imaging method envisions a new potential for a sensitive diagnostic tool in the evaluation of cervical tissue composition.

Photoacoustic image improvement based on a combination of sparse coding and filtering.

SIGNIFICANCE: Photoacoustic imaging (PAI) has been greatly developed in a broad range of diagnostic applications. The efficiency of light to sound conversion in PAI is limited by the ubiquitous noise arising from the tissue background, leading to a low signal-to-noise ratio (SNR), and thus a poor quality of images. Frame averaging has been widely used to reduce the noise; however, it compromises the temporal resolution of PAI. AIM: We propose an approach for photoacoustic (PA) signal denoising based on a combination of low-pass filtering and sparse coding (LPFSC). APPROACH: LPFSC method is based on the fact that PA signal can be modeled as the sum of low frequency and sparse components, which allows for the reduction of noise levels using a hybrid alternating direction method of multipliers in an optimization process. RESULTS: LPFSC method was evaluated using in-silico and experimental phantoms. The results show a 26% improvement in the peak SNR of PA signal compared to the averaging method for in-silico data. On average, LPFSC method offers a 63% improvement in the image contrast-to-noise ratio and a 33% improvement in the structural similarity index compared to the averaging method for objects located at three different depths, ranging from 10 to 20 mm, in a porcine tissue phantom. CONCLUSIONS: The proposed method is an effective tool for PA signal denoising, whereas it ultimately improves the quality of reconstructed images, especially at higher depths, without limiting the image acquisition speed.

Catheter Ablation Lesion Visualization With Intracardiac Strain Imaging in Canines and Humans.

Catheter ablation is a common treatment for arrhythmia, but can fail if lesion lines are noncontiguous. Identification of gaps and nontransmural lesions can reduce the likelihood of treatment failure and recurrent arrhythmia. Intracardiac myocardial elastography (IME) is a strain imaging technique that provides visualization of the lesion line. Estimation of lesion size and gap resolution were evaluated in an open-chest canine model ( n = 3 ), and clinical feasibility was investigated in patients undergoing ablation to treat typical cavotricuspid isthmus (CTI) atrial flutter ( n = 5 ). A lesion line consisting of three lesions and two gaps was generated on the canine left ventricle via epicardial ablation. One lesion was generated in one canine right ventricle. Average lesion and gap areas were measured with high agreement (33 ± 14 and 30 ± 15 mm2, respectively) when compared against gross pathology (34 ± 19 and 26 ± 11 mm2, respectively). Gaps as small as 11 mm2 (3.6 mm on epicardial surface) were identifiable. Absolute error and relative error in estimated lesion area were 9.3 ± 8.4 mm2 and 31% ± 34%; error in estimated gap area was 11 ± 9.0 mm2 and 40% ± 29%. Flutter patients were imaged throughout the procedure. Strain was shown to be capable of differentiating between baseline and after ablation completion as confirmed by conduction block. In all patients, strain decreased in the CTI after ablation (mean paired difference of -17% ± 11%, ). IME could potentially become a useful ablation monitoring tool in health facilities.

Photoacoustic imaging of the uterine cervix to assess collagen and water content changes in murine pregnancy.

The uterine cervix plays a central role in the maintenance of pregnancy and in the process of parturition. Cervical remodeling involves dramatic changes in extracellular matrix composition and, in particular, of collagen and water content during cervical ripening (a term that describes the anatomical, biochemical, and physiologic changes in preparation for labor). Untimely cervical ripening in early gestation predisposes to preterm labor and delivery, the leading cause of infant death worldwide. Inadequate ripening of the cervix is associated with failure of induction or prolonged labor. The current approach to evaluate the state of the cervix relies on digital examination and sonographic examination. Herein, we present a novel imaging method that combines ultrasound (US) and photoacoustic (PA) techniques to evaluate cervical remodeling by assessing the relative collagen and water content of this organ. The method was tested in vitro in extracted collagen phantoms and ex vivo in murine cervical tissues that were collected in mid-pregnancy and at term. We report, for the first time, that our imaging approach provides information about the molecular changes in the cervix at different gestational ages. There was a strong correlation between the results of PA imaging and the histological assessment of the uterine cervix over the course of gestation. These findings suggest that PA imaging is a powerful method to assess the biochemical composition of the cervix and open avenues to non-invasively investigate the composition of this organ, which is essential for reproductive success.

Miniaturized phased-array ultrasound and photoacoustic endoscopic imaging system.

Visualization and detection of early-stage gynecological malignancies represents a challenge for imaging due to limiting factors including tissue accessibility, device ease of use, and accuracy of imaging modalities. In this work, we introduce a miniaturized phased-array ultrasound and photoacoustic endoscopic probe which is capable of providing structural, functional, and molecular data for the characterization of gynecologic disease. The proposed probe consists of a 64-element ultrasound phased-array transducer coupled to a fiber-optic light delivery system for co-registered ultrasound and photoacoustic imaging. The fabricated US and PA imaging endoscope's diameter is 7.5 mm, allowing for potential passage through the cervical canal and thus an intimate contact with gynecological tissues such as the cervical canal and uterus. The developed endoscopic probe was tested and characterized in a set of tissue-mimicking phantoms. US and PA resolutions were measured experimentally using 200 µm diameter wires, resulting in apparent axial and lateral diameters of 289 µm and 299 µm for US, and 308 µm and 378 µm for PA, respectively. The probe's abilities to operate in both discrete and integrated illumination/acquisition were tested in gelatin phantoms with embedded optical absorbers with the results demonstrating the ability to acquire volumetric dual-modal US and PA images.

Image improvement in linear-array photoacoustic imaging using high resolution coherence factor weighting technique.

BACKGROUND: In Photoacoustic imaging (PAI), the most prevalent beamforming algorithm is delay-and-sum (DAS) due to its simple implementation. However, it results in a low quality image affected by the high level of sidelobes. Coherence factor (CF) can be used to address the sidelobes in the reconstructed images by DAS, but the resolution improvement is not good enough, compared to the high resolution beamformers such as minimum variance (MV). In this paper, it is proposed to use high-resolution-CF (HRCF) weighting technique in which MV is used instead of the existing DAS in the formula of the conventional CF. RESULTS: The higher performance of HRCF is proved numerically and experimentally. The quantitative results obtained with the simulations show that at the depth of 40 mm, in comparison with DAS+CF and MV+CF, HRCF improves the full-width-half-maximum of about 91% and 15% and the signal-to-noise ratio about 40% and 14%, respectively. CONCLUSION: Proposed method provides a high resolution along with a low level of sidelobes for PAI.

Validation of delay-multiply-and-standard-deviation weighting factor for improved photoacoustic imaging of sentinel lymph node.

Delay-and-sum (DAS) is one of the most common algorithms used to construct the photoacoustic images due to its low complexity. However, it results in images with high sidelobes and low resolution. Delay-and-standard-deviation (DASD) weighting factor can improve the contrast of the images compared to DAS. However, it still suffers from high sidelobes. In this work, a new weighting factor, named delay-multiply-and-standard-deviation (DMASD) is introduced to enhance the contrast of the reconstructed images compared to other mentioned methods. In the proposed method, the SD of the mutual multiplied delayed signals are calculated, normalized and multiplied to DAS beamformed data. The results show that DMASD improves the signal-to-noise-ratio about 19.29 and 7.3 dB compared to DAS and DASD, respectively, for in vivo imaging of the sentinel lymph node. Moreover, the contrast ratio is improved by the DMASD about 23.61 and 10.81 dB compared to DAS and DASD, respectively.