Accelerated High-Resolution Photoacoustic Tomography via Compressed Sensing

Current 3D photoacoustic tomography (PAT) systems offer either high image quality or high frame rates but are not able to deliver high spatial and temporal resolution simultaneously, which limits their ability to image dynamic processes in living tissue. A particular example is the planar Fabry-Perot (FP) scanner, which yields high-resolution images but takes several minutes to sequentially map the photoacoustic field on the sensor plane, point-by-point. However, as the spatio-temporal complexity of many absorbing tissue structures is rather low, the data recorded in such a conventional, regularly sampled fashion is often highly redundant. We demonstrate that combining variational image reconstruction methods using spatial sparsity constraints with the development of novel PAT acquisition systems capable of sub-sampling the acoustic wave field can dramatically increase the acquisition speed while maintaining a good spatial resolution: First, we describe and model two general spatial sub-sampling schemes. Then, we discuss how to implement them using the FP scanner and demonstrate the potential of these novel compressed sensing PAT devices through simulated data from a realistic numerical phantom and through measured data from a dynamic experimental phantom as well as from in-vivo experiments. Our results show that images with good spatial resolution and contrast can be obtained from highly sub-sampled PAT data if variational image reconstruction methods that describe the tissues structures with suitable sparsity-constraints are used. In particular, we examine the use of total variation regularization enhanced by Bregman iterations. These novel reconstruction strategies offer new opportunities to dramatically increase the acquisition speed of PAT scanners that employ point-by-point sequential scanning as well as reducing the channel count of parallelized schemes that use detector arrays.Comment: submitted to "Physics in Medicine and Biology

Dynamic Changes in Microvascular Density Can Predict Viable and Non-Viable Areas in High-Risk Neuroblastoma

Despite aggressive treatments, the prognosis of high-risk NB remains poor. Surgical oncology needs innovative intraoperative devices to help surgeons discriminate malignant tissue from necrotic and surrounding healthy tissues. Changes within the tumor vasculature could be used intraoperatively as a diagnostic tool to guide surgical resection. Here, we retrospectively analyzed the mean vascular density (MVD) of different NB subtypes at diagnosis and after induction chemotherapy using scanned histological samples. One patient was prospectively enrolled, and an ex vivo photoacoustic imaging (PAI) scan was performed on two representative sections to assess its capacity to discriminate different tumor regions. We found that post-chemotherapy, viable areas of differentiating NBs and ganglioneuroblastomas are associated with higher MVD compared to poorly differentiated NBs. Early necrotic regions showed higher MVD than late necrotic and viable regions. Finally, calcified areas showed significantly lower MVD than any other histological component. The acquired PAI images showed a good high-resolution ex vivo 3D delineation of NB margins. Overall, these results suggest that a high-definition preclinical imaging device such as PAI could potentially be exploited to guide surgical resection by identifying different vasculature signatures

Dynamic Changes in Microvascular Density Can Predict Viable and Non-Viable Areas in High-Risk Neuroblastoma

Despite aggressive treatments, the prognosis of high-risk NB remains poor. Surgical oncology needs innovative intraoperative devices to help surgeons discriminate malignant tissue from necrotic and surrounding healthy tissues. Changes within the tumor vasculature could be used intraoperatively as a diagnostic tool to guide surgical resection. Here, we retrospectively analyzed the mean vascular density (MVD) of different NB subtypes at diagnosis and after induction chemotherapy using scanned histological samples. One patient was prospectively enrolled, and an ex vivo photoacoustic imaging (PAI) scan was performed on two representative sections to assess its capacity to discriminate different tumor regions. We found that post-chemotherapy, viable areas of differentiating NBs and ganglioneuroblastomas are associated with higher MVD compared to poorly differentiated NBs. Early necrotic regions showed higher MVD than late necrotic and viable regions. Finally, calcified areas showed significantly lower MVD than any other histological component. The acquired PAI images showed a good high-resolution ex vivo 3D delineation of NB margins. Overall, these results suggest that a high-definition preclinical imaging device such as PAI could potentially be exploited to guide surgical resection by identifying different vasculature signatures

Characterisation of hydrophone sensitivity with temperature using a broadband laser-generated ultrasound source

In this work, we present a novel method for characterising the relative variation in hydrophone sensitivity with temperature, addressing a key aspect of measurements in the field of ultrasound metrology. Our study focused on a selection of miniature ultrasonic hydrophones commonly used in medical applications. The method is based on using water as a temperature-sensitive laser-generated ultrasound (LGUS) source for calibration, allowing for flexible characterisation across a wide temperature range. The measurements were performed using both the LGUS method and the established self-reciprocity method. Our results demonstrate good agreement within 5% between the two methods, validating the effectiveness of the LGUS approach. We found that the sensitivity of the tested hydrophones exhibited low temperature dependence less than −0.2% per ∘C within the studied temperature range from 17 ∘C up to 50 ∘C. The presented LGUS method offers greater flexibility than current approaches as it allows for characterisation of membrane hydrophones with small element sizes and non-electrical transducers. By combining the relative sensitivity variation obtained through the LGUS method with the standard calibration at room temperature, absolute values of hydrophone sensitivity can be determined. The expanded uncertainty of our measurements, which was evaluated at temperature intervals of 8 ∘C, was determined to be on average 10%. Our work provides valuable insights into the temperature dependence of hydrophone sensitivity and lays the foundation for further investigations in this area. The LGUS method holds promise for future enhancements, such as increased bandwidth of the LGUS source and frequency domain analysis, to explore the frequency dependency of sensitivity variation with temperature

Mitigating the limited view problem in photoacoustic tomography for a planar detection geometry by regularised iterative reconstruction

The use of a planar detection geometry in photoacoustic tomography results in the so-called limited-view problem due to the finite extent of the acoustic detection aperture. When images are reconstructed using one-step reconstruction algorithms, image quality is compromised by the presence of streaking artefacts, reduced contrast, image distortion and reduced signal-to-noise ratio. To mitigate this, model-based iterative reconstruction approaches based on least squares minimisation with and without total variation regularisation were evaluated using in-silico , experimental phantom, ex vivo and in vivo data. Compared to one-step reconstruction methods, it has been shown that iterative methods provide better image quality in terms of enhanced signal-to-artefact ratio, signal-to-noise ratio, amplitude accuracy and spatial fidelity. For the total variation approaches, the impact of the regularisation parameter on image feature scale and amplitude distribution was evaluated. In addition, the extent to which the use of Bregman iterations can compensate for the systematic amplitude bias introduced by total variation was studied. This investigation is expected to inform the practical application of model-based iterative image reconstruction approaches for improving photoacoustic image quality when using finite aperture planar detection geometries

EGFR-targeted semiconducting polymer nanoparticles for photoacoustic imaging

Semiconducting polymer nanoparticles (SPN), formulated from organic semiconducting polymers and lipids, show promise as exogenous contrast agents for photoacoustic imaging (PAI). To fully realise the potential of this class of nanoparticles for imaging and therapeutic applications, a broad range of active targeting strategies, where ligands specific to receptors on the target cells are displayed on the SPN surface, are urgently needed. In addition, effective strategies for quantifying the level of surface modification are also needed to support development of ligand-targeted SPN. In this paper, we have developed methods to prepare SPN bearing peptides targeted to Epidermal Growth Factor Receptors (EGFR), which are overexpressed at the surface of a wide variety of cancer cell types. In addition to fully characterising these targeted nanoparticles by standard methods (UV-visible, photoacoustic absorption, dynamic light scattering, zeta potential and SEM), we have developed a powerful new NMR method to determine the degree of conjugation and the number of targeting peptides attached to the SPN. Preliminary in vitro experiments with the colorectal cancer cell line LIM1215 indicated that the EGFR-targeting peptide conjugated SPN were either ineffective in delivering the SPN to the cells, or that the targeting peptide itself destabilised the formulation. This in reinforces the need for effective characterisation techniques to measure the surface accessibility of targeting ligands attached to nanoparticles

EGFR-targeted semiconducting polymer nanoparticles for photoacoustic imaging

Semiconducting polymer nanoparticles (SPN), formulated from organic semiconducting polymers and lipids, show promise as exogenous contrast agents for photoacoustic imaging (PAI). To fully realise the potential of this class of nanoparticles for imaging and therapeutic applications, a broad range of active targeting strategies, where ligands specific to receptors on the target cells are displayed on the SPN surface, are urgently needed. In addition, effective strategies for quantifying the level of surface modification are also needed to support development of ligand-targeted SPN. In this paper, we have developed methods to prepare SPN bearing peptides targeted to Epidermal Growth Factor Receptors (EGFR), which are overexpressed at the surface of a wide variety of cancer cell types. In addition to fully characterising these targeted nanoparticles by standard methods (UV–visible, photoacoustic absorption, dynamic light scattering, zeta potential and SEM), we have developed a powerful new NMR method to determine the degree of conjugation and the number of targeting peptides attached to the SPN. Preliminary in vitro experiments with the colorectal cancer cell line LIM1215 indicated that the EGFR-targeting peptide conjugated SPN were either ineffective in delivering the SPN to the cells, or that the targeting peptide itself destabilised the formulation. This in reinforces the need for effective characterisation techniques to measure the surface accessibility of targeting ligands attached to nanoparticles

Tunable Semiconducting Polymer Nanoparticles with INDT-Based Conjugated Polymers for Photoacoustic Molecular Imaging.

Photoacoustic imaging combines both excellent spatial resolution with high contrast and specificity, without the need for patients to be exposed to ionizing radiation. This makes it ideal for the study of physiological changes occurring during tumorigenesis and cardiovascular disease. In order to fully exploit the potential of this technique, new exogenous contrast agents with strong absorbance in the near-infrared range, good stability and biocompatibility, are required. In this paper, we report the formulation and characterization of a novel series of endogenous contrast agents for photoacoustic imaging in vivo. These contrast agents are based on a recently reported series of indigoid π-conjugated organic semiconductors, coformulated with 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, to give semiconducting polymer nanoparticles of about 150 nm diameter. These nanoparticles exhibited excellent absorption in the near-infrared region, with good photoacoustic signal generation efficiencies, high photostability, and extinction coefficients of up to three times higher than those previously reported. The absorption maximum is conveniently located in the spectral region of low absorption of chromophores within human tissue. Using the most promising semiconducting polymer nanoparticle, we have demonstrated wavelength-dependent differential contrast between vasculature and the nanoparticles, which can be used to unambiguously discriminate the presence of the contrast agent in vivo

Short-wave infrared imaging enables high-contrast fluorescence-guided surgery in neuroblastoma

Fluorescence-guided surgery is set to play a pivotal role in the intraoperative management of pediatric tumors. Short-wave infrared imaging (SWIR) has advantages over conventional near-infrared I (NIR-I) imaging with reduced tissue scattering and autofluorescence. Here, two NIR-I dyes (IRDye800CW and IR12), with long tails emitting in the SWIR range, were conjugated with a clinical-grade anti-GD2 monoclonal antibody (Dinutuximab-beta) to compare NIR-I and SWIR imaging for neuroblastoma surgery. A first-of-its-kind multispectral NIR-I/SWIR fluorescence imaging device was constructed to allow an objective comparison between the two imaging windows. Conjugates were first characterized in vitro. Tissue-mimicking phantoms, imaging specimens of known geometric and material composition, were used to assess the sensitivity and depth penetration of the NIR-I/SWIR device, showing a minimum detectable volume of ~0.9 mm3 and depth penetration up to 3 mm. In vivo, fluorescence imaging using the NIR-I/SWIR device showed a high tumor-to-background ratio (TBR) for both dyes, with anti-GD2-IR800 being significantly brighter than anti-GD2-IR12. Crucially, the system enabled higher TBR at SWIR wavelengths than at NIR-I wavelengths, verifying SWIR imaging enables high-contrast delineation of tumor margins. This work demonstrates that by combining the high-specificity of anti-GD2 antibodies with the availability and translatability of existing NIR-I dyes, along with the advantages of SWIR in terms of depth and tumor signal-to-background ratio, GD2-targeted NIR-I/SWIR-guided surgery could improve the treatment of neuroblastoma patients, warranting investigation in future clinical trials

Ultrasensitive plano-concave optical microresonators for ultrasound sensing

Highly sensitive broadband ultrasound detectors are needed to expand the capabilities of biomedical ultrasound, photoacoustic imaging and industrial ultrasonic non-destructive testing techniques. Here, a generic optical ultrasound sensing concept based on a novel plano-concave polymer microresonator is described. This achieves strong optical confinement (Q-factors > 105) resulting in very high sensitivity with excellent broadband acoustic frequency response and wide directivity. The concept is highly scalable in terms of bandwidth and sensitivity. To illustrate this, a family of microresonator sensors with broadband acoustic responses up to 40 MHz and noise-equivalent pressures as low as 1.6 mPa per √Hz have been fabricated and comprehensively characterized in terms of their acoustic performance. In addition, their practical application to high-resolution photoacoustic and ultrasound imaging is demonstrated. The favourable acoustic performance and design flexibility of the technology offers new opportunities to advance biomedical and industrial ultrasound-based techniques