Dual-modality rigid endoscope for photoacoustic imaging and white light videoscopy.

Significance: There has been significant interest in the development of miniature photoacoustic imaging probes for a variety of clinical uses, including the in situ assessment of tumors and minimally invasive surgical guidance. Most of the previously implemented probes are either side viewing or operate in the optical-resolution microscopy mode in which the imaging depth is limited to ∼1 mm. We describe a forward-viewing photoacoustic probe that operates in tomography mode and simultaneously provides white light video images. Aim: We aim to develop a dual-modality endoscope capable of performing high-resolution PAT imaging and traditional white light videoscopy simultaneously in the forward-viewing configuration. Approach: We used a Fabry-Pérot ultrasound sensor that operates in the 1500 to 1600 nm wavelength range and is transparent in the visible and near infrared region (580 to 1250 nm). The FP sensor was optically scanned using a miniature MEMs mirror located at the proximal end of the endoscope, resulting in a system that is sufficiently compact (10 mm outer diameter) and lightweight for practical endoscopic use. Results: The imaging performance of the endoscope is evaluated, and dual-mode imaging capability is demonstrated using phantoms and abdominal organs of an ex vivo mouse including spleen, liver, and kidney. Conclusions: The proposed endoscope design offers several advantages including the high acoustic sensitivity and wide detection bandwidth of the FP sensor, dual-mode imaging capability, compact footprint, and an all-optical distal end for improved safety. The dual-mode imaging capability also offers the advantage of correlating the tissue surface morphology with the underlying vascular anatomy. Potential applications include the guidance of laparoscopic surgery and other interventional procedures.

Laser frequency noise characterization using high-finesse plano-concave optical microresonators.

Characterizing laser frequency noise is essential for applications including optical sensing and coherent optical communications. Accurate measurement of ultra-narrow linewidth lasers over a wide frequency range using existing methods is still challenging. Here we present a method for characterizing the frequency noise of lasers using a high-finesse plano-concave optical microresonator (PCMR) acting as a frequency discriminator. To enable noise measurements at a wide range of laser frequencies, an array of PCMRs was produced with slight variations of thickness resulting in a series of discriminators operating at a series of periodical frequencies. This method enables measuring the frequency noise over a wide linewidth range (15 Hz to <100 MHz) over the 1440-1630 nm wavelength range. To assess the performance of the method, four different lasers were characterized, and the results were compared to the estimations of a commercial frequency noise analyzer.

Spatially resolved readout of a Fabry-Perot ultrasound sensor interrogated through a multimode optical fiber using wavefront shaping.

The spatially resolved interrogation of a Fabry-Perot ultrasound sensor using a laser beam focused through a multimode fiber is demonstrated. To scan the beam across the sensor as required to read it out, optical wavefront shaping was employed to compensate for the scrambling of light in the fiber. By providing a means to map ultrasound through inexpensive, lightweight fibers, this could lead to new ultrasonic and photoacoustic imaging systems, such as endoscopes and flexible handheld probes.

All-optical ultrasound catheter for rapid B-mode oesophageal imaging.

All-optical ultrasound (OpUS) is an imaging paradigm that uses light to both generate and receive ultrasound, and has progressed from benchtop to in vivo studies in recent years, demonstrating promise for minimally invasive surgical applications. In this work, we present a rapid pullback imaging catheter for side-viewing B-mode ultrasound imaging within the upper gastrointestinal tract. The device comprised an ultrasound transmitter configured to generate ultrasound laterally from the catheter and a plano-concave microresonator for ultrasound reception. This imaging probe was capable of generating ultrasound pressures in excess of 1 MPa with corresponding -6 dB bandwidths > 20 MHz. This enabled imaging resolutions as low as 45 µm and 120 µm in the axial and lateral extent respectively, with a corresponding signal-to-noise ratio (SNR) of 42 dB. To demonstrate the potential of the device for clinical imaging, an ex vivo swine oesophagus was imaged using the working channel of a mock endoscope for device delivery. The full thickness of the oesophagus was resolved and several tissue layers were present in the resulting ultrasound images. This work demonstrates the promise for OpUS to provide rapid diagnostics and guidance alongside conventional endoscopy.

Miniaturised dual-modality all-optical ultrasound probe for laser interstitial thermal therapy (LITT) monitoring.

All-optical ultrasound (OpUS) has emerged as an imaging paradigm well-suited to minimally invasive imaging due to its ability to provide high resolution imaging from miniaturised fibre optic devices. Here, we report a fibre optic device capable of concurrent laser interstitial thermal therapy (LITT) and real-time in situ all-optical ultrasound imaging for lesion monitoring. The device comprised three optical fibres: one each for ultrasound transmission, reception and thermal therapy light delivery. This device had a total lateral dimension of <1 mm and was integrated into a medical needle. Simultaneous LITT and monitoring were performed on ex vivo lamb kidney with lesion depth tracked using M-mode OpUS imaging. Using one set of laser energy parameters for LITT (5 W, 60 s), the lesion depth varied from 3.3 mm to 8.3 mm. In all cases, the full lesion depth could be visualised and measured with the OpUS images and there was a good statistical agreement with stereomicroscope images acquired after ablation (t=1.36, p=0.18). This work demonstrates the feasibility and potential of OpUS to guide LITT in tumour resection.

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.

ABCD transfer matrix model of Gaussian beam propagation in plano-concave optical microresonators.

Plano-concave optical microresonators (PCMRs) are optical microcavities formed of one planar and one concave mirror separated by a spacer. PCMRs illuminated by Gaussian laser beams are used as sensors and filters in fields including quantum electrodynamics, temperature sensing, and photoacoustic imaging. To predict characteristics such as the sensitivity of PCMRs, a model of Gaussian beam propagation through PCMRs based on the ABCD matrix method was developed. To validate the model, interferometer transfer functions (ITFs) calculated for a range of PCMRs and beams were compared to experimental measurements. A good agreement was observed, suggesting the model is valid. It could therefore constitute a useful tool for designing and evaluating PCMR systems in various fields. The computer code implementing the model has been made available online.

Mitigating the Limited View Problem in Photoacoustic Tomography for a Planar Detection Geometry by Regularized 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 regularization 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 regularization 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.

Shortwave 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. Shortwave 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 patients with neuroblastoma, warranting investigation in future clinical trials. SIGNIFICANCE: Multispectral near-infrared I/shortwave infrared fluorescence imaging is a versatile system enabling high tumor-to-background signal for safer and more complete resection of pediatric tumors during surgery.

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.

Bend-insensitive fiber optic ultrasonic tracking probe for cardiovascular interventions.

BACKGROUND: Transesophageal echocardiography (TEE) is widely used to guide medical device placement in minimally invasive cardiovascular procedures. However, visualization of the device tip with TEE can be challenging. Ultrasonic tracking, enabled by an integrated fiber optic ultrasound sensor (FOUS) that receives transmissions from the TEE probe, is very well suited to improving device localization in this context. The problem addressed in this study is that tight deflections of devices such as a steerable guide catheter can result in bending of the FOUS beyond its specifications and a corresponding loss of ultrasound sensitivity. PURPOSE: A bend-insensitive FOUS was developed, and its utility with ultrasonic tracking of a steerable tip during TEE-based image guidance was demonstrated. METHODS: Fiberoptic ultrasound sensors were fabricated using both standard and bend insensitive single mode fibers and subjected to static bending at the distal end. The interference transfer function and ultrasound sensitivities were compared for both types of FOUS. The bend-insensitive FOUS was integrated within a steerable guide catheter, which served as an exemplar device; the signal-to-noise ratio (SNR) of tracking signals from the catheter tip with a straight and a fully deflected distal end were measured in a cardiac ultrasound phantom for over 100 frames. RESULTS: With tight bending at the distal end (bend radius < 10 mm), the standard FOUS experienced a complete loss of US sensitivity due to high attenuation in the fiber, whereas the bend-insensitive FOUS had largely unchanged performance, with a SNR of 47.7 for straight fiber and a SNR of 36.8 at a bend radius of 3.0 mm. When integrated into the steerable guide catheter, the mean SNRs of the ultrasonic tracking signals recorded with the catheter in a cardiac phantom were similar for straight and fully deflected distal ends: 195 and 163. CONCLUSION: The FOUS fabricated from bend-insensitive fiber overcomes the bend restrictions associated with the FOUS fabricated from standard single mode fiber, thereby enabling its use in ultrasonic tracking in a wide range of cardiovascular devices.

ABCD transfer matrix model of Gaussian beam propagation in Fabry-Perot etalons.

A numerical model of Gaussian beam propagation in planar Fabry-Perot (FP) etalons is presented. The model is based on the ABCD transfer matrix method. This method is easy to use and interpret, and readily connects models of lenses, mirrors, fibres and other optics to aid simulating complex multi-component etalon systems. To validate the etalon model, its predictions were verified using a previously validated model based on Fourier optics. To demonstrate its utility, three different etalon systems were simulated. The results suggest the model is valid and versatile and could aid in designing and understanding a range of systems containing planar FP etalons. The method could be extended to model higher order beams, other FP type devices such as plano-concave resonators, and more complex etalon systems such as those involving tilted components.

Intraoperative Needle Tip Tracking with an Integrated Fibre-Optic Ultrasound Sensor.

Ultrasound is an essential tool for guidance of many minimally-invasive surgical and interventional procedures, where accurate placement of the interventional device is critical to avoid adverse events. Needle insertion procedures for anaesthesia, fetal medicine and tumour biopsy are commonly ultrasound-guided, and misplacement of the needle may lead to complications such as nerve damage, organ injury or pregnancy loss. Clear visibility of the needle tip is therefore critical, but visibility is often precluded by tissue heterogeneities or specular reflections from the needle shaft. This paper presents the in vitro and ex vivo accuracy of a new, real-time, ultrasound needle tip tracking system for guidance of fetal interventions. A fibre-optic, Fabry-Pérot interferometer hydrophone is integrated into an intraoperative needle and used to localise the needle tip within a handheld ultrasound field. While previous, related work has been based on research ultrasound systems with bespoke transmission sequences, the new system-developed under the ISO 13485 Medical Devices quality standard-operates as an adjunct to a commercial ultrasound imaging system and therefore provides the image quality expected in the clinic, superimposing a cross-hair onto the ultrasound image at the needle tip position. Tracking accuracy was determined by translating the needle tip to 356 known positions in the ultrasound field of view in a tank of water, and by comparison to manual labelling of the the position of the needle in B-mode US images during an insertion into an ex vivo phantom. In water, the mean distance between tracked and true positions was 0.7 ± 0.4 mm with a mean repeatability of 0.3 ± 0.2 mm. In the tissue phantom, the mean distance between tracked and labelled positions was 1.1 ± 0.7 mm. Tracking performance was found to be independent of needle angle. The study demonstrates the performance and clinical compatibility of ultrasound needle tracking, an essential step towards a first-in-human study.

High-resolution sub-millimetre diameter side-viewing all-optical ultrasound transducer based on a single dual-clad optical fibre.

All-optical ultrasound (OpUS), where ultrasound is both generated and received using light, has emerged as a modality well-suited to highly miniaturised applications. In this work we present a proof-of-concept OpUS transducer built onto a single optical fibre with a highly miniaturised lateral dimension (<0.8 mm). A key innovation was to use a dual-clad optical fibre (DCF) to provide multimode light for ultrasound generation and single mode light for ultrasound reception. The transducer comprised a proximal section of DCF spliced to a short section of single mode fibre (SMF). Multimode light was outcoupled at the splice joint and guided within a square capillary to provide excitation for ultrasound generation. Whilst single mode light was guided to the distal tip of the SMF to a plano-concave microresonator for ultrasound reception. The device was capable of generating ultrasound with pressures >0.4 MPa and a corresponding bandwidth >27 MHz. Concurrent ultrasound generation and reception from the transducer enabled imaging via motorised pull-back allowing image acquisition times of 4 s for an aperture of 20 mm. Image resolution was as low as ~50 µm and 190 µm in the axial and lateral extents, respectively, without the need for image reconstruction. Porcine aorta was imaged ex vivo demonstrating detailed ultrasound images. The unprecedented level of miniaturisation along with the high image quality produced by this device represents a radical new paradigm for minimally invasive imaging.

Ultrathin, high-speed, all-optical photoacoustic endomicroscopy probe for guiding minimally invasive surgery.

Photoacoustic (PA) endoscopy has shown significant potential for clinical diagnosis and surgical guidance. Multimode fibres (MMFs) are becoming increasingly attractive for the development of miniature endoscopy probes owing to their ultrathin size, low cost and diffraction-limited spatial resolution enabled by wavefront shaping. However, current MMF-based PA endomicroscopy probes are either limited by a bulky ultrasound detector or a low imaging speed that hindered their usability. In this work, we report the development of a highly miniaturised and high-speed PA endomicroscopy probe that is integrated within the cannula of a 20 gauge medical needle. This probe comprises a MMF for delivering the PA excitation light and a single-mode optical fibre with a plano-concave microresonator for ultrasound detection. Wavefront shaping with a digital micromirror device enabled rapid raster-scanning of a focused light spot at the distal end of the MMF for tissue interrogation. High-resolution PA imaging of mouse red blood cells covering an area 100 µm in diameter was achieved with the needle probe at ∼3 frames per second. Mosaicing imaging was performed after fibre characterisation by translating the needle probe to enlarge the field-of-view in real-time. The developed ultrathin PA endomicroscopy probe is promising for guiding minimally invasive surgery by providing functional, molecular and microstructural information of tissue in real-time.

Ultrasonic Needle Tracking with Dynamic Electronic Focusing.

Accurate identification of the needle tip is a key challenge with ultrasound-guided percutaneous interventions in regional anaesthesia, foetal surgery and cardiovascular medicine. In this study, we developed an ultrasonic needle tracking system in which the measured needle tip location was used to set the electronic focus of the external ultrasound imaging probe. In this system, needle tip tracking was enabled with a fibre-optic ultrasound sensor that was integrated into a needle stylet, and the A-lines recorded by the sensor were processed to generate tracking images of the needle tip. The needle tip position was estimated from the tracking images. The dependency of the tracking image on the electronic focal depth of the external ultrasound imaging probe was studied in a water bath and with needle insertions into a clinical training phantom. The variability in the estimated tracked position of the needle tip, with the needle tip at fixed depths in the imaging plane across a depth range from 0.5 to 7.5 cm, was studied. When the electronic focus was fixed, the variability of tracked position was found to increase with distance from that focus. The variability with the fixed focus was found to depend on the the relative distance between the needle tip and focal depth. It was found that with dynamic focusing, the maximum variability of tracked position was below 0.31 mm, as compared with 3.97 mm for a fixed focus.

Dual-modality fibre optic probe for simultaneous ablation and ultrasound imaging.

All-optical ultrasound (OpUS) is an emerging high resolution imaging paradigm utilising optical fibres. This allows both therapeutic and imaging modalities to be integrated into devices with dimensions small enough for minimally invasive surgical applications. Here we report a dual-modality fibre optic probe that synchronously performs laser ablation and real-time all-optical ultrasound imaging for ablation monitoring. The device comprises three optical fibres: one each for transmission and reception of ultrasound, and one for the delivery of laser light for ablation. The total device diameter is < 1 mm. Ablation monitoring was carried out on porcine liver and heart tissue ex vivo with ablation depth tracked using all-optical M-mode ultrasound imaging and lesion boundary identification using a segmentation algorithm. Ablation depths up to 2.1 mm were visualised with a good correspondence between the ultrasound depth measurements and visual inspection of the lesions using stereomicroscopy. This work demonstrates the potential for OpUS probes to guide minimally invasive ablation procedures in real time.

CuInS2 Quantum Dot and Polydimethylsiloxane Nanocomposites for All-Optical Ultrasound and Photoacoustic Imaging.

Dual-modality imaging employing complementary modalities, such as all-optical ultrasound and photoacoustic imaging, is emerging as a well-suited technique for guiding minimally invasive surgical procedures. Quantum dots are a promising material for use in these dual-modality imaging devices as they can provide wavelength-selective optical absorption. The first quantum dot nanocomposite engineered for co-registered laser-generated ultrasound and photoacoustic imaging is presented. The nanocomposites developed, comprising CuInS2 quantum dots and medical-grade polydimethylsiloxane (CIS-PDMS), are applied onto the distal ends of miniature optical fibers. The films exhibit wavelength-selective optical properties, with high optical absorption (> 90%) at 532 nm for ultrasound generation, and low optical absorption (< 5%) at near-infrared wavelengths greater than 700 nm. Under pulsed laser irradiation, the CIS-PDMS films generate ultrasound with pressures exceeding 3.5 MPa, with a corresponding bandwidth of 18 MHz. An ultrasound transducer is fabricated by pairing the coated optical fiber with a Fabry-Pérot (FP) fiber optic sensor. The wavelength-selective nature of the film is exploited to enable co-registered all-optical ultrasound and photoacoustic imaging of an ink-filled tube phantom. This work demonstrates the potential for quantum dots as wavelength-selective absorbers for all-optical ultrasound generation.

Freehand and video-rate all-optical ultrasound imaging.

All-optical ultrasound (AOUS) imaging, which uses light to both generate and detect ultrasound, is an emerging alternative to conventional electronic ultrasound imaging. To date, AOUS imaging has been performed using paradigms that either resulted in long acquisition times or employed bench-top imaging systems that were impractical for clinical use. In this work, we present a novel AOUS imaging paradigm where scanning optics are used to rapidly synthesise an imaging aperture. This paradigm enabled the first AOUS system with a flexible, handheld imaging probe, which represents a critical step towards clinical translation. This probe, which provides video-rate imaging and a real-time display, is demonstrated with phantoms and in vivo human tissue.

Broadband All-Optical Plane-Wave Ultrasound Imaging System Based on a Fabry-Perot Scanner.

A broadband all-optical plane-wave ultrasound imaging system for high-resolution 3-D imaging of biological tissues is presented. The system is based on a planar Fabry-Perot (FP) scanner for ultrasound detection and the photoacoustic generation of ultrasound in a carbon-nanotube-polydimethylsiloxane (CNT-PDMS) composite film. The FP sensor head was coated with the CNT-PDMS film which acts as an ultrasound transmitting layer for pulse-echo imaging. Exciting the CNT-PDMS coating with nanosecond laser pulses generated monopolar plane-wave ultrasound pulses with MPa-range peak pressures and a -6-dB bandwidth of 22 MHz, which were transmitted into the target. The resulting scattered acoustic field was detected across a 15 mm ×15 mm scan area with a step size of 100 [Formula: see text] and an optically defined element size of [Formula: see text]. The -3-dB bandwidth of the sensor was 30 MHz. A 3-D image of the scatterer distribution was then recovered using a k -space reconstruction algorithm. To obtain a measure of spatial resolution, the instrument line-spread function (LSF) was measured as a function of position. At the center of the scan area, the depth-dependent lateral LSF ranged from 46 to 65 [Formula: see text] for depths between 1 and 12 mm. The vertical LSF was independent of position and measured to be [Formula: see text] over the entire field of view. To demonstrate the ability of the system to provide high-resolution 3-D images, phantoms with well-defined scattering structures of arbitrary geometry were imaged. To demonstrate its suitability for imaging biological tissues, phantoms with similar impedance mismatches, sound speed and scattering properties to those present in the tissue, and ex vivo tissue samples were imaged. Compared with conventional piezoelectric-based ultrasound scanners, this approach offers the potential for improved image quality and higher resolution for superficial tissue imaging. Since the FP scanner is capable of high-resolution 3-D photoacoustic imaging of in vivo biological tissues, the system could ultimately be developed into an instrument for dual-mode all-optical ultrasound and photoacoustic imaging.