Towards clinical application of freehand optical ultrasound imaging.

Freehand optical ultrasound (OpUS) imaging is an emerging ultrasound imaging paradigm that uses an array of fibre-optic, photoacoustic ultrasound sources and a single fibre-optic ultrasound detector to perform ultrasound imaging without the need for electrical components in the probe head. Previous freehand OpUS devices have demonstrated capability for real-time, video-rate imaging of clinically relevant targets, but have been hampered by poor ultrasound penetration, significant imaging artefacts and low frame rates, and their designs limited their clinical applicability. In this work we present a novel freehand OpUS imaging platform, including a fully mobile and compact acquisition console and an improved probe design. The novel freehand OpUS probe presented utilises optical waveguides to shape the generated ultrasound fields for improved ultrasound penetration depths, an extended fibre-optic bundle to improve system versatility and an overall ruggedised design with protective elements to improve probe handling and protect the internal optical components. This probe is demonstrated with phantoms and the first multi-participant in vivo imaging study conducted with freehand OpUS imaging probes, this represents several significant steps towards the clinical translation of freehand OpUS imaging.

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.

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.

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.

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.

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.

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.

Miniature all-optical flexible forward-viewing photoacoustic endoscopy probe for surgical guidance.

A miniature flexible photoacoustic endoscopy probe that provides high-resolution 3D images of vascular structures in the forward-viewing configuration is described. A planar Fabry-Perot ultrasound sensor with a -3dB bandwidth of 53 MHz located at the tip of the probe is interrogated via a flexible fiber bundle and a miniature optical relay system to realize an all-optical probe measuring 7.4 mm in outer diameter at the tip. This approach to photoacoustic endoscopy offers advantages over previous piezoelectric based distal-end scanning probes. These include a forward-viewing configuration in widefield photoacoustic tomography mode, finer spatial sampling (87 µm spatial sampling interval), and wider detection bandwidth (53 MHz) than has been achievable with conventional ultrasound detection technology and an all-optical passive imaging head for safe endoscopic use.

Single-shot hybrid photoacoustic-fluorescent microendoscopy through a multimode fiber with wavefront shaping.

We present a minimally-invasive endoscope based on a multimode fiber that combines photoacoustic and fluorescence sensing. From the measurement of a transmission matrix during a prior calibration step, a focused spot is produced and raster-scanned over a sample at the distal tip of the fiber by use of a fast spatial light modulator. An ultra-sensitive fiber-optic ultrasound sensor for photoacoustic detection placed next to the fiber is combined with a photodetector to obtain both fluorescence and photoacoustic images with a distal imaging tip no larger than 250 µm. The high signal-to-noise ratio provided by wavefront shaping based focusing and the ultra-sensitive ultrasound sensor enables imaging with a single laser shot per pixel, demonstrating fast two-dimensional hybrid in vitro imaging of red blood cells and fluorescent beads.

High pulse energy fibre laser as an excitation source for photoacoustic tomography.

A custom fibre laser designed as an excitation source for biomedical photoacoustic tomography has been developed. It is based on a custom-drawn large core diameter fibre (200 µm) that enables high pulse energies (∼10 mJ) to be achieved. The system can provide variable pulse durations (10 - 500 ns) and pulse repetition frequencies (100 Hz - 1 kHz), as well as arbitrary pulse bursts according to specific user defined sequences. The system is also compact and does not require external water cooling. This, along with the flexibility in the temporal characteristics of its output that it offers, will aid the translation of photoacoustic imaging to practical application in medicine and biology.

Modelling Fabry-Pérot etalons illuminated by focussed beams.

Fabry-Pérot (FP) etalons are used as filters and sensors in a range of optical systems. Often FP etalons are illuminated by collimated laser beams, in which case the transmitted and reflected light fields can be calculated analytically using well established models. However, FP etalons are sometimes illuminated by more complex beams such as focussed Gaussian beams, which may also be aberrated. Modelling the response of FP etalons to these beams requires a more sophisticated model. To address this need, we present a model that can describe the response of an FP etalon that is illuminated by an arbitrary beam. The model uses an electromagnetic wave description of light and can therefore compute the amplitude, phase and polarization of the optical field at any position in the system. It can also account for common light delivery and detection components such as lenses, optical fibres and photo-detectors, allowing practical systems to be simulated. The model was validated against wavelength resolved measurements of transmittance and reflectance obtained using a system consisting of an FP etalon illuminated by a focussed Gaussian beam. Experiments with focal spot sizes ranging from 30 µm to 250 µm and FP etalon mirror reflectivities in the range 97.2 % to 99.2 % yielded excellent visual agreement between simulated and experimental data and an average error below 10% for a range of quantitative comparative metrics. We expect the model to be a useful tool for designing, understanding and optimising systems that use FP etalons.

Photoacoustic imaging of the human placental vasculature.

Minimally invasive fetal interventions require accurate imaging from inside the uterine cavity. Twin-to-twin transfusion syndrome (TTTS), a condition considered in this study, occurs from abnormal vascular anastomoses in the placenta that allow blood to flow unevenly between the fetuses. Currently, TTTS is treated fetoscopically by identifying the anastomosing vessels, and then performing laser photocoagulation. However, white light fetoscopy provides limited visibility of placental vasculature, which can lead to missed anastomoses or incomplete photocoagulation. Photoacoustic (PA) imaging is an alternative imaging method that provides contrast for hemoglobin, and in this study, two PA systems were used to visualize chorionic (fetal) superficial and subsurface vasculature in human placentas. The first system comprised an optical parametric oscillator for PA excitation and a 2D Fabry-Pérot cavity ultrasound sensor; the second, light emitting diode arrays and a 1D clinical linear-array ultrasound imaging probe. Volumetric photoacoustic images were acquired from ex vivo normal term and TTTS-treated placentas. It was shown that superficial and subsurface branching blood vessels could be visualized to depths of approximately 7 mm, and that ablated tissue yielded negative image contrast. This study demonstrated the strong potential of PA imaging to guide minimally invasive fetal therapies.

Use of a flexible optical fibre bundle to interrogate a Fabry-Perot sensor for photoacoustic imaging.

Photoacoustic imaging systems based on a Fabry Perot (FP) ultrasound sensor that is read-out by scanning a free-space laser beam over its surface can provide high resolution photoacoustic images. However, this type of free-space scanning usually requires a bulky 2-axis galvanometer based scanner that is not conducive to the realization of a lightweight compact imaging head. It is also unsuitable for endoscopic applications that may require complex and flexible access. To address these limitations, the use of a flexible, coherent fibre bundle to interrogate the FP sensor has been investigated. A laboratory set-up comprising an x-y scanner, a commercially available, 1.35 mm diameter, 18,000 core flexible fibre bundle with a custom-designed telecentric optical relay at its distal end was used. Measurements of the optical and acoustic performance of the FP sensor were made and compared to that obtained using a conventional free-space FP based scanner. Spatial variations in acoustic sensitivity were greater and the SNR lower with the fibre bundle implementation but high quality photoacoustic images could still be obtained. 3D images of phantoms and ex vivo tissues with a spatial resolution and fidelity consistent with a free-space scanner were acquired. By demonstrating the feasibility of interrogating the FP sensor with a flexible fibre bundle, this study advances the realization of compact hand-held clinical scanners and flexible endoscopic devices based on the FP sensing concept.