Contrast agents for molecular photoacoustic imaging.

Photoacoustic imaging (PAI) is an emerging tool that bridges the traditional depth limits of ballistic optical imaging and the resolution limits of diffuse optical imaging. Using the acoustic waves generated in response to the absorption of pulsed laser light, it provides noninvasive images of absorbed optical energy density at depths of several centimeters with a resolution of ∼100 μm. This versatile and scalable imaging modality has now shown potential for molecular imaging, which enables visualization of biological processes with systemically introduced contrast agents. Understanding the relative merits of the vast range of contrast agents available, from small-molecule dyes to gold and carbon nanostructures to liposome encapsulations, is a considerable challenge. Here we critically review the physical, chemical and biochemical characteristics of the existing photoacoustic contrast agents, highlighting key applications and present challenges for molecular PAI.This work was supported by CRUK (Career Establishment Award no. C47594/A16267 to J.W. and S.E.B., Core Funding C14303/A17197 to J.W. and S.E.B.), the European Commission (CIG FP7-PEOPLE- 2013-CIG-630729 to J.W. and S.E.B.), the EPSRC-CRUK Cancer Imaging Centre in Cambridge and Manchester (C197/A16465 to J.W. and S.E.B.), King’s College London and University College London Comprehensive Cancer Imaging Centre Cancer Research UK & Engineering and Physical Sciences Research Council, in association with the Medical Research Council and the Department of Health, UK (P.B.), and the European Union (project FAMOS FP7 ICT, contract 317744 to P.B.).This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nmeth.392

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 (0.4 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

Concurrent Optical Ultrasound and CT Imaging

Optical ultrasound imaging is an emerging paradigm that utilises fiber-optic ultrasound sources and detectors to perform pulse-echo imaging. Using rapid-prototyping techniques, flexible fiber-optic free-hand probes, capable of video-rate imaging can be constructed entirely from glass and plastic. As such, these devices are expected to be inherently compatible with electromagnetic imaging modalities such as magnetic resonance imaging and computed tomography imaging. However, to date, this multimodal capability has not been demonstrated. In this work, a new free-hand optical ultrasound (OpUS) imaging system is introduced, its real-time imaging capability demonstrated on a range of phantoms, and the first concurrent use of OpUS alongside cone-beam CT (CBCT) imaging is presented

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

Laser frequency noise characterisation using high-finesse plano-concave optical microresonators

Characterising laser frequency noise is essential for applications including optical sensing and coherent optical communications. Accurate measurement of ultranarrow linewidth lasers over a wide frequency range using existing methods is still challenging. Here we present a method for characterising the frequency noise of lasers using a high finesse plano-concave optical microresonator (PCMR) acting as 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 (15Hz to &lt;100MHz) over the 1440nm-1630nm wavelength range. To assess the performance of the method, four different lasers were characterised, and the results were compared to the estimations of a commercial frequency noise analyser

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 all-optical ultrasound probe for thrombus imaging

All-Optical Ultrasound (OpUS) has emerged as an imaging paradigm well-suited for minimally invasive procedures. In particular, OpUS has demonstrated potential in endovascular imaging due to its high degree of miniaturization and mechanical flexibility, high imaging resolution and immunity to electromagnetic interference. Here, we present the first human thrombus imaging using an OpUS device, which was performed on an extracted clot. The results demonstrate the feasibility of using OpUS for thrombus imaging, with the ultimate goal of guiding minimally invasive endovascular clot retrieval procedures

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 &lt;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