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.

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.

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 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 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.

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.

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.

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.

In vivo three-dimensional photoacoustic imaging of the renal vasculature in preclinical rodent models.

Noninvasive imaging of the kidney vasculature in preclinical murine models is important for the assessment of renal development, studying diseases and evaluating new therapies but is challenging to achieve using existing imaging modalities. Photoacoustic imaging is a promising new technique that is particularly well suited to visualizing the vasculature and could provide an alternative to existing preclinical imaging methods for studying renal vascular anatomy and function. To investigate this, an all-optical Fabry-Perot-based photoacoustic scanner was used to image the abdominal region of mice. High-resolution three-dimensional, noninvasive, label-free photoacoustic images of the mouse kidney and renal vasculature were acquired in vivo. The scanner was also used to visualize and quantify differences in the vascular architecture of the kidney in vivo due to polycystic kidney disease. This study suggests that photoacoustic imaging could be utilized as a novel preclinical imaging tool for studying the biology of renal disease.

Rapid volumetric photoacoustic tomographic imaging with a Fabry-Perot ultrasound sensor depicts peripheral arteries and microvascular vasomotor responses to thermal stimuli.

PURPOSE: To determine if a new photoacoustic imaging (PAI) system successfully depicts (1) peripheral arteries and (2) microvascular circulatory changes in response to thermal stimuli. METHODS: Following ethical permission, 8 consenting subjects underwent PAI of the dorsalis pedis (DP) artery, and 13 completed PAI of the index fingertip. Finger images were obtained after immersion in warm (30-35 °C) or cold (10-15 °C) water to promote vasodilation or vasoconstriction. The PAI instrument used a Fabry-Perot interferometeric ultrasound sensor and a 30-Hz 750-nm pulsed excitation laser. Volumetric images were acquired through a 14 × 14 × 14-mm volume over 90 s. Images were evaluated subjectively and quantitatively to determine if PAI could depict cold-induced vasoconstriction. The full width at half maximum (FWHM) of resolvable vessels was measured. RESULTS: Fingertip vessels were visible in all participants, with mean FWHM of 125 µm. Two radiologists used PAI to correctly identify vasoconstricted fingertip capillary beds with 100% accuracy (95% CI 77.2-100.0%, p < 0.001). The number of voxels exhibiting vascular signal was significantly smaller after cold water immersion (cold: 5263 voxels; warm: 363,470 voxels, p < 0.001). The DP artery was visible in 7/8 participants (87.5%). CONCLUSION: PAI achieves rapid, volumetric, high-resolution imaging of peripheral limb vessels and the microvasculature and is responsive to vasomotor changes induced by thermal stimuli. KEY POINTS: • Fabry-Perot interferometer-based photoacoustic imaging (PAI) generates volumetric, high-resolution images of the peripheral vasculature. • The system reliably detects thermally induced peripheral vasoconstriction (100% correct identification rate, p < 0.001). • Vessels measuring less than 100 µm in diameter can be depicted in vivo.

Gold-silica quantum rattles for multimodal imaging and therapy.

Gold quantum dots exhibit distinctive optical and magnetic behaviors compared with larger gold nanoparticles. However, their unfavorable interaction with living systems and lack of stability in aqueous solvents has so far prevented their adoption in biology and medicine. Here, a simple synthetic pathway integrates gold quantum dots within a mesoporous silica shell, alongside larger gold nanoparticles within the shell's central cavity. This "quantum rattle" structure is stable in aqueous solutions, does not elicit cell toxicity, preserves the attractive near-infrared photonics and paramagnetism of gold quantum dots, and enhances the drug-carrier performance of the silica shell. In vivo, the quantum rattles reduced tumor burden in a single course of photothermal therapy while coupling three complementary imaging modalities: near-infrared fluorescence, photoacoustic, and magnetic resonance imaging. The incorporation of gold within the quantum rattles significantly enhanced the drug-carrier performance of the silica shell. This innovative material design based on the mutually beneficial interaction of gold and silica introduces the use of gold quantum dots for imaging and therapeutic applications.

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.

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.

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.

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.

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.

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.