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.

Biohybrid microrobots regulate colonic cytokines and the epithelium barrier in inflammatory bowel disease.

Cytokines have been identified as key contributors to the development of inflammatory bowel disease (IBD), yet conventional treatments often prove inadequate and carry substantial side effects. Here, we present an innovative biohybrid robotic system, termed "algae-MΦNP-robot," for addressing IBD by actively neutralizing colonic cytokine levels. Our approach combines moving green microalgae with macrophage membrane-coated nanoparticles (MΦNPs) to efficiently capture proinflammatory cytokines "on the fly." The dynamic algae-MΦNP-robots outperformed static counterparts by enhancing cytokine removal through continuous movement, better distribution, and extended retention in the colon. This system is encapsulated in an oral capsule, which shields it from gastric acidity and ensures functionality upon reaching the targeted disease site. The resulting algae-MΦNP-robot capsule effectively regulated cytokine levels, facilitating the healing of damaged epithelial barriers. It showed markedly improved prevention and treatment efficacy in a mouse model of IBD and demonstrated an excellent biosafety profile. Overall, our biohybrid algae-MΦNP-robot system offers a promising and efficient solution for IBD, addressing cytokine-related inflammation effectively.

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.

Extending the In Vivo Residence Time of Macrophage Membrane-Coated Nanoparticles through Genetic Modification.

Nanoparticles coated with natural cell membranes have emerged as a promising class of biomimetic nanomedicine with significant clinical potential. Among them, macrophage membrane-coated nanoparticles hold particular appeal due to their versatility in drug delivery and biological neutralization applications. This study employs a genetic engineering approach to enhance their in vivo residence times, aiming to further improve their performance. Specifically, macrophages are engineered to express proline-alanine-serine (PAS) peptide chains, which provide additional protection against opsonization and phagocytosis. The resulting modified nanoparticles demonstrate prolonged residence times when administered intravenously or introduced intratracheally, surpassing those coated with the wild-type membrane. The longer residence times also contribute to enhanced nanoparticle efficacy in inhibiting inflammatory cytokines in mouse models of lipopolysaccharide-induced lung injury and sublethal endotoxemia, respectively. This study underscores the effectiveness of genetic modification in extending the in vivo residence times of macrophage membrane-coated nanoparticles. This approach can be readily extended to modify other cell membrane-coated nanoparticles toward more favorable biomedical applications.

Capsulated Cellular Nanosponges for the Treatment of Experimental Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a chronic gastrointestinal tract disorder characterized by uncontrolled inflammatory responses to the disrupted intestinal epithelial barrier and gut microbiome dysbiosis. Currently available small-molecule immunosuppressive agents and anticytokine biologics show limited potency, mainly due to the complexity of the inflammatory network involved in IBD. Here, we develop an oral formulation of macrophage membrane-coated nanoparticles capsulated in enteric polymer-coated gelatin capsules (denoted "cp-MΦ-NPs") for IBD treatment. The capsules protect the nanoparticles from gastric degradation and allow for targeted delivery to the colon. At the inflamed colon, cp-MΦ-NPs act as macrophage decoys that bind and neutralize pro-inflammatory cytokines. The in vivo treatment efficacy of cp-MΦ-NPs is tested in a mouse model of dextran sulfate sodium-induced colitis. In both prophylactic and delayed treatment regimens, the oral delivery of cp-MΦ-NPs significantly alleviates IBD severity, reflected by reduced intestinal inflammation and intestinal barrier restoration. Overall, cp-MΦ-NPs provide a biomimetic nanomedicine strategy for the treatment of IBD.

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.

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.

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.

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.

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.

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.

A lymphatic-absorbed multi-targeted kinase inhibitor for myelofibrosis therapy.

Activation of compensatory signaling nodes in cancer often requires combination therapies that are frequently plagued by dose-limiting toxicities. Intestinal lymphatic drug absorption is seldom explored, although reduced toxicity and sustained drug levels would be anticipated to improve systemic bioavailability. A potent orally bioavailable multi-functional kinase inhibitor (LP-182) is described with intrinsic lymphatic partitioning for the combined targeting of phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways without observable toxicity. We demonstrate selectivity and therapeutic efficacy through reduction of downstream kinase activation, amelioration of disease phenotypes, and improved survival in animal models of myelofibrosis. Our further characterization of synthetic and physiochemical properties for small molecule lymphatic uptake will support continued advancements in lymphatropic therapy for altering disease trajectories of a myriad of human disease indications.

A systematic review of patient-reported outcome measures in paediatric endocrinology.

CONTEXT: Patient reported outcome measures (PROMs) are useful tools in paediatric endocrinology to gauge health status in children, especially since they are often unable to clearly communicate it themselves. We aimed to systematically search and appraise all available PROMs relevant to paediatric endocrinology and provide a curated resource for health professionals to utilise. EVIDENCE ACQUISITION: We identified PROMs in paediatric endocrinology by systematically searching the Cochrane Library, MEDLINE, World Health Organisation International Clinical Trials Registry Platform, and the Cumulative Index to Nursing and Allied Health Literature on May 20, 2022. Additional studies were located through hand searching and content area expert contributions. We assessed the quality of each PROM using the COSMIN risk of bias checklist. EVIDENCE SYNTHESIS: We identified 5003 papers in the initial search. After applying exclusion criteria we included seven PROMs in the review. Six PROMs were specific to Type I Diabetes and one to Hypothyroidism. We gave all studies an overall COSMIN score of 'inadequate' due to poorly detailed PROM development. CONCLUSION: The scope and quality of PROMs in paediatric endocrinology is limited. Further research and development of PROM tools are required in paediatric endocrinology to allow for improved patient care.

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.

Structural effects of morpholine replacement in ZSTK474 on Class I PI3K isoform inhibition: Development of novel MEK/PI3K bifunctional inhibitors.

Established roles for PI3K and MAPK signaling pathways in tumorigenesis has prompted extensive research towards the discovery of small-molecule inhibitors as cancer therapeutics. However, significant compensatory regulation exists between these two signaling cascades, leading to redundancy among survival pathways. Consequently, initial clinical trials aimed at either PI3K or MEK inhibition alone have proven ineffective and highlight the need for development of targeted and innovative therapeutic combination strategies. We designed a series of PI3K inhibitor derivatives wherein a single morpholine group of the PI3K inhibitor ZSTK474 was substituted with a variety of 2-aminoethyl functional groups. Analogs with pendant hydroxyl or methoxy groups maintained low nanomolar inhibition towards PI3Kα, PI3Kγ, and PI3Kδ isoforms in contrast to those with pendant amino groups which were significantly less inhibitory. Synthesis of prototype PI3K/MEK bifunctional inhibitors (6r, 6s) was guided by the structure-activity data, where a MEK-targeting inhibitor was tethered directly via a short PEG linker to the triazine core of the PI3K inhibitor analogs. These compounds (6r, 6s) displayed nanomolar inhibition towards PI3Kα, δ, and MEK (IC50 ∼105-350 nM), and low micromolar inhibition for PI3Kß and PI3Kγ (IC50 ∼1.5-3.9 µM) in enzymatic inhibition assays. Cell viability assays demonstrated superior anti-proliferative activity for 6s over 6r in three tumor-derived cell lines (A375, D54, SET-2), which correlated with inhibition of downstream AKT and ERK1/2 phosphorylation. Compounds 6r and 6s also demonstrated in vivo tolerability with therapeutic efficacy through reduction of kinase activation and amelioration of disease phenotypes in the JAK2V617F mutant myelofibrosis mouse cancer model. Taken together, these results support further structure optimization of 6r and 6s as promising leads for combination therapy in human cancer as a new class of PI3K/MEK bifunctional inhibitors.

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.