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

Beard, Paul C

Colchester, Richard J

Desjardins, Adrien E

Lim, Chung S

Zhang, Edward Z

Zhang, Shaoyan

English

UCL Discovery

PROCEEDINGS OF SPIESPIEDigitalLibrary.org/conference-proceedings-of-spieMiniaturised all-optical ultrasoundprobe for thrombus imagingShaoyan Zhang, Chung Lim, Edward Zhang, Paul Beard,Adrien Desjardins, et al.Shaoyan Zhang, Chung S. Lim, Edward Z. Zhang, Paul C. Beard, Adrien E.Desjardins, Richard J. Colchester, "Miniaturised all-optical ultrasound probefor thrombus imaging," Proc. SPIE 12631, Opto-Acoustic Methods andApplications in Biophotonics VI, 1263110 (11 August 2023); doi:10.1117/12.2669613Event: European Conferences on Biomedical Optics, 2023, Munich, GermanyDownloaded From: https://www.spiedigitallibrary.org/conference-proceedings-of-spie on 14 Sep 2023  Terms of Use: https://www.spiedigitallibrary.org/terms-of-useMiniaturised all-optical ultrasound probe for thrombusimagingShaoyan Zhanga,b, Chung S. Limc, Edward Z. Zhanga, Paul C. Bearda,b, Adrien E.Desjardinsa,b, and Richard J. Colchestera,baDepartment of Medical Physics and Biomedical Engineering, University College London,Gower Street, London WC1E 6BT, UKbWellcome/EPSRC Centre for Interventional and Surgical Sciences, University CollegeLondon, Charles Bell House, Foley Street, London W1W 7TY, UKcDepartment of Vascular Surgery, Royal Free London NHS Foundation Trust, London NW32QG, UKABSTRACTAll-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 miniaturisationand mechanical flexibility, high imaging resolution and immunity to electromagnetic interference. Here, wepresent 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 guidingminimally invasive endovascular clot retrieval procedures.Keywords: Optical ultrasound, Photoacoustic, Minimally invasive surgery, Thrombus imaging1. INTRODUCTIONVenous thromboembolism (VTE), encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE),is the third most common cardiovascular disease with an overall annual incidence of 100–200 per 100, 000 peo-ple.1,2 If untreated, acute PE is associated with a significant mortality rate, and accompanying humanisticand economic burden. Early thrombus removal with minimally invasive interventions reduces the risks of VTEcomplications. However, the thrombus age and molecular characteristics including its fibrin composition maydetermine the success of interventions.3,4 Therefore, peri-operative objective assessment of the thrombus age andmolecular characteristics will help improve the clinical decision making, risk stratification, treatment includinganti-coagulation regimen, and reduce complications. There is no such assessment tool available currently, andclinical decision is based solely on subjective history and conventional imaging. The challenge we propose is todevelop a pre- or peri-operative biomedical imaging and sensing material that can objectively determine the ageand molecular characteristics of in vivo venous thrombus.All-optical ultrasound (OpUS) is emerging as an alternative paradigm which is well suited for minimallyinvasive cardiovascular procedures. With this technique, ultrasound waves are both generated and receivedusing light.5 OpUS can provide broad ultrasound transmission bandwidths and high reception sensitivity forhigh-resolution interventional imaging.5,6 Additionally, the use of optical fibres for light delivery allows forminiaturisation of the device and immunity to electromagnetic interference.7 When integrated into a medicalcatheter, these devices are well-suited for imaging within the human body, in areas such as intravascular imag-ing, where space constraints are crucial. Furthermore, OpUS devices utilise low-cost materials and fabricationprocesses which are ideal for single use devices.Previously, OpUS has been used for 2D imaging of vascular tissues ex vivo5 and for M-mode intracardiacimaging ex vivo.6,7 Recently, rotational, side-viewing OpUS imaging has shown strong potential for intravascu-lar imaging.8 In this study, we performed a feasibility study for OpUS imaging of an ex vivo human thrombus,Further author information: (Send correspondence to Richard J. Colchester)Richard J. Colchester: E-mail: richard.colchester@ucl.ac.ukOpto-Acoustic Methods and Applications in Biophotonics VI, edited by Chulhong Kim, Jan Laufer, Vasilis Ntziachristos, Roger J. Zemp, Proc. of SPIE Vol. 12631, 1263110© 2023 SPIE · 0277-786X · doi: 10.1117/12.2669613Proc. of SPIE Vol. 12631  1263110-1Downloaded From: https://www.spiedigitallibrary.org/conference-proceedings-of-spie on 14 Sep 2023Terms of Use: https://www.spiedigitallibrary.org/terms-of-useextracted from a peripheral vessel of a patient during a clot retrieval procedure. The OpUS device used herecomprised two optical fibres; a multimode fibre with an optically absorbing composite coating for ultrasoundgeneration via the photoacoustic effect, and a single mode fibre with a plano-concave microresonator for ultra-sound reception. The high-resolution images acquired by the OpUS device demonstrated imaging through thefull thickness of the thrombus. These first-of-their-kind images of ex vivo human tissue represent a first steptowards using OpUS for diagnosis and treatment guidance during endovascular surgery.2. MATERIALS AND METHODS2.1 Optical ultrasound imaging systemThe all-optical ultrasound imaging system comprised two parts: the fibre-optic device and an opto-electronicconsole for interrogation (Figure 1). The fibre-optic device comprised two optical fibres; one for ultrasoundgeneration and one for ultrasound reception. For ultrasound generation, a 400 µm core multimode opticalfibre delivered photoacoustic excitation light to a composite coating consiting of reduced graphene oxide (rGO)and polydimethylsiloxane (PDMS). The fabrication process for the composite and transmitter was describedin a previous work.9 In brief, a solution of rGO and xylene was prepared by adding 500 mg rGO to 2.5 mlxylene. Then, the prepared optical fibre with a flat end face was dipped into the rGO and xylene solution andremoved to form a coating on the fibre end face. The coated fibre was left for 24 h in ambient conditions to dry.Figure 1. The schematic of the OpUS system for thrombus imaging. DAQ: data acquisition.Subsequently, the coated fibre was dipped into a PDMS solution (MED-1000, Polymer Systems Technology, UK)and directly removed. The rGO and PDMS coated fibre was left to cure in ambient conditions for a further 24 h.The fabricated ultrasound transmitter generated ultrasound peak-to-peak pressure in excess of 1 MPa, withcorressponding bandwidth of > 20 MHz, allowing for promising ultrasound wave penetration depth and highimaging resolution. The optical ultrasound receiver comprised a plano-concave microresonator on a single modeoptical fibre using the design and fabrication process described in previous work.10 Briefly, a dielectric mirror wasdeposited onto the end face of the single mode fibre. Subsequently, the fibre was coated with an epoxy dome andthen another dielectric mirror was deposited. For protection, a Parylene C overcoat was applied to the distal fibreend. The optical ultrasound imaging console that controlled ultrasound generation and interrogated the plano-concave microresonator comprised two lasers. A Q-switched Nd:YAG laser (SPOT-10-500-1064, Elforlight, UK)with wavelength of 1064 nm, a pulse width of 2 ns, pulse energy of 30 µJ, and repetition rate of 100 Hz was usedto irradiate the rGO-PDMS composite coating for ultrasound generation. For ultrasound detection, a wavelengthtuneable laser (Tunics T100S-HP CL, Yenista Optics, France) with operating wavelength ranging from 1500 nmto 1600 nm was used to interrogate the plano-concave microresonator. The laser was connected via a fibre opticProc. of SPIE Vol. 12631  1263110-2Downloaded From: https://www.spiedigitallibrary.org/conference-proceedings-of-spie on 14 Sep 2023Terms of Use: https://www.spiedigitallibrary.org/terms-of-usecirculator, allowing the reflected light to be detected by a photoreceiver that split the output into DC (< 50 kHz)and AC (> 500 kHz) components. The DC component was used to track the optimum bias point, whilst theAC component recorded the modulation of the reflected optical power caused by impinging ultrasound waves.To optimise the sensitivity of the plano-concave microresonator, the wavelength of tuneable laser was biased toa local maximum derivative of the interferometer transfer function (ITF). In this case, the received ultrasoundsignal can be converted from the variations of the reflected optical power induced by impinging ultrasound waves.To form the OpUS device, the fibre optic ultrasound transmitter and receiver were held together using the heatshrink tubing and their end faces were aligned at the same level (Figure 1). The total lateral dimension of thedevice was less than 1 mm.2.2 Ex vivo human thrombus imagingResearch ethical approval for obtaining human clots was obtained from the Royal Free London NHS FoundationTrust and UCL Biobank (REC reference: 21/WA/0388). For imaging ex vivo, the thrombus sample was placedin a syringe (10 ml) filled with saline. The syringe had a customised window (30 mm × 20 mm) on the sidewall. The OpUS device was mounted on a motorised stage (MTS50/M-Z8, Thorlabs, UK) and placed abovethe thrombus sample through the window on the syringe (Figure 1). During imaging, the OpUS device wastranslated laterally, across the whole segment of the thrombus sample with a step size of 50 µm. For each step,an ultrasound A-line was acquired. Prior to display, the signals acquired underwent several image processingsteps. The A-lines were concatenated and underwent bandpass filtering (Butterworth, 10-40 MHz, 4th order).The cross-talk signals originating from the direct transmission of ultrasound wave from the coating were reducedusing a general linear model.5 Subsequently, image reconstruction was performed using a k-space method.11Finally, envelope detection was effected with the Hilbert transform; logarithmic transformation was performedprior to display.3. RESULTS AND DISCUSSIONWith the ex vivo human thrombus sample, the OpUS imaging provided visualisation through the full thickness ofdBCross-talkSyringewallThrombusFigure 2. Ex vivo human thrombus OpUS image showing contrast throughout the full extent (7 mm) and beyond it tothe syringe wall. The cross-talk arising from direct transmissions from the fibre-optic generator to the receiver is apparentin the first 3 mm.Proc. of SPIE Vol. 12631  1263110-3Downloaded From: https://www.spiedigitallibrary.org/conference-proceedings-of-spie on 14 Sep 2023Terms of Use: https://www.spiedigitallibrary.org/terms-of-usethe thrombus (7 mm), with a dynamic range of 35 dB (Figure 2). The OpUS image had a granular texture withseveral hyperechoic regions of unknown provenance. Speculatively, the texture and the ultrasonic attenuationcharateristics obtained with OpUS could be used to provide information about the composition of a thrombusfrom within a vessel, which could in turn be used to determine its age (Figure 2). The age of a thrombusmay influence the treatment strategy: acute and subacute thrombi can be treated with pharmacomechanicalthrombectomy, while chronic thrombus can be treated with balloon angioplasty and stenting.12,13 Additionally,OpUS could be used to determine the source of a thrombus, such as whether it was of arterial or venous origin,whether it was related to cancer or benign conditions, and whether it was caused by an embolus from cardiacarrhythmia or a localised rupture atherosclerotic plaque. This information could be useful in determining theunderlying pathology and formulating an appropriate treatment plan. Furthermore, therapeutic modalities suchas laser thrombolysis could be integrated, thereby providing concurrent treatment and imaging guidance. Futurestudies will explore the histological correlates of ex vivo thrombi of different ages and sources, and progress toin vivo imaging.4. CONCLUSIONThis study demonstrated the first-ever ex vivo human blood imaging by a miniaturised all-optical ultrasounddevice. With this device, high-resolution OpUS images containing potentially clinically relevant features wereobtained. This proof-of-concept work provides a very early demonstration of the capability of OpUS imaging tovisualise thrombi, and sets the stage for more detailed studies to assess the clinical utility of this modality forguiding endovascular treatment of venous thromboembolism (VTE) and deep vein thrombosis (DVT).ACKNOWLEDGMENTSThis work was supported by the Royal Academy of Engineering under the Research Fellowship Scheme (RF/201819/18/125) and the Wellcome/EPSRC Centre for Interventional and Surgical Sciences (203145/Z/16/Z) and anERC Advanced Grant (74119).REFERENCES[1] Heit, J. A., Spencer, F. A., and White, R. H., “The epidemiology of venous thromboembolism,” Journal ofThrombosis and Thrombolysis 41, 3–14 (1 2016).[2] Glynn, R. J. and Rosner, B., “Comparison of Risk Factors for the Competing Risks of Coronary HeartDisease, Stroke, and Venous Thromboembolism,” American Journal of Epidemiology 162, 975–982 (112005).[3] Jolugbo, P. and Ariëns, R. A., “Thrombus Composition and Efficacy of Thrombolysis and Thrombectomyin Acute Ischemic Stroke,” Stroke 52, 1131–1142 (3 2021).[4] Czaplicki, C., Albadawi, H., Partovi, S., Gandhi, R. T., Quencer, K., Deipolyi, A. R., and Oklu, R., “Canthrombus age guide thrombolytic therapy?,” Cardiovascular Diagnosis and Therapy 7, S186–S196 (12 2017).[5] Colchester, R. J., Zhang, E. Z., Mosse, C. A., Beard, P. C., Papakonstantinou, I., and Desjardins, A. E.,“Broadband miniature optical ultrasound probe for high resolution vascular tissue imaging,” BiomedicalOptics Express 6(4), 1502 (2015).[6] Finlay, M. C., Mosse, C. A., Colchester, R. J., Noimark, S., Zhang, E. Z., Ourselin, S., Beard, P. C., Schilling,R. J., Parkin, I. P., Papakonstantinou, I., and Desjardins, A. 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Miniaturised all-optical ultrasound probe for thrombus imaging

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Miniaturised all-optical ultrasound probe for thrombus imaging

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