Silicon-photonics focused ultrasound detector for minimally invasive optoacoustic imaging.

ptoacoustic image of a double-loop-shaped

Biomedical Optics Express Vol. 13, Issue 12, pp. 6229-6244 (2022)
© 2022 Optica Publishing Group under the terms of the Optica Open Access Publishing Agreement

Michael Nagli, Jürgen Koch, Yoav Hazan, Oleg Volodarsky, Resmi Ravi Kumar, Ahiad Levi, Evgeny Hahamovich, Orna Ternyak, Ludger Overmeyer, and Amir Rosenthal

Abstract
One of the main challenges in miniaturizing optoacoustic technology is the low sensitivity of sub-millimeter piezoelectric ultrasound transducers, which is often insufficient for detecting weak optoacoustic signals. Optical detectors of ultrasound can achieve significantly higher sensitivities than their piezoelectric counterparts for a given sensing area but generally lack acoustic focusing, which is essential in many minimally invasive imaging configurations. In this work, we develop a focused sub-millimeter ultrasound detector composed of a silicon-photonics optical resonator and a micro-machined acoustic lens. The acoustic lens provides acoustic focusing, which, in addition to increasing the lateral resolution, also enhances the signal. The developed detector has a wide bandwidth of 84 MHz, a focal width smaller than 50 µm, and noise-equivalent pressure of 37 mPa/Hz1/2 – an order of magnitude improvement over conventional intravascular ultrasound. We show the feasibility of the approach and the detector’s imaging capabilities by performing high-resolution optoacoustic microscopy of optical phantoms with complex geometries.

[Read more…]

The detector’s fabrication process.
Image generated by GPL Ghostscript (device=ppmraw)

Fig. The detector’s fabrication process. (a) Schematic description of the bonding and the substrate etching steps. (b) A waveguide array fabricated on top of an SOI die (left), an acoustic lens within a quartz substrate (center), and an etched waveguide array bonded to the acoustic lens (right). (c) Fiber bonding setup. The detector is placed under a microscope and between two rotating fiber holders, each connected to a 5-degree of freedom manipulator (x, y, z, pitch, yaw). (d) The assembled detector mounted on the scanning system (3D stage) inside a water tank.

Michael Nagli, Jürgen Koch, Yoav Hazan, Oleg Volodarsky, Resmi Ravi Kumar, Ahiad Levi, Evgeny Hahamovich, Orna Ternyak, Ludger Overmeyer, and Amir Rosenthal.

Biomedical Optics Express Vol. 13, Issue 12, pp. 6229-6244 (2022) •https://doi.org/10.1364/BOE.470295
© 2022 Optica Publishing Group under the terms of the Optica Open Access Publishing Agreement

Everolimus-eluting stents stabilize plaque inflammation in vivo: assessment by intravascular fluorescence molecular imaging.

source: © 2016 European Heart Journal

Aims
Inflammation drives atherosclerosis complications and is a promising therapeutic target for plaque stabilization. At present, it is unknown whether local stenting approaches can stabilize plaque inflammation in vivo. Here, we investigate whether everolimus-eluting stents (EES) can locally suppress plaque inflammatory protease activity in vivo using intravascular near-infrared fluorescence (NIRF) molecular imaging.
Methods and results
Balloon-injured, hyperlipidaemic rabbits with atherosclerosis received non-overlapping EES and bare metal stents (BMS) placement into the infrarenal aorta (n = 7 EES, n = 7 BMS, 3.5 mm diameter x 12 mm length). Four weeks later, rabbits received an injection of the cysteine protease-activatable NIRF imaging agent Prosense VM110. Twenty-four hours later, co-registered intravascular 2D NIRF, X-ray angiography and intravascular ultrasound imaging were performed. In vivo EES-stented plaques contained substantially reduced NIRF inflammatory protease activity compared with untreated plaques and BMS-stented plaques (P = 0.006). Ex vivo macroscopic NIRF imaging of plaque protease activity corroborated the in vivo results (P = 0.003). Histopathology analyses revealed that EES-treated plaques showed reduced neointimal and medial arterial macrophage and cathepsin B expression compared with unstented and BMS-treated plaques.
Conclusions
EES-stenting stabilizes plaque inflammation as assessed by translational intravascular NIRF molecular imaging in vivo. These data further support that EES may provide a local approach for stabilizing inflamed plaques.[Read more…]

FRI of plaque

Fig. Ex vivo FRI analyses of plaque inflammatory cysteine protease activity in BMS-, EES-treated, and unstented plaque zones. (A–C) Ex vivo FRI alignments from three representative animals. All NIRF images were obtained with a one second exposure. Image windows optimized for individual images.

Marcella A. Calfon Press, Georgios Mallas, Amir Rosenthal, Tetsuya Hara, Adam Mauskapf, R. Nika Nudelman, Alexander Sheehy, Igor V. Polyakov, Frank Kolodgie, Renu Virmani, J. Luis Guerrero, Vasilis Ntziachristos, Farouc A. Jaffer.European Heart Journal – Cardiovascular Imaging, Volume 18, Issue 5, 1 May 2017, Pages 510–518.

Quantitative intravascular biological fluorescence-ultrasound imaging of coronary and peripheral arteries in vivo.

source: © 2016 European Heart Journal

Aims
(i) to evaluate a novel hybrid near-infrared fluorescence—intravascular ultrasound (NIRF-IVUS) system in coronary and peripheral swine arteries in vivo;  (ii) to assess simultaneous quantitative biological and morphological aspects of arterial disease.
Methods and results
Two 9F/15MHz peripheral and 4.5F/40MHz coronary near-infrared fluorescence (NIRF)-IVUS catheters were engineered to enable accurate co-registrtation of biological and morphological readings simultaneously in vivo. A correction algorithm utilizing IVUS information was developed to account for the distance-related fluorescence attenuation due to through-blood imaging. Corrected NIRF (cNIRF)-IVUS was applied for in vivo imaging of angioplasty-induced vascular injury in swine peripheral arteries and experimental fibrin deposition on coronary artery stents, and of atheroma in a rabbit aorta, revealing feasibility to intravascularly assay plaque structure and inflammation. The addition of ICG-enhanced NIRF assessment improved the detection of angioplasty-induced endothelial damage compared to standalone IVUS. In addition, NIRF detection of coronary stent fibrin by in vivo cNIRF-IVUS imaging illuminated stent pathobiology that was concealed on standalone IVUS. Fluorescence reflectance imaging and microscopy of resected tissues corroborated the in vivo findings.
Conclusions
Integrated cNIRF-IVUS enables simultaneous co-registered through-blood imaging of disease related morphological and biological alterations in coronary and peripheral arteries in vivo. Clinical translation of cNIRF-IVUS may significantly enhance knowledge of arterial pathobiology, leading to improvements in clinical diagnosis and prognosis, and helps to guide the development of new therapeutic approaches for arterial diseases.[Read more…]

Intravascular cNIRF-IVUS image

Intravascular cNIRF-IVUS imaging with the 4.5F/40MHz catheter reveals the value of IVUS-based distance correction of the NIRF signal in blood. In vivo cNIRF-IVUS imaging of a swine carotid artery was performed following local injection of an NIR fluorophore into the artery wall. Panels (A), (B) and (C) illustrate the in vivo cNIRF image, the corresponding longitudinal IVUS image, and the FRI image of the resected artery, respectively. (D) A 3D representation of the lumen and arterial wall NIR fluorescence signal rendered based on the in vivo cNIRF-IVUS image stack. Insets (C1–C3) show representative examples of the cross-sectional cNIRF-IVUS images corresponding to pullback positions C1, C2, and C3 in (B), (C), and (D). The cNIRF signal in C1, C2, and C3 is fused onto the interior of the IVUS catheter and also replicated at the exterior (outlined with red dotted lines) of the IVUS image. (E) Serial imaging of the same vessel region demonstrates that the raw NIRF signal (top row) is affected by variable intraluminal catheter position that changes the distance between the NIR fluorescence source and imaging catheter detector, leading to fluctuations in the measured NIRF signal. Note that applying the NIRF distance correction (bottom row) substantially improved the reproducibility of the NIRF image and reduced the variability due to changes in catheter position. (F) Quantitative assessment of the improvement of the reproducibility by NIRF distance correction: black dots correspond to the maximum NIRF signal vs. pullback position, and the blue line indicates the average distribution function. Distance correction improved the correspondence between NIRF signals from all three pullbacks from R2 = 0.89 to R2 = 0.96.

Dmitry Bozhko, Eric A Osborn, Amir Rosenthal, Johan W Verjans, Tetsuya Hara, Stephan Kellnberger, Georg Wissmeyer, Saak V Ovsepian, Jason R McCar. European Heart Journal – Cardiovascular Imaging, Volume 18, Issue 11, 1 November 2017, Pages 1253–1261.

Histopathological evaluation of thrombus in patients presenting with stent thrombosis. A multicenter European study: a report of the prevention of late stent thrombosis by an interdisciplinary global European effort consortium.

Histopathological evaluation

source: © 2015 European Heart Journal

Background
Stent thrombosis (ST) is a rare but serious complication following percutaneous coronary intervention. Analysis of thrombus composition from patients undergoing catheter thrombectomy may provide important insights into the pathological processes leading to thrombus formation. We performed a large-scale multicentre study to evaluate thrombus specimens in patients with ST across Europe.

Methods
Patients presenting with ST and undergoing thrombus aspiration were eligible for inclusion. Thrombus collection was performed according to a standardized protocol and specimens were analysed histologically at a core laboratory. Serial tissue cross sections were stained with haematoxylin–eosin (H&E), Carstairs and Luna. Immunohistochemistry was performed to identify leukocyte subsets, prothrombotic neutrophil extracellular traps (NETs), erythrocytes, platelets, and fibrinogen.

Results
Overall 253 thrombus specimens were analysed; 79 (31.2%) from patients presenting with early ST, 174 (68.8%) from late ST; 79 (31.2%) were from bare metal stents, 166 (65.6%) from drug-eluting stents, 8 (3.2%) were from stents of unknown type. Thrombus specimens displayed heterogeneous morphology with platelet-rich thrombus and fibrin/fibrinogen fragments most abundant; mean platelet coverage was 57% of thrombus area. Leukocyte infiltrations were hallmarks of both early and late ST (early: 2260 ± 1550 per mm2 vs. late: 2485 ± 1778 per mm2; P = 0.44); neutrophils represented the most prominent subset (early: 1364 ± 923 per mm2 vs. late: 1428 ± 1023 per mm2; P = 0.81). Leukocyte counts were significantly higher compared with a control group of patients with thrombus aspiration in spontaneous myocardial infarction. Neutrophil extracellular traps were observed in 23% of samples. Eosinophils were present in all stent types, with higher numbers in patients with late ST in sirolimus-and everolimus-eluting stents.

Conclusion
In a large-scale study of histological thrombus analysis from patients presenting with ST, thrombus specimens displayed heterogeneous morphology. Recruitment of leukocytes, particularly neutrophils, appears to be a hallmark of ST. The presence of NETs supports their pathophysiological relevance. Eosinophil recruitment suggests an allergic component to the process of ST.[Read more….]

eukocyte accumulation in stent thrombus specimens.

Fig. Leukocyte accumulation in stent thrombus specimens. (A) Leukocyte accumulation in human stent thrombus specimens. Left images: Haematoxylin–eosin staining (n = 253). Arrows indicate granulocytes, arrowheads indicate mononuclear cells. Right images: immunofluorescence staining of neutrophil elastase to identify neutrophils (n = 229). Nuclei are counterstained with Hoechst. Bars, 200 µm (upper row) and 50 µm (bottom row); (B) Quantification of leukocytes and neutrophils in early (n = 67) vs. late (n = 162) stent thrombosis (leukocytes: P = 0.44; neutrophils: P = 0.81); (C) Leukocytes and neutrophils in stent thrombosis from drug-eluting stents (n = 149) and bare metal stents (n = 73) and in thrombi aspirated from patients with spontaneous myocardial infarction (spont. myocardial infarction; n = 104) (P < 0.05 for drug-eluting stents vs. spont. myocardial infarction and bare metal stents vs. spont. myocardial infarction). Shown are mean + SD, each symbol in (B) and (C) represents one individual patient.

++These authors contributed equally to this work.
Julia Riegger, Robert A. Byrne, Michael Joner, Sue Chandraratne, Anthony H. Gershlick, Jurrien M. ten Berg, Tom Adriaenssens, Giulio Guagliumi, Thea C. Godschalk, Franz-Josef Neumann, Dietmar Trenk, Laurent J. Feldman, Philippe Gabriel, Steg Walter Desmet, Fernando Alfonso, Alison H. Goodall, Roman Wojdyla, Dariusz Dudek, Vanessa Philippi, Sheryl Opinaldo, Anna Titova, Nikesh Malik, James Cotton, Darshni A. Jhagroe, Antonius A.C.M. Heestermans, Peter Sinnaeve, Paul Vermeersch, Christian Valina, Christian Schulz, Adnan Kastrati, Steffen Massberg the Prevention of Late Stent Thrombosis by an Interdisciplinary Global European Effort (PRESTIGE) Investigators On Behalf of the Prevention of Late Stent Thrombosis by an Interdisciplinary Global European Effort (PRESTIGE) Investigators,Tom Adriaenssens, Ian Buysschaert, Mickaël Chausson, Dries De Cock, Jo Dens, Emanuele Barbato, Walter Desmet, Sandrine Gautier, Paul Vermeersch, Peter Sinnaeve, Helene Abergel, Laurent Feldman, Martine Jandrot-Perrus, Didier Letourneur, Pierre Mangin, Véronique Olivier, Caroline Roques, Robert A. Byrne, Sue Chandraratne, Matthias Gratz, Michael Joner, Adnan Kastrati, Elisabeth Kennerknecht, Ildiko Konrad, Tobias Koppara, Steffen Massberg, Franz-Josef Neumann, Vasilis Ntziachristos, Sheryl Opinaldo, Vanessa Philippi, Julia Riegger, Amir Rosenthal, Alexander Rzany, Christian Schulz, Kristin Steigerwald, Tomohiso Tada, Anna Titova, Dietmar Trenk, Christian Valina, Andreas Vogelsang, Erion Xhepa, Chiara Bernelli, Micol Coccato, Giulio Guagliumi, Kenichi Komukai, Vasile Sirbu, Garry Kerch, Giovanni Amoroso, Jurriën ten Berg, Willem J.M. Dewilde, Thea C. Godschalk, Antonius A.C.M. Heestermans, Darshni A. Jhagroe, Joanne J. Wykrzykowska, Mark H.M. Winkens, Dariusz Dudek, Łukasz Rzeszutko, Roman Wojdyla, Wojciech Zasada, Fernando Alfonso, Javier Cuesta, Miguel Medina, Colin Berry, James Cotton, Nick Curzen, Margaret McEntegart, Robert Gerber, Anthony Gershlick, Alison H. Goodall, Simon Hetherington, Jonathan Hill, Damian Kelly, Nikesh Malik, Keith Oldroyd, Helen Routledge, Joanne Shannon, Venkatesan Suresh, Azfar Zahman.

European Heart Journal, Volume 37, Issue 19, 14 May 2016, Pages 1538–1549, https://doi.org/10.1093/eurheartj/ehv419