Abnormal formation of solid thrombus inside a blood vessel can cause thrombotic morbidity and mortality. This necessitates early stage diagnosis, which requires quantitative assessment with a small volume, for effective therapy with low risk to unwanted development of various diseases. We propose a micro-ultrasonic diagnosis using an all-optical ultrasound-based spectral sensing (AOUSS) technique for sensitive and quantitative characterization of early stage and whole blood coagulation. The AOUSS technique detects and analyzes minute viscoelastic variations of blood at a micro-ultrasonic spot (<100 μm) defined by laser-generated focused ultrasound (LGFU). This utilizes (1) a uniquely designed optical transducer configuration for frequency-spectral matching and wideband operation (6 dB widths: 7–32 MHz and d.c. ∼ 46 MHz, respectively) and (2) an empirical mode decomposition (EMD)-based signal process particularly adapted to nonstationary LGFU signals backscattered from the spot. An EMD-derived spectral analysis enables one to assess viscoelastic variations during the initiation of fibrin formation, which occurs at a very early stage of blood coagulation (1 min) with high sensitivity (frequency transition per storage modulus increment = 8.81 MHz/MPa). Our results exhibit strong agreement with those obtained by conventional rheometry (Pearson’s R > 0.95), which are also confirmed by optical microscopy. The micro-ultrasonic and high-sensitivity detection of AOUSS poses a potential clinical significance, serving as a screening modality to diagnose early stage clot formation (e.g., as an indicator for hypercoagulation of blood) and stages of blood-to-clot transition to check a potential risk for development into thrombotic diseases.
Previous laser-generated focused ultrasound (LGFU) systems have been operated with >15 MHz frequency, allowing for high spatial precision (<100 μm). However, they have been limited only to proximal biomedical applications ex vivo with treatment depths smaller than 10 mm from the lens surface. Although the low-megahertz frequency operation has the advantage of a longer range of therapy, this requires a proper photoacoustic lens made of a nanocomposite coating over a spherically curved substrate whose transmission layer is physically designed for frequency-tuned outputs. This demands a fabrication method that can provide such a nanocomposite structure. We demonstrate photoacoustic lenses operated in an unexplored frequency range of 1–10 MHz, which can simultaneously produce high-amplitude pressure outputs sufficient for pulsed acoustic cavitation. We physically design a spatially elongated photoacoustic output and then fabricate a transmitter by controlling the density of light-absorbing nanoscale elements in a solution form and by using a replica mold to shape the lens curvature. Our approach is validated by fabricating and characterizing planar transmitters and then applied to focal configurations. This offers various possibilities for LGFU-based treatments (e.g., pulsed cavitational therapy such as histotripsy) over the low-megahertz frequency range, which has not been realized by conventional LGFU systems.
We demonstrate a photoacoustic sensor capable of measuring high-energy nanosecond optical pulses in terms of temporal width and energy fluence per pulse. This was achieved by using a hybrid combination of a carbon nanotube-polydimethylsiloxane (CNT-PDMS)-based photoacoustic transmitter (i.e., light-to-sound converter) and a piezoelectric receiver (i.e., sound detector). In this photoacoustic energy sensor (PES), input pulsed optical energy is heavily absorbed by the CNT-PDMS composite film and then efficiently converted into an ultrasonic output. The output ultrasonic pulse is then measured and analyzed to retrieve the input optical characteristics. We quantitatively compared the PES performance with that of a commercial thermal energy meter. Due to the efficient energy transduction and sensing mechanism of the hybrid structure, the minimum-measurable pulsed optical energy was significantly lowered, ~157 nJ/cm2, corresponding to 1/760 of the reference pyroelectric detector. Moreover, despite the limited acoustic frequency bandwidth of the piezoelectric receiver, laser pulse widths over a range of 6–130 ns could be measured with a linear relationship to the ultrasound pulse width of 22–153 ns. As CNT has a wide electromagnetic absorption spectrum, the proposed pulsed sensor system can be extensively applied to high-energy pulse measurement over visible through terahertz spectral ranges.
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