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Abstract
Photoacoustic (PA) imaging is a high-fidelity biomedical imaging technique based on the principle of molecular-specific optical absorption of biological tissue constitute. Because PA imaging shares the same basic principle as that of ultrasound (US) imaging, the use of PA/US dual-modal imaging can be achieved using a single system. However, because PA imaging is limited to a shallower depth than US imaging due to the optical extinction in biological tissue, the PA signal yields a lower signal-to-noise ratio (SNR) than US images. To selectively amplify the PA signal, we propose a switchable preamplifier for acoustic-resolution PA microscopy implemented on an application-specific integrated circuit. Using the preamplifier, we measured the increments in the SNR with both carbon lead and wire phantoms. Furthermore, in vivo whole-body PA/US imaging of a mouse with a preamplifier showed enhancement of SNR in deep tissues, unveiling deeply located organs and vascular networks. By selectively amplifying the PA signal range to a level similar to that of the US signal without contrast agent administration, our switchable amplifier strengthens the mutual complement between PA/US imaging. PA/US imaging is impending toward clinical translation, and we anticipate that this study will help mitigate the imbalance of image depth between the two imaging modalities.
© 2022 Optica Publishing Group under the terms of the Optica Open Access Publishing Agreement
1. Introduction
Photoacoustic (PA) imaging and ultrasound (US) imaging are currently being studied in various fields of biomedical imaging applications. PA images are formed by the US signal generated by thermal expansion-relaxation from biological molecules when pulsed light is absorbed. Red blood cells [1], glucose [2,3], melanin [4,5], lipids [6,7], and DNA/RNA [8], each of which has different absorption coefficients, respond to the light excitation of different wavelengths. In the PA imaging technology, PA microscopy (PAM) and PA computed tomography (PACT) are primarily used, and PAM is divided into optical-resolution PAM (OR-PAM) and acoustic-resolution PAM (AR-PAM) [9–12]. Though OR-PAM, AR-PAM, and PACT capture the generated acoustic wave and decrypt it into the image, the trade-off relationship between the penetration depth and image resolution lets the user carefully select the imaging technique depending on the target application (Fig. S1). In other words, PAM would be more appropriate to resolve superficial microvascular capillary networks where RBC distribution is confined over a bloodless tissue bed, whereas PACT could be more efficient for imaging the macroscopic distribution of major vessels under a depth of tissue bed. In addition, PA imaging is a promising tool for the future of biomedical imaging, which will keep expanding its applications, including but not limited to cancer imaging [13–18], cellular imaging [8,19], and clinical imaging [20–25].
Thankfully, PA imaging and US imaging share the same fundamental properties, enabling the combination of PA/US imaging into one system. Although US imaging provides an in-depth visualization of the anatomical structures of the organ, PA imaging unveils the photochemical content of the biological tissue. With its associated benefits of a more comprehensive understanding of physiology under the tissue, dual-modal PA/US imaging has been actively developed and translated to the preclinical/clinical trial stage. PA/US imaging with OR-PAM has been investigated for the in vivo imaging of blood vessels in the eyeball of a mouse [16], AR-PAM for whole-body imaging and melanoma imaging in mice [14,26], and PACT for sentinel lymph node imaging, liver fibrosis detection, human melanoma, and preclinical and clinical image quality improvement [5,20,27–32]. The advent of a commercial PACT system has even accelerated the approaching speed of the translation of this technique to the patient bedside [13,33–38].
Typically, when acquiring both PA/US images from a single system, the yield of the PA signal is smaller than that of the US signal. Compared with the deep, penetrating acoustic beam of US imaging, the light pulse, which is the energy source of PA imaging, is significantly attenuated while traveling through opaque tissue media, and consequently, only a small amount of photons reaches the absorber in the deep tissue [20,39]. Hence, the PA images have a lower signal-to-noise ratio (SNR) in deep tissue than US images and are bounded to a shallow region.
To overcome this limitation, the most intuitive method is first to enhance the PA signal by administering an exogenous contrast agent [40,41]. To avoid the absorption of ambient tissue that is rich in hemoglobin and water, the absorption peak of the contrast agents is favored to fall in the near-infrared zone (700–1100 nm) [42–44], and some contrast agents are further implemented for dual-modal imaging that enhances both the PA and US contrast [45,46]. However, because the procedure involves an injection from outside the human body, US Food and Drug Administration-approved agents are very rare, which eventually limits the method practically to clinical translation.
With regard to label-free PA imaging of the endogenous chromophores as the ultimate solution, one could try to restore the original PA from the acquired PA signal data as much as possible. More specifically, PA reconstruction using backpropagation of the recorded PA signal could be helpful. The receive focusing techniques include as the synthetic aperture focusing technique for a single-element system application and the multichannel beam-forming technique for the PACT in multi-element system applications. However, neither of these methods can provide a full restoration of the original PA signals due to hardware limitations, such as limited-view artifact [47], multichannel complexity, and further vulnerabilities that arise in practice [48].
Another way to amplify a PA signal at the analog level is by using a preamplifier. It is adopted in many established PACT systems [34,49]. A commonly used preamplifier is located behind the ultrasound transducer cable and at the front end of the imaging system. For more effective signal recovery, a front-end preamplifier, located directly behind the transducer, is also used [50–52]. This requires electrical matching with the transducer, adequate power consumption, and robustness to noise. However, the front-end preamplifier developed so far is difficult to apply to dual-modal PA/US imaging. Because it is designed exclusively for receiving PA signals, it causes several problems, such as overamplification of US signals, further amplification of US transmits pulse that is already large enough, and differences in noise response between US and PA signals.
In this study, we present a switchable preamplifier that selectively amplifies the PA signal where both US and PA signals are sequentially acquired with one transducer. To the best of our knowledge, our reporting is the first study to present a preamplifier to increase the penetration depth of PA images in dual-modal PA/US imaging. Since our primary goal of this study was to improve the penetration depth for PA images, we chose a lower frequency band than conventional AR-PAM imaging. The center frequency of the ultrasound transducer was 4.7 MHz and its -6 dB passband was from 3.1 MHz to 6.2 MHz, which can be fully covered by the cutoff frequency of 12 MHz of the preamplifier. This frequency specification was chosen to maximize the detection range of the PA signal from the region of interest (Fig. S1). For dual-modal imaging, we fabricated a switchable application-specific integrated circuit (ASIC) preamplifier. This was to simultaneously implement a US mode circuit suitable for high-voltage and a PA mode circuit robust to noise, select the frequency band, and control power consumption and current. This approach differs from that of previous studies, which functioned only to turn the amplification of the PA signal on and off [50–52]. The noise-optimized ASIC induced greater improvement in the SNR and contrast-to-noise ratio (CNR) in the deep region than in the shallow region by achieving a greater amplification of small signals. We expect this study to provide a solution for clinical PA/US imaging that will overcome the limitations of penetration depth due to the low contrast of PA images, including human hand and foot imaging in OR-PAM and human organ imaging in PACT.
2. Methods
2.1 Switchable preamplifier design
We implemented the switchable preamplifier in a 180-nm high-voltage bipolar-CMOS-DMOS (BCD) process, and the chip was packaged (Fig. 1(a)). The ASIC primarily consists of three high-voltage (HV) DMOS switches, a preamplifier, and an analog buffer (Fig. 1(b)). To support the two operational modes, the circuit contained two parallel signal paths. In the US mode, the HV DMOS switch, denoted as US SW in Fig. 1(b), was turned on, and the other HV DMOS switches, denoted as PA SW in Fig. 1(b), were turned off. A HV impulse signal with several tens of volts from the micro-coaxial cable was delivered to a US transducer through the aforementioned US SW. The US can be generated using an impulse signal and reflected off the sample, and a US transducer can obtain an echo signal. The echo signal with a peak-to-peak amplitude of up to a few hundred millivolts travels from the US transducer to the micro-coaxial cable. Because a sufficiently high acoustic energy is applied and the SNR of the echo signal is decent, amplification of the obtained echo is not essential. One of the primary requirements for the US mode is the reliability of the transistors for withstanding intermittent HV pulses. To address the reliability of US SW, we used lateral DMOS transistors, which are dedicated to HV circuit topologies. Another primary requirement for the US mode is the low resistance of US SW. We adopted a switch topology of a back-to-back connection along with a bootstrapping scheme to sufficiently reduce the resistance of the US SW within a relatively smaller chip area [53].
Fig. 1. Switchable preamplifier specification. (a) Photo of the test board for the preamplifier chip. (b) ASIC block diagram. (c) Frequency response in three types of frequency bands. Input voltage = 1 mVpp (d) The amplification depends on the input voltage in three types of frequency bands. Measurement frequency = 5 MHz. UT, ultrasound transducer; US SW, ultrasound-mode switch; PA SW, photoacoustic-mode switch; MCC, micro-coaxial cable.
In the PA mode, a signal path including a preamplifier was activated to amplify the PA signal. The signal path for the PA mode was composed of two PA switches, a preamplifier, and an analog buffer. Typically, an echo signal of PA imaging is relatively weak compared with the US mode, and there is a discrepancy between the dynamic range of the PA echo signal and that of a commercial US imaging system [51,52]. Hence, a preliminary amplification of an echo signal of PA imaging is beneficial for the enhancement of dual-modal PA/US imaging system compatibility. In addition, a low-noise performance is required for the preamplifier so as not to degrade the SNR of the weak echo signal. In this study, to achieve a sufficient voltage gain range, we adopted a capacitive feedback cascode-amplifier topology as a preamplifier [54,55]. In addition, a thermal-noise floor was lowered by optimizing the operational region of transistors, and a bandwidth was set by considering the echo bandwidth to smooth the out-of-band noise [56]. That is, the input transistors and load transistors of the preamplifier were designed to operate in weak inversion and strong inversion, respectively. The prototype ASIC illustrates three operational modes in terms of bandwidth at the maximum gain condition (Fig. 1(c)). The measured −3-dB bandwidth values for each of the modes were 5, 8, and 12 MHz, respectively. Because of the limited linearity range, the voltage gain decreased with respect to the amplitude of the input signal. The measured voltage gain values for the 5-MHz sinusoidal input with an amplitude of 1 mVpp were approximately 44.7, 46.0, and 47.2 dB, respectively (Fig. 1(d)). The amplified PA echo signal was delivered into the imaging system through the micro-coaxial cable. The capacitive load of the micro-coaxial cable corresponds to several hundreds of pF; thus, the preamplifier should be followed by an analog buffer with high drivability. In this study, we used the super-source follower as the analog buffer to achieve a power-efficient operation with low quiescent current [57].
2.2 Dual-modal PA and US imaging system
The designed preamplifier was applied to the dual-modal PA and US imaging system (Fig. 2(a)). For PA excitation, a tunable laser system at the near-infrared range is involved in the system. A Q-switched Nd:YAG pump laser (Surelite III-10, Continuum, USA) emits high-power 532-nm beam at a 10-Hz pulse repetition frequency. After passing the second harmonic generator, a 532-nm signal beam is delivered to the optical parametric oscillator (OPO) unit (Surelite OPO PLUS, Continuum, USA), which tunes the beam’s wavelength to the wavelength of user’s demand under the range of 690 to 930 nm. The laser power is controlled by manipulating Q-delay time between the flashlamp and Q-switch events. The pump laser controller offers two trigger outputs per event timing (Fig. 2(b)). The flashlamp output is connected to the pulser/receiver (P/R; 5072, Olympus NDT, USA) and oscilloscope (MSO 5204, Tektronix, USA) and cues US acquisition by starting the US pulse transmission and reception. In contrast, the actual laser beam emits with the Q-switch output and triggers the oscilloscope to start the PA signal acquisition. Hence, the US and PA acquisitions are interleaved by two off-beat trigger signals. The sampling frequency was set to 50 MS/sec, and the sampling length for US and PA was set to 4000 and 2000, respectively, considering the twice time-of-flight difference between a roundtrip and one-way traveling distance. The acquired data were further segmented following the reasonable depth of interest (23–30 mm), and the segment size for US and PA was 500 and 250, respectively.
Fig. 2. Schematic diagrams of a dual-modal PA/US imaging system with preamplifier. (a) Schematic diagram of system configuration. (b) Timing diagram of system operation. UT, ultrasound transducer; OC, optical condenser; RAP, right-angle prism; BCL, bi-convex lens; CL, conical lens; OPO, optical parametric oscillator; P/R, pulser/receiver; OSC, oscilloscope; PC, personal computer; Tx, transmission; Rx, reception; TOF, time of flight.
The laser beam was delivered in free-space using four right-angle prisms and involved bi-convex collimating lens pairs to rectify the divergence along the long free-space optical path. The conical lens-optical condenser relay that comes after is the key module of the system that concentrically aligns the optical and acoustic beams. It provides a spatially symmetric PA beam pattern and achieves an optimal PA SNR [16]. The laser beam detours the opaque US transducer through a conical lens that reforms the Gaussian beam shape into a ring shape and converges back to a point through an acrylic optical condenser with total reflectance. A 5-MHz single-element US transducer (Fig. S2, V308, Olympus NDT, USA) was fitted in the middle of the optical condenser and detected the US echo signals generated by the PA signals. To spatially homogenize the beam amplitude, the conical lens was capped with an engineered diffuser. The installed free-space delivery optics were carried and translated in the X-Y plane with a two-dimensional motorized stage to enable the raster scan. Acoustic coupling of the imaging target was required to insonify with the US pulse or to receive the PA signals following laser pulse emission. Thus, depending on the experiment, the objects were matched to an aqueous condition based on whether they were submerged into the water tank filled with optically diffusive media (∼5% diluted milk solution) or, in the case of in vivo experiments, placed on the stage beneath the windowed water tank sealed with optically and acoustically transparent thin polyethylene film.
2.3 Phantom and in vivo imaging
To validate the proper preamplifier operation, we obtained two phantom images using a carbon lead phantom and thin Nylon string pattern under optically diffusive media. For both phantom images, we uniformly used an optical wavelength of 700 nm at a fluence level of 9 mJ/cm2 (Q-delay: 300 µs). First, a 0.5-mm-thick carbon lead was an adequate target to provide a preliminary understanding of the PA signal amplification by means of SNR and CNR, as the lead thickness was adequate for both PA and US imaging in terms of the reported resolution of the system (Fig. S4a). A small triangular geometry was prepared by fixing three leads on the frame and then submerging them into 5% diluted milk solution. For a given system’s gain settings, we conducted simultaneous PA/US raster scanning using an isotropic 0.2-mm step in the X and Y directions with a full field of view (FOV) of 20 × 20 mm. The SNR was obtained from the root-mean-square (RMS) voltage of the largest signal and the RMS voltage of the noise. The CNR was obtained from the mean and standard deviation of the signal and noise. In addition, we measured the gain of the preamplifier on the PA signal. These results were compared with those already measured with the sine wave shown in Figs. 1(c, d). Because the sine wave generated by the function generator could specify the amplitude and frequency of the waveform, the exact gain of the preamplifier could be measured by comparing the signal before and after amplification. However, since PA signals cannot specify amplitude and frequency, the gain of the preamplifier was estimated by comparing the PA signal obtained using only the P/R amplifier whose gain was verified and the PA signal obtained using the preamplifier together.
Second, we used a black nylon wire phantom to compare the SNR and resolution at different depths after amplification. The series of 0.1-mm-thick Nylon strings were sewed to a custom-designed acrylic string rack (Fig. S4b). With regard to the lateral extension of the image for the off-focused target, the strings were equally spaced by about a 1.5-mm step in the Z direction but rather wider than a 5-mm step in the X direction. After matching the distance between the first wire (Fig. S4b) and the transducer to the focal depth, the immersed rack was imaged with a precise step size of 0.1-mm in both the X and Y directions. Before quantification, the imaging was repeated 20 times at the same plane and averaged, considering a maximum deviation in laser pulse energy of ±10%. The pixels in each line of depth were divided by the mean of the noise (lower 90%) so that the noise level did not vary with depth. The SNR was calculated by taking the highest-peak pixel value as the signal and the RMS value of the lower 90% of all pixels of the same depth as the noise.
As a final step, we acquired the whole-body scan of healthy 6-week-old nude Balb/c mice with and without the preamplifier. All experimental animal procedures were performed after the protocol was approved by the institutional animal care and use committee of Pohang University of Science and Technology (POSTECH-2021-0052-C2, approved on 17 Feb. 2022). To anesthetize the mouse throughout the imaging procedure, we used a respiratory anesthetic system (1.0% isoflurane/oxygen at 1.5-L/min flow rate). After removing the fine hair using depilatory cream, the mouse posture was fixed on the heating pad while exposing the dorsal plane. Acoustic gel (Ecosonic, SANIPIA, Republic of Korea) was applied over the mouse and placed under the windowed water tank containing clear polyethylene film. Trapped small air bubbles that could disrupt the PA and US image were removed before imaging. We used a scanning FOV of 60 × 40 mm2 covering the mouse thorax to the mouse pelvis and set the scanning step size equally to 0.4 mm in the X and Y directions. We used 700-nm optical wavelength at 9 mJ/cm2 (Q-delay: 300 µs) and did not exceed the recommended American National Standard Institute (ANSI) maximum permissible exposure limit. The qualitative evaluation was conducted based on whether the blood vessels and organs were clearly visible in the PA image.
2.4 Image processing and data analysis
Using raw time-domain data, we acquired maximum amplitude projection (MAP) images from three-dimensional (3D) volumetric data postprocessed using MATLAB (R2020a, MathWorks, USA). The sequentially acquired data were reshaped into volume and followed by IQ demodulation to its carrier frequency as a center frequency of the transducer (5 MHz). FIR bandpass filter (ωc = [1 MHz, 8 MHz]) was applied before C-scan image presentation to filter out noise included in the recorded data. All images were normalized because each had a different dynamic range. Each pixel is normalized by subtracting the minimum value and dividing by the difference of the maximum and minimum values. Depth-encoded MAP images were generated using the 3D PA Visualization Studio (3D PHOVIS) [58], a toolkit of MATLAB.
2.5 System gain settings
Our system contains two signal amplifiers: P/R and preamplifier. The gain of the P/R was adjustable from −59 to 59 dB, and the gain of the preamplifier was about 40–47 dB when adopting the maximum mode (Fig. 1(d)). Without a preamplifier, the PA signal was small; thus, the amplification of the P/R had to be set high, at 59 dB (maximum setting of P/R). However, the image quality deteriorated when the P/R and preamplifier were amplified together. We detected this problem due to the saturation in the raw time-domain data (Fig. S3). To solve this problem, we found an appropriate P/R gain for our system. We set the P/R gain to 25 dB, which we found as a threshold that does not degrade the image. On this basis, we compared the best image quality on a system without a preamplifier (hereinafter referred to as P/R 59-dB) to the best image quality with a preamplifier (hereinafter referred to as P/R 25-dB + preamplifier). In addition, we compared the conditions with (P/R 25-dB + preamplifier) and without (hereinafter referred to as P/R 25-dB) the preamplifier at the same P/R gain.
3. Results and discussion
3.1 Switchable preamplifier fabrication
The ASIC was fabricated using the TSMC 180-nm HV BCD process with a total area of 0.308 mm2 (Fig. 3(a)). Building blocks of switchable preamplifier were arranged in series for the compact layout form, thus facilitating a multichannel implementation by increasing a number of unit layouts in parallel. The preamplifier, along with the analog buffer, was designed using standard CMOS transistors, and HV switches, such as PA SW and US SW, were designed with lateral DMOS transistors. The power consumption primarily depends on the imaging mode and the amplitude of the ultrasonic echo. The quiescent power consumption of ASIC is 6.3 mW. The voltage gain of ASIC ranges from 34 to 47 dB, and its value can be adjusted by reconfiguring the capacitive feedback network of the preamplifier [55]. The maximum bandwidth of ASIC is 12 MHz, which can be tuned for noise reduction by considering the signal bandwidth (Fig. 1(d)). We measured the input-referred noise spectral density with a network analyzer (4395A, Agilent, USA), and the noise floor was 1.7 nV/√Hz (Fig. 3(b)). To evaluate the bypass operation in the US mode, the on-resistance characteristic of the DMOS switch was measured (Fig. 3(c)). This shows an equivalent resistance of about 22 Ω, and the value starts to increase in the vicinity of 8 MHz due to the limited bandwidth of the bootstrapping scheme within the ASIC.
Fig. 3. Switchable preamplifier ASIC implementation results. (a) Chip micrograph and layout photo. (b) Measured input-referred noise spectral density of preamplifier at the maximum mode. (c) Measured on-resistance of the DMOS switch.
The preamplifier increases the SNR the closer it is to the signal source [51,59]. Through simple circuit configuration and experimentation, we found that the fabricated preamplifier also follows this (Fig. S5). The SNRs of the circuits were $\frac{{G \cdot S}}{{G({N + {N_{cable1}}} )+ {N_{cable2}} + {N_{cable3}}}}$ and $\frac{{G \cdot S}}{{G({N + {N_{cable1}} + {N_{cable2}}} )+ {N_{cable3}}}}$, respectively, in Fig. S5a and S5b. The circuit of Fig. S5a has a higher SNR because the noise after preamplifier is equivalently attenuated in terms of SNR calculation, as shown in the above equation. Note that the noise of cable (${N_{cable1}}$, ${N_{cable2}}$, ${N_{cable3}}$) includes a cable loss, a noise coupled from ambient environment, and a reflection at interface. As a result of amplifying a 5 MHz sine wave of 1mVpp, the SNRs in each circuit were 44.7 and 21.6 dB, respectively, indicating that it is better to place the preamplifier close to the US transducer (Fig. S5c). The proposed circuit of this work was compared with other PA imaging studies that place the preamplifier close to the signal detector (Table 1). Compared with other works, the designed ASIC includes HV switches to enable the bypass operation for the US mode, so that this work can support the dual-modal imaging of PA and US by using the dedicated ASIC. In addition, the role of the preamplifier was redefined to amplify only the echo signal with minimal addition of noise by sufficiently reducing the bandwidth. Instead, by employing the high drivability analog buffer, the amplified echo signal could be driven through the micro-coaxial cable with a relatively heavy capacitive load. The designed ASIC can adjust the voltage gain and bandwidth by considering the measurement environment. Note that the bandwidth of the preamplifier corresponds to the operational modes of Fig. 1(d). The operational mode can be selected by manually adjusting the internal load capacitance of the preamplifier.
Table 1. Circuit-Specification Comparison with Prior Art
The effects of the preamplifier on the overall performance of the imaging system can be evaluated in terms of an input impedance of the preamplifier, a return loss at cable-preamplifier interface, and noise performance of the preamplifier. In simulations including parasitic components of the ASIC package, the input impedance of preamplifier was 88 Ω at the center frequency of the transducer. Since the input of the preamplifier was interfaced with a coaxial cable, the specification of the input impedance of the preamplifier was determined considering the characteristic impedance of the coaxial cable. The implemented preamplifier had a negative feedback structure. Accordingly, it had a constant input impedance of 88 Ω for a relatively wide frequency band. By using this feature, the preamplifier was designed so that the intrinsic input impedance was close to that of the interface component. Considering the characteristic impedance of the coaxial cable, the input impedance of the preamplifier corresponds to the return loss of 11.2 dB. This return loss equivalently results in a variation of voltage gain in the preamplifier by about 4% [60]. Considering the voltage-gain range of the preamplifier, the equivalent gain variation of preamplifier due to return loss can be negligible. In addition, the measured input-referred noise voltage of the preamplifier was 7.2 µVRMS, so the preamplifier could achieve a sufficient noise performance to amplify the weak PA signal. Moreover, when the noise from stages after the preamplifier is referred into the transducer, the noise figure of the following stages of preamplifier can be primarily attenuated by the gain of the preamplifier [60]. Accordingly, the preamplifier can improve the overall noise performance of the system by suppressing the noise contribution of the following stages.
3.2 Carbon lead phantom imaging
We made a phantom by weaving three carbon leads and acquired signals under the three non-saturation conditions. Using the acquired PA signal, the MAP was imaged, and we obtained images of the woven lead shape. In the P/R 25-dB condition, the phantom signal was weak, and in the P/R 25-dB and P/R 25-dB + preamplifier condition, the phantom signal was sufficient (Fig. 4(a)). In the comparison of the P/R 25-dB image with the P/R 25-dB + preamplifier image, the addition of a preamplifier significantly improved the image quality, as presented in Fig. 4(a). In addition, there was a definite difference in the image quality between P/R 59-dB and P/R 25-dB + preamplifier; however, a quantitative analysis was required because the difference was smaller than the comparison with P/R 25-dB.
Fig. 4. PA imaging of carbon lead depending on amplification conditions. (a) MIP images are expressed as normalized values of three conditions. The blue markers are ROIs for SNR calculations. (b) Signals at ROIs in each condition. (c) Comparison of PA intensities obtained from signals segmented by Otsu's method in each condition (two-tailed t-test, ***P < 0.001). The bar graph represents the mean ± s.d. Scale bars are 2 mm.
To conduct a quantitative comparison of image quality, we measured the SNR and CNR. In addition, we calculated the SNR from the raw data of the region of interest (ROI) (Fig. 4(b)) using the voltage at 22–28 mm as the signal and the voltage at 28–31 mm as the noise. The ROI was set to the highest pixel in the condition of P/R 25-dB + preamplifier, and there was no significant difference in SNR obtained from other pixels, even at the P/R 59-dB condition. The SNRs were 4.74, 20.1, and 26.6 dB at P/R 25-dB, P/R 59-dB, and P/R 25-dB + preamplifier, respectively. To distinguish between signal and noise, we calculated the CNR using Otsu’s method and found a statistically significant separation (Figs. 4(c), S6). The CNRs were 12.4 and 12.9 dB at P/R 59-dB and P/R 25-dB + preamplifier, respectively. In the P/R 25-dB image, the signal was too small to distinguish the signal from the noise. Therefore, we have quantitatively demonstrated that the best image quality is achieved with the P/R 25-dB + preamplifier condition. All of these results support that the preamplifier amplifies the signal more than the noise does, thus further improving the image quality.
The gain of the preamplifier for the PA signal was estimated by comparing the P/R 59-dB and P/R 25-dB + preamplifier image. Comparing the pixels of the signal separated by the Otsu’s method (Fig. 4(c)), P/R 25-dB + preamplifier image was at least 1.59 times (4.03 dB) and up to 4.69 times (13.4 dB) higher than P/R 59-dB image. Subtracting the 25-dB contribution of the P/R from the total derived gain (63–72 dB), the gain of the preamplifier was calculated to be 38-47 dB. This result was similar to the result measured using a sine wave (Fig. 1(d)), indicating that the preamplifier can amplify the PA signal as designed.
3.3 Wire phantom imaging
We constructed a Nylon wire phantom arranged diagonally into seven pieces of different depths. The wire depths were located 24.6, 26.1, 27.4, 29.0, 30.5, 32.1, and 33.7 mm from the US transducer, respectively. B-mode images were averaged and imaged after 20 scans (Fig. 5(a)). In the P/R 25-dB image, the signal was invisible from the fifth line, and the noise was considerable. In the P/R 59-dB, it was difficult to see from the sixth wire, whereas the P/R 25-dB + preamplifier image showed well all seven wires. This indicates that the P/R 25-dB + preamplifier condition could get the best image.
Fig. 5. PA imaging of the wire depending on the amplification conditions. (a) Two-dimensional B-mode images are expressed as normalized values of three conditions (n = 20). (b) The SNR was measured at seven depths in each condition. (c) Lateral resolution of the second wire. Data were fitted to a Gaussian model (R2 = 0.951 for P/R 59-dB, R2 = 0.990 for P/R 25-dB + preamp.). (d) Axial resolution of the second wire. Data were fitted to a Gaussian model (R2 = 0.982 for P/R 59-dB, R2 = 0.921 for P/R 25-dB + preamp.). Scale bars in (a) are 2 mm
For the quantitative analysis of the wire signal, the SNR was calculated by setting the same depth with each wire as the ROI (Fig. 5(b)). As a result, the best image quality at all depths was demonstrated by the P/R 25-dB + preamplifier. Furthermore, on the sixth and seventh wires, the SNR difference from the P/R 59-dB was larger because the preamplifier amplified the small signal more (Fig. 1(d)). The difference in the SNR of the second wire was 4.1 dB, whereas that in the sixth wire was 6.0 dB. Although this is not a huge difference, it is advantageous for the imaging of deep soft tissue.
Because preamplifiers can negatively affect resolution while amplifying the signal, we compared the resolutions. The focus of the transducer used was 25 mm; thus, the resolution was measured on the second wire in the near-focus and far-field regions (Figs. 5(c), d). Based on the wire’s highest pixel, we calculated the full width at half maximum of the horizontal and vertical pixels. We measured the lateral resolutions of the P/R 59-dB and P/R 25-dB + preamplifiers to be 0.516 and 0.614 mm, respectively, and the axial resolutions to be 0.340 and 0.384 mm, respectively. The relative error exhibited a small error of 19% in the lateral resolution and 13% in the axial resolution. This error occurs because when the wire goes out of focus on the US transducer, the signal spreads, and the preamplifier amplifies this tiny signal. The spread of the signal worsened when further away from the focus, which might result in a lower resolution. This problem was caused by the lack of PA signal reception rather than the preamplifier. Thus, we have proven that the preamplifier does not significantly affect the resolution.
3.4 In vivo imaging
We obtained the PA and US images from the back of the anesthetized nude mice, and the scan area was 30 × 44 mm (Fig. 6(a)). The histograms of the pixel PA amplitude for the image under each condition indicate that the image with the P/R 25-dB + preamplifier had fewer low-amplitude pixels (Fig. 6(b)). If the preamplifier had the same gain for all intensities, the histogram distribution of the P/R 25-dB + preamplifier would have shifted only from the distribution of P/R 59-dB. This result provides evidence that the small signal was more amplified.
Fig. 6. In vivo whole-body imaging of a mouse depending on the amplification conditions. (a) Photo of the mouse and the measurement location (red dashed area). (b) Normalized histograms of intensity for each condition of the PA MIP top-view images. (c) PA MIP images expressed as normalized values. (d) US MIP images expressed as normalized values. (e) Depth-encoded PA MIP top-view images are described as 0 to 7 mm depth. The depth is the distance from the mouse's back, which is the highest point when viewed from the side. The deep organs indicated by arrows in (c) and (e) were the spleen (yellow arrow) and the cecum (red arrow). Scale bars in (c), (d), and (e) are 4 mm.
The P/R 25-dB + preamplifier contained more information in the PA MAP image (Fig. 6(c)). Comparing the vessels and organs indicated by arrows in the top view, the P/R 25-dB + preamplifier was clearer. The deep organs were barely visible in the side view at P/R 59-dB but were clearly visible in the P/R 25-dB + preamplifier. These results indicated that the preamplifier improved the image quality of the deep tissue.
The US MAP image had similar P/R 59-dB and P/R 25-dB + preamplifiers (Fig. 6(d)). There was a slight difference in image depth and resolution, but not as noticeable as the PA MAP image. Therefore, there was no image quality degradation by the preamplifier, and modality switching of the preamplifier was well performed.
The depth-encoded MAP image expresses depth information on the PA MAP image (Fig. 6(e)). The organs in this image indicated in yellow and red in the deep regions of the P/R 25-dB + amplifier image had significantly better visibility. This was the same for the blood vessels indicated in blue. Thus, all of these results prove that a system with a preamplifier could acquire better images than a system using only the P/R.
4. Conclusion
We proposed a switchable preamplifier to address the low SNR of PA imaging in a PA/US dual-mode imaging system. Because the proposed preamplifier was located close to the US transducer, the influence of cable noise was minimized. In addition, since it was developed as an ASIC, it has various functions such as PA/US mode switching, gain control, frequency band control, and miniaturization. Through these features, the AR-PAM system using the proposed preamplifier together (P/R 25-dB + preamplifier condition) was able to achieve deeper penetration than the conventional system using only the P/R preamplifier (P/R 59-dB condition). In particular, we showed the limitations of the conventional AR-PAM system that it is difficult to image deep organs (spleen, cecum), and we succeeded in imaging these organs by adding only a preamplifier under all the same conditions. This proved that our preamplifier overcomes AR-PAM's limitation of low SNR in deep tissue without degradation of US images.
Another advantage of ASICs—beyond what we intended—is that the preamplifiers can be miniaturized and implanted in US transducers [50,51]. A preamplifier implanted just behind the transducer can further increase the SNR because noise has a minimal effect. Because we did not use a homemade US transducer for this study, we were unable to implant it in the US transducer. In future research, we plan to fabricate a high-frequency US transducer (>20 MHz) and implant a preamplifier into the transducer. Resolution can be improved by using higher frequencies, and implantable preamplifiers can compensate for the reduced SNR caused by higher frequencies. We will also design the preamplifier to have higher bandwidth and set a target that has been difficult to image, such as a human hand or foot. In addition, this method could be applied to an array US transducer by mounting a multichannel multiplexer function. Still, for many applications, such as breast cancer or thyroid cancer imaging, the penetration depth of PA images remains an unresolved issue [20]. It is expected to be a breakthrough that challenges the limits of clinical PACT imaging.
Funding
Ministry of Education (2019R1I1A3A01060591, 2020R1A6A1A03047902); Ministry of Science and ICT, South Korea (2021M3C1C3097624, COMPA_2021I100); Korea Medical Device Development Fund (KMDFPR_202009010140, 9991007019, KMDF_PR_20200901_0008); BK21 FOUR.
Acknowledgments
Chip fabrication and EDA tools were supported by IDEC, South Korea.
Disclosures
C. Kim have financial interests in OPTICHO, which, however, did not support this work.
Data availability
Data underlying the results presented in this paper are not publicly available at this time but may be obtained from the authors upon reasonable request.
Supplemental document
See Supplement 1 for supporting content.
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