Light on Alzheimer's disease: from basic insights to preclinical studies.

Alzheimer's disease (AD), referring to a gradual deterioration in cognitive function, including memory loss and impaired thinking skills, has emerged as a substantial worldwide challenge with profound social and economic implications. As the prevalence of AD continues to rise and the population ages, there is an imperative demand for innovative imaging techniques to help improve our understanding of these complex conditions. Photoacoustic (PA) imaging forms a hybrid imaging modality by integrating the high-contrast of optical imaging and deep-penetration of ultrasound imaging. PA imaging enables the visualization and characterization of tissue structures and multifunctional information at high resolution and, has demonstrated promising preliminary results in the study and diagnosis of AD. This review endeavors to offer a thorough overview of the current applications and potential of PA imaging on AD diagnosis and treatment. Firstly, the structural, functional, molecular parameter changes associated with AD-related brain imaging captured by PA imaging will be summarized, shaping the diagnostic standpoint of this review. Then, the therapeutic methods aimed at AD is discussed further. Lastly, the potential solutions and clinical applications to expand the extent of PA imaging into deeper AD scenarios is proposed. While certain aspects might not be fully covered, this mini-review provides valuable insights into AD diagnosis and treatment through the utilization of innovative tissue photothermal effects. We hope that it will spark further exploration in this field, fostering improved and earlier theranostics for AD.

Optical ultrasound sensors for photoacoustic imaging: a review.

Significance: Photoacoustic (PA) imaging is an emerging biomedical imaging modality that can map optical absorption contrast in biological tissues by detecting ultrasound signal. Piezoelectric transducers are commonly used in PA imaging to detect the ultrasound signals. However, piezoelectric transducers suffer from low sensitivity when the dimensions are reduced and are easily influenced by electromagnetic interference. To avoid these limitations, various optical ultrasound sensors have been developed and shown their great potential in PA imaging. Aim: Our study aims to summarize recent progress in optical ultrasound sensor technologies and their applications in PA imaging. Approach: The commonly used optical ultrasound sensing techniques and their applications in PA systems are reviewed. The technical advances of different optical ultrasound sensors are summarized. Results: Optical ultrasound sensors can provide wide bandwidth and improved sensitivity with miniatured size, which enables their applications in PA imaging. Conclusions: The optical ultrasound sensors are promising transducers in PA imaging to provide higher-resolution images and can be used in new applications with their unique advantages.

A study of wide unfocused wavefront for convex-array ultrasound imaging.

Ultrafast ultrasound imaging modalities have attracted a lot of attention in the ultrasound community. It breaks the compromise between the frame rate and the region of interest by insonifying the whole medium with wide unfocused waves. Coherent compounding can be performed to enhance the image quality at a cost of frame rate. Ultrafast imaging has wide clinical applications, such as vector Doppler imaging and shear elastography. On the other hand, the use of unfocused waves is still marginal with convex-array transducers. For convex array, plane wave imaging is limited by the complicated transmission delay calculation, limited field-of-view, and inefficient coherent compounding. In this article, we study three wide unfocused wavefronts, namely, lateral virtual-source defined diverging wave imaging (latDWI), tilt virtual-source defined diverging wave imaging (tiltDWI), and Archimedean-spiral-based imaging (AMI) for convex-array imaging using the full-aperture transmission. The analytical monochromatic wave solutions to this three imaging are given. The mainlobe width and grating lobe position are given explicitly. Theoretical -6 dB beamwidth and synthetic transmit field response are studied. Simulation studies are carried on with the point targets and hypoechoic cysts. Time-of-flight formulas are given explicitly for beamforming. The conclusions are in good agreement with the theory: latDWI provides the finest lateral resolution but generates the severest axial lobe level for scatterers with large obliquities (i.e., for scatterers located at the image border) which degrades the image contrast. This effect gets worsen as the compound number increases. The tiltDWI and AMI give a very close performance on resolution and image contrast. AMI displays better contrast with a small compound number.

Super-Low-Dose Functional and Molecular Photoacoustic Microscopy.

Photoacoustic microscopy can image many biological molecules and nano-agents in vivo via low-scattering ultrasonic sensing. Insufficient sensitivity is a long-standing obstacle for imaging low-absorbing chromophores with less photobleaching or toxicity, reduced perturbation to delicate organs, and more choices of low-power lasers. Here, the photoacoustic probe design is collaboratively optimized and a spectral-spatial filter is implemented. A multi-spectral super-low-dose photoacoustic microscopy (SLD-PAM) is presented that improves the sensitivity by ≈33 times. SLD-PAM can visualize microvessels and quantify oxygen saturation in vivo with ≈1% of the maximum permissible exposure, dramatically reducing potential phototoxicity or perturbation to normal tissue function, especially in imaging of delicate tissues, such as the eye and the brain. Capitalizing on the high sensitivity, direct imaging of deoxyhemoglobin concentration is achieved without spectral unmixing, avoiding wavelength-dependent errors and computational noises. With reduced laser power, SLD-PAM can reduce photobleaching by ≈85%. It is also demonstrated that SLD-PAM achieves similar molecular imaging quality using 80% fewer contrast agents. Therefore, SLD-PAM enables the use of a broader range of low-absorbing nano-agents, small molecules, and genetically encoded biomarkers, as well as more types of low-power light sources in wide spectra. It is believed that SLD-PAM offers a powerful tool for anatomical, functional, and molecular imaging.

An ultrasound-activatable platinum prodrug for sono-sensitized chemotherapy.

Despite the great success achieved by photoactivated chemotherapy, eradicating deep tumors using external sources with high tissue penetration depth remains a challenge. Here, we present cyaninplatin, a paradigm of Pt(IV) anticancer prodrug that can be activated by ultrasound in a precise and spatiotemporally controllable manner. Upon sono-activation, mitochondria-accumulated cyaninplatin exhibits strengthened mitochondrial DNA damage and cell killing efficiency, and the prodrug overcomes drug resistance as a consequence of combined effects from released Pt(II) chemotherapeutics, the depletion of intracellular reductants, and the burst of reactive oxygen species, which gives rise to a therapeutic approach, namely sono-sensitized chemotherapy (SSCT). Guided by high-resolution ultrasound, optical, and photoacoustic imaging modalities, cyaninplatin realizes the overall theranostics of tumors in vivo with superior efficacy and biosafety. This work highlights the practical utility of ultrasound to precisely activate Pt(IV) anticancer prodrugs for the eradication of deep tumor lesions and broadens the biomedical uses of Pt coordination complexes.

Simultaneous dual-modal photoacoustic and harmonic ultrasound microscopy with an optimized acoustic combiner.

Simultaneous photoacoustic (PA) and ultrasound (US) imaging provides rich optical and acoustic contrasts with high sensitivity, specificity, and resolution, making it a promising tool for diagnosing and assessing various diseases. However, the resolution and penetration depth tend to be contradictory due to the increased attenuation of high-frequency ultrasound. To address this issue, we present simultaneous dual-modal PA/US microscopy with an optimized acoustic combiner that can maintain high resolution while improving the penetration of ultrasound imaging. A low-frequency ultrasound transducer is used for acoustic transmission, and a high-frequency transducer is used for PA and US detection. An acoustic beam combiner is utilized to merge the transmitting and receiving acoustic beams with a predetermined ratio. By combining the two different transducers, harmonic US imaging and high-frequency photoacoustic microscopy are implemented. In vivo experiments on the mouse brain demonstrate the simultaneous PA and US imaging ability. The harmonic US imaging of the mouse eye reveals finer iris and lens boundary structures than conventional US imaging, providing a high-resolution anatomical reference for co-registered PA imaging.

Signal restoration algorithm for photoacoustic imaging systems.

In a photoacoustic (PA) imaging system, the detectors are bandwidth-limited. Therefore, they capture PA signals with some unwanted ripples. This limitation degrades the resolution/contrast and induces sidelobes and artifacts in the reconstructed images along the axial direction. To compensate for the limited bandwidth effect, we present a PA signal restoration algorithm, where a mask is designed to extract the signals at the absorber positions and remove the unwanted ripples. This restoration improves the axial resolution and contrast in the reconstructed image. The restored PA signals can be considered as the input of the conventional reconstruction algorithms (e.g., Delay-and-sum (DAS) and Delay-multiply-and-sum (DMAS)). To compare the performance of the proposed method, DAS and DMAS reconstruction algorithms were performed with both the initial and restored PA signals on numerical and experimental studies (numerical targets, tungsten wires, and human forearm). The results show that, compared with the initial PA signals, the restored PA signals can improve the axial resolution and contrast by 45% and 16.1 dB, respectively, and suppress background artifacts by 80%.

Array-based high-intensity focused ultrasound therapy system integrated with real-time ultrasound and photoacoustic imaging.

High-intensity focused ultrasound (HIFU) is a promising non-invasive therapeutic technique in clinical applications. Challenges in stimulation or ablation HIFU therapy are to accurately target the treatment spot, flexibly deliver or fast-move focus points in the treatment region, and monitor therapy progress in real-time. In this paper, we develop an array-based HIFU system integrated with real-time ultrasound (US) and photoacoustic (PA) imaging. The array-based HIFU transducer can be dynamically focused in a lateral range of ∼16 mm and an axial range of ∼40 mm via electronically adjusting the excitation phase map. To monitor the HIFU therapy progress in real-time, sequential HIFU transmission, PA imaging, PA thermometry, and US imaging are implemented to display the dual-modal images and record the local temperature changes. Co-registered dual-modal images show structural and functional information and thus can guide the HIFU therapy for precise positioning and dosage control. Besides therapy, the multi-element HIFU transducer can also be used to acquire US images to precisely align the imaging coordinates with the HIFU coordinates. Phantom experiments validate the precise and dynamic steering capability of HIFU ablation. We also show that dual-modal imaging can guide HIFU in the designated region and monitor the temperature in biological tissue in real-time.

Second Near-Infrared (NIR-II) Window for Imaging-Navigated Modulation of Brain Structure and Function.

For a long time, optical imaging of the deep brain with high resolution has been a challenge. Recently, with the advance in second near-infrared (NIR-II) bioimaging techniques and imaging contrast agents, NIR-II window bioimaging has attracted great attention to monitoring deeper biological or pathophysiological processes with high signal-to-noise ratio (SNR) and spatiotemporal resolution. Assisted with NIR-II bioimaging, the modulation of structure and function of brain is promising to be noninvasive and more precise. Herein, in this review, first the advantage of NIR-II light in brain imaging from the interaction between NIR-II and tissue is elaborated. Then, several specific NIR-II bioimaging technologies are introduced, including NIR-II fluorescence imaging, multiphoton fluorescence imaging, and photoacoustic imaging. Furthermore, the corresponding contrast agents are summarized. Next, the application of various NIR-II bioimaging technologies in visualizing the characteristics of cerebrovascular network and monitoring the changes of the pathology signals will be presented. After that, the modulation of brain structure and function based on NIR-II bioimaging will be discussed, including treatment of glioblastoma, guidance of cell transplantation, and neuromodulation. In the end, future perspectives that would help improve the clinical translation of NIR-II light are proposed.

Optical-resolution functional gastrointestinal photoacoustic endoscopy based on optical heterodyne detection of ultrasound.

Photoacoustic endoscopy shows promise in the detection of gastrointestinal cancer, inflammation, and other lesions. High-resolution endoscopic imaging of the hemodynamic response necessitates a small-sized, high-sensitivity ultrasound sensor. Here, we utilize a laser ultrasound sensor to develop a miniaturized, optical-resolution photoacoustic endoscope. The sensor can boost the acoustic response by a gain factor of ωo/Ω (the frequency ratio of the signal light and measured ultrasound) by measuring the acoustically induced optical phase change. As a result, we achieve a noise-equivalent pressure density (NEPD) below 1.5 mPa·Hz-1/2 over the measured range of 5 to 25 MHz. The heterodyne phase detection using dual-frequency laser beams of the sensor can offer resistance to thermal drift and vibrational perturbations. The endoscope is used to in vivo image a rat rectum and visualize the oxygen saturation changes during acute inflammation, which can hardly be observed with other imaging modalities.

Freehand scanning photoacoustic microscopy with simultaneous localization and mapping.

Optical-resolution photoacoustic microscopy offers high-resolution, label-free hemodynamic and functional imaging to many biomedical applications. However, long-standing technical barriers, such as limited field of view, bulky scanning probes, and slow imaging speed, have limited the application of optical-resolution photoacoustic microscopy. Here, we present freehand scanning photoacoustic microscopy (FS-PAM) that can flexibly image various anatomical sites. We develop a compact handheld photoacoustic probe to acquire 3D images with high speed, and great flexibility. The high scanning speed not only enables video camera mode imaging but also allows for the first implementation of simultaneous localization and mapping (SLAM) in photoacoustic microscopy. We demonstrate fast in vivo imaging of some mouse organs, and human oral mucosa. The high imaging speed greatly reduces motion artifacts and distortions from tissue moving, breathing, and unintended handshaking. We demonstrate small-lesion localization in a large region of the brain. FS-PAM offers a flexible high-speed imaging tool with an extendable field of view, enabling more biomedical imaging applications.

Targeted Multifunctional Nanoplatform for Imaging-Guided Precision Diagnosis and Photothermal/Photodynamic Therapy of Orthotopic Hepatocellular Carcinoma.

Background: Effective theranostic of hepatocellular carcinoma (HCC) in an early-stage is imminently demanded to improve its poor prognosis. Combination of the near-infrared (NIR) photoacoustic imaging (PAI) and fluorescence imaging (FLI) can provide high temporospatial resolution, outstanding optical contrast, and deep penetration and thus is promising for accurate and sensitive HCC diagnosis. Methods: A versatile CXCR4-targeted Indocyanine green (ICG)/Platinum (Pt)-doped polydopamine melanin-mimic nanoparticle (designated ICG/Pt@PDA-CXCR4, referred to as IPP-c) is synthesized as an HCC-specific contrast agent for high-resolution precise diagnostic PAI/FLI and optical imaging-guided targeted photothermal therapy (PTT)/photodynamic therapy (PDT) of orthotopic small hepatocellular carcinoma (SHCC). Results: The multifunctional targeted nanoparticle yields superior HCC specificity, high imaging contrast in both PAI and FLI, good stability, reliable biocompatibility, effective singlet oxygen generation and superior photothermal conversion efficiency (PCE, 58.7%) upon 808-nm laser irradiation. The targeting ability of IPP-c was validated in in vitro experiments on selectively killing the CXCR4-overexpressing HCC cells. Moreover, we test the efficient dual-modal optical precision diagnosis properties of IPP-c via in vivo experiments on targeted particle accumulation in an early-stage SHCC mouse model (tumor diameter about 1.2 mm). Then, under the guidance of real-time optical imaging, effective and mini-invasive PTT/PDT of orthotopic SHCCs were demonstrated without damaging adjacent liver tissues or other major organs. Conclusion: This study presented a multifunctional CXCR4-targeted nanoparticle to conduct effective and mini-invasive phototherapeutics of orthotopic SHCCs via the real-time quantitative guidance by optical imaging, which provided a new perception for building a versatile targeted nanoplatform for phototheranostics of early-stage HCC.

Multi-focus image fusion with enhancement filtering for robust vascular quantification using photoacoustic microscopy.

Accurate identification and quantification of microvascular patterns are important for clinical diagnosis and therapeutic monitoring using optical-resolution photoacoustic microscopy (OR-PAM). Due to its limited depth of field, conventional OR-PAM may not fully reveal microvascular patterns with enough details in depth range, which affects the segmentation and quantification. Here, we propose a robust vascular quantification approach via combining multi-focus image fusion with enhancement filtering (MIFEF). The multi-focus image fusion is constructed based on multi-scale gradients and image matting to improve image fusion quality by considerably achieving accurate focus measurement for initial segmentation as well as decision map refinement. The enhancement filtering identifies the vessels and handles noise without deforming microvasculature. The performance of the MIFEF were evaluated employing a leaf phantom, mouse livers and brains. The proposed method for OR-PAM can significantly facilitate the clinical provision of optical biopsy of vascular-related diseases.

Video-rate full-ring ultrasound and photoacoustic computed tomography with real-time sound speed optimization.

Full-ring dual-modal ultrasound and photoacoustic imaging provide complementary contrasts, high spatial resolution, full view angle and are more desirable in pre-clinical and clinical applications. However, two long-standing challenges exist in achieving high-quality video-rate dual-modal imaging. One is the increased data processing burden from the dense acquisition. Another one is the object-dependent speed of sound variation, which may cause blurry, splitting artifacts, and low imaging contrast. Here, we develop a video-rate full-ring ultrasound and photoacoustic computed tomography (VF-USPACT) with real-time optimization of the speed of sound. We improve the imaging speed by selective and parallel image reconstruction. We determine the optimal sound speed via co-registered ultrasound imaging. Equipped with a 256-channel ultrasound array, the dual-modal system can optimize the sound speed and reconstruct dual-modal images at 10 Hz in real-time. The optimized sound speed can effectively enhance the imaging quality under various sample sizes, types, or physiological states. In animal and human imaging, the system shows co-registered dual contrasts, high spatial resolution (140 µm), single-pulse photoacoustic imaging (< 50 µs), deep penetration (> 20 mm), full view, and adaptive sound speed correction. We believe VF-USPACT can advance many real-time biomedical imaging applications, such as vascular disease diagnosing, cancer screening, or neuroimaging.

Implantable Electronic Medicine Enabled by Bioresorbable Microneedles for Wireless Electrotherapy and Drug Delivery.

A combined treatment using medication and electrostimulation increases its effectiveness in comparison with one treatment alone. However, the organic integration of two strategies in one miniaturized system for practical usage has seldom been reported. This article reports an implantable electronic medicine based on bioresorbable microneedle devices that is activated wirelessly for electrostimulation and sustainable delivery of anti-inflammatory drugs. The electronic medicine is composed of a radio frequency wireless power transmission system and a drug-loaded microneedle structure, all fabricated with bioresorbable materials. In a rat skeletal muscle injury model, periodic electrostimulation regulates cell behaviors and tissue regeneration while the anti-inflammatory drugs prevent inflammation, which ultimately enhance the skeletal muscle regeneration. Finally, the electronic medicine is fully bioresorbable, excluding the second surgery for device removal.

Two-step proximal gradient descent algorithm for photoacoustic signal unmixing.

Photoacoustic microscopy uses multiple wavelengths to measure concentrations of different absorbers. The speed of sound limits the shortest wavelength switching time to sub-microseconds, which is a bottleneck for high-speed broad-spectrum imaging. Via computational separation of overlapped signals, we can break the sound-speed limit on the wavelength switching time. This paper presents a new signal unmixing algorithm named two-step proximal gradient descent. It is advantageous in separating multiple wavelengths with long overlapping and high noise. In the simulation, we can unmix up to nine overlapped signals and successfully separate three overlapped signals with 12-ns delay and 15.9-dB signal-to-noise ratio. We apply this technique to separate three-wavelength photoacoustic images in microvessels. In vivo results show that the algorithm can successfully unmix overlapped multi-wavelength photoacoustic signals, and the unmixed data can improve accuracy in oxygen saturation imaging.

Adaptive dual-speed ultrasound and photoacoustic computed tomography.

Full-ring dual-modal ultrasound and photoacoustic computed tomography has unique advantages of nearly isotropic spatial resolution, complementary contrast, deep penetration, and full-view detection. However, the imaging quality may be deteriorated by the inaccurate sound speed estimation. Automatic determining and compensation for sound speed has been a long-standing problem in image reconstruction. Here, we present new adaptive dual-speed ultrasound and photoacoustic computed tomography (ADS-USPACT) to address this challenge. The system features full-view coverage (360°), high-speed dual-modal imaging (10-Hz), automated dual sound speed correction, and synergistic high imaging quality. To correct the sound speed, we develop a two-compartment method that can automatically segment the sample boundary and search for the optimal sound speed based on the rich ultrasonic pulse-echo signals. The method does not require the operator's intervention. We validate this technique in numerical simulation, phantom study, and in vivo experiments. The ADS-USPACT represents significant progress in dual-modal imaging.

Super-Resolution Photoacoustic Microscopy via Modified Phase Compounding.

Acoustic-resolution photoacoustic micro- scopy (AR-PAM) system can provide 3-D images of facial tissues. The lateral resolution of AR-PAM depends on the numerical aperture (NA) of the acoustic lens and the central frequency of the ultrasonic transducer. There is a trade-off between resolution enhancement and imaging depth. The acoustic beam is tight in the acoustic focal plane but expands in the out-of-focus regions, deteriorating the resolution. High-NA AR-PAM has depth-variant resolution. Synthetic aperture focusing technique (SAFT) based on a virtual detector (VD) concept can compensate for the beam shape and improve the lateral resolution via beamforming. Although, beamforming can enhance the resolution but the lateral resolution in the focal plane is still limited by acoustic diffraction. Structured-illumination can shift the spatial spectrum of an image to low frequencies hence high-frequency contents can be reserved to overcome the diffraction limit. Conventional structured-illumination via using a three-phase-shifting method can improve the resolution by two folds. Here, a modified phase-shifting method is used to generate the second harmonic of the fringes and double the spectral shift. In this idea, higher frequency information compared to the three-phase shifting method can fall into the band-limited system response. The modified phase-shifting method expands the spatial bandwidth and increases the lateral resolution by five folds. The mathematical relations and the theory are discussed in the context. Tungsten filament result shows resolution improvement from 44.6 [Formula: see text] to 11.3 [Formula: see text] by the modified structured illumination. In vivo and ex vivo experimental results validate the system performance.

Functional photoacoustic microscopy of hemodynamics: a review.

Functional blood imaging can reflect tissue metabolism and organ viability, which is important for life science and biomedical studies. However, conventional imaging modalities either cannot provide sufficient contrast or cannot support simultaneous multi-functional imaging for hemodynamics. Photoacoustic imaging, as a hybrid imaging modality, can provide sufficient optical contrast and high spatial resolution, making it a powerful tool for in vivo vascular imaging. By using the optical-acoustic confocal alignment, photoacoustic imaging can even provide subcellular insight, referred as optical-resolution photoacoustic microscopy (OR-PAM). Based on a multi-wavelength laser source and developed the calculation methods, OR-PAM can provide multi-functional hemodynamic microscopic imaging of the total hemoglobin concentration (CHb), oxygen saturation (sO2), blood flow (BF), partial oxygen pressure (pO2), oxygen extraction fraction, and metabolic rate of oxygen (MRO2). This concise review aims to systematically introduce the principles and methods to acquire various functional parameters for hemodynamics by photoacoustic microscopy in recent studies, with characteristics and advantages comparison, typical biomedical applications introduction, and future outlook discussion.

Photoacoustic/Fluorescence Dual-Modality Probe for Biothiol Discrimination and Tumor Diagnosis in Cells and Mice.

Developing probes to simultaneously detect and discriminate biothiols is important, yet challenging. Activatable photoacoustic (PA) probes for discriminating biothiols in vivo are still lacking, and this hinders the diagnosis of thiol-related diseases. Herein we present the first PA and fluorescence dual-modality probe MB-NBD for discriminating different biothiol species. The probe has the advantages of both fluorescence imaging and PA imaging (high sensitivity and deep penetration) with distinct signal patterns toward hydrogen sulfide (H2S), cysteine/homocysteine (Cys/Hcy), and glutathione (GSH) treatment. The biothiol-activated product of MB-NBD exhibits enhancements in near-infrared fluorescence (NIRF) at 690 nm and absorbance/PA at 664 nm upon fast reaction, allowing it to selectively detect biothiol species over other reactive species. On the other hand, MB-NBD displays characteristic absorbance enhancement at 547 nm toward H2S, rendering specific detection of H2S. In addition, the specific enhancements in absorbance/PA at 470 nm and fluorescence at 550 nm toward Cys/Hcy treatment endows the probe with the capability of selectively detecting Cys/Hcy. Furthermore, MB-NBD is able to discriminate Cys and GSH by fluorescent imaging in live-cell and ratiometric PA imaging in mice experiments. MB-NBD has been successfully used to diagnose tumors by dual-channel ratiometric PA imaging.