Deep Penetrating and Sensitive Targeted Magnetic Particle Imaging and Photothermal Therapy of Early-Stage Glioblastoma Based on a Biomimetic Nanoplatform.

Early diagnosis can effectively improve the survival of glioblastoma multiforme (GBM). A specific imaging technique that is simultaneously deep penetrating and sensitive to small tissue changes is desired to identify GBM. Due to its excellent features in signal contrast, detection sensitivity, and none or little attenuation in tissue, magnetic particle imaging (MPI) possesses great potential in cancer diagnosis, especially when the imaging modality is equipped with specifically targeted nanoprobes. However, when gliomas are small, the blood-brain barrier (BBB) is complete and prevents nanoprobes from entering the brain, which negates the theranostic effect. This study proposes a biomimetic nanoplatform that assist the MPI tracers in breaking through the BBB and then demonstrate a targeted and sensitive diagnosis of GBM. Afterward, the photothermal therapy and immune regulation show an excellent therapeutic effect on the GBM. It is experimentally confirmed that the MPI signal does not decay with tissue depth and shows excellent sensitivity for thousands-cells. Only small animals are conducted in this study due to the limitations of the current commercial MPI scanner, however, this research theoretically enables large animal and human studies, which encourages a promising pathway toward the noninvasive diagnosis of early-stage GBM in clinics.

Small Animal In Situ Drug Delivery Effects via Transdermal Microneedles Array versus Intravenous Injection: A Pilot Observation Based on Photoacoustic Tomography.

Intravenous injection is a rapid, low-cost, and direct method that is commonly used to deliver multifarious biotherapeutics and vaccines. However, intravenous injection often causes trauma or tissue injury that requires professional operation. Transdermal drug delivery overcomes the aforementioned defects, and the microneedles (MNs) array is one of the most promising transdermal drug delivery platforms. Timely, precise, and non-invasive monitoring and evaluation of the effects of MNs in transdermal administration is significant to the research of drug efficiency response to specific diseases. In this sense, photoacoustic computed tomography (PACT), which provides wavelength-selective and deep-penetrating optical contrast, could be a promising imaging tool for in situ evaluation of the treatment effects. In this work, we propose the use of PACT to non-invasively assess the effects of real-time drug delivery in glioma tumors through transdermal administration with degradable indocyanine green-loaded hyaluronic acid MNs (ICG-HA-MNs). The outcome is systematically and quantitatively compared with that via intravenous injection. It is found that the photoacoustic signals of ICG in the tumor site express a faster elevation and shorter duration time in the intravenous injection group; by contrast, the photoacoustic signals demonstrate a lower intensity but prolonged duration time in the MNs group. The observed phenomenon indicates faster response but shorter drug duration for intravenous injection, which is in contrast with the lower loading but prolonged performance for transdermal drug delivery with MNs. These results exhibit good consistency with the earlier, common-sense findings reported from other aspects, confirming that PACT can serve as a potential imaging tool to precisely, non-invasively, and quickly evaluate in situ drug delivery effects and provide constructive guidance for the design and fabrication of microneedles.

Wavefront shaping: A versatile tool to conquer multiple scattering in multidisciplinary fields.

Optical techniques offer a wide variety of applications as light-matter interactions provide extremely sensitive mechanisms to probe or treat target media. Most of these implementations rely on the usage of ballistic or quasi-ballistic photons to achieve high spatial resolution. However, the inherent scattering nature of light in biological tissues or tissue-like scattering media constitutes a critical obstacle that has restricted the penetration depth of non-scattered photons and hence limited the implementation of most optical techniques for wider applications. In addition, the components of an optical system are usually designed and manufactured for a fixed function or performance. Recent advances in wavefront shaping have demonstrated that scattering- or component-induced phase distortions can be compensated by optimizing the wavefront of the input light pattern through iteration or by conjugating the transmission matrix of the scattering medium. This offers unprecedented opportunities in many applications to achieve controllable optical delivery or detection at depths or dynamically configurable functionalities by using scattering media to substitute conventional optical components. In this article, the recent progress of wavefront shaping in multidisciplinary fields is reviewed, from optical focusing and imaging with scattering media, functionalized devices, modulation of mode coupling, and nonlinearity in multimode fiber to multimode fiber-based applications. Apart from insights into the underlying principles and recent advances in wavefront shaping implementations, practical limitations and roadmap for future development are discussed in depth. Looking back and looking forward, it is believed that wavefront shaping holds a bright future that will open new avenues for noninvasive or minimally invasive optical interactions and arbitrary control inside deep tissues. The high degree of freedom with multiple scattering will also provide unprecedented opportunities to develop novel optical devices based on a single scattering medium (generic or customized) that can outperform traditional optical components.

3D acoustic resolution-based photoacoustic endoscopy with dynamic focusing.

BACKGROUND: Acoustic resolution-based photoacoustic endoscopy (ARPAE) is a non-invasive potential tool for imaging gastrointestinal and urogenital tracts. However, current ARPAE systems usually only provide 2D sectorial B-mode images, and have the limitation of the image quality significantly deteriorating out-of-focus regions due to transducers with fixed focus in these systems. To overcome these limitations, we put forward a modified back-projection method that can provide 3D images with dynamic focusing in ARPAE. METHODS: A graphics processing unit (GPU)-based parallel computation technique was adopted for efficient computation. Both simulated and phantom/ex-vivo experiments were conducted to validate our method. RESULTS: The findings indicated that our proposed method can effectively improve the lateral resolution and signal-to-noise ratio (SNR) in the out-of-focus regions. For a target 3 mm from the transducer focus, the new method can improve 11 times in the lateral resolution, along with an improvement of up to 37 dB in the SNR. CONCLUSIONS: 3D ARPAE provides high-quality imaging in both focus and out-of-focus regions.

Two-Dimensional Photoacoustic/Ultrasonic Endoscopic Imaging Based on a Line-Focused Transducer.

Existing acoustic-resolution photoacoustic/ultrasonic endoscopy (PA/USE) generally employs a point-focused transducer for ultrasound detection, which is only sensitive in its focal region, thus the lateral resolution and sensitivity drop dramatically when the targets move far from its focus. Even if a dynamic focusing algorithm is applied, the sensitivity out of the transducer focus is still much lower than that in the focus in ultrasonic imaging mode. In this work, we propose an acoustic-resolution PA/USE with a line-focused transducer to realize automatic focusing for the first time. In comparison to a point-focused transducer, the line-focused transducer emits a more uniform sound field, causing the original signal intensity and signal-to-noise ratio (SNR) of the front and rear targets to be closer in the radial direction, which is beneficial for improving target signal uniformity in ultrasonic imaging. Simultaneously, we improved the resolution of the defocus area by modifying a prior work of back-projection (BP) reconstruction algorithm typically used in point-focused transducer based PAE and applying it to line-focused PA/USE. This combined approach may significantly enhance the depth of field of ultrasonic imaging and the resolution of the defocus zone in PA/US imaging, compared to the conventional method. Sufficient numerical simulations and phantom experiments were performed to verify this method. The results show that our method can effectively improve the lateral resolution in the image's defocused region to achieve automatic focusing and perfectly solve the defect of the target signal difference in the far-focus region in ultrasonic imaging, while also enhancing the image SNR and contrast. The proposed method in this paper lays foundations for the realization of photoacoustic/ultrasonic combined endoscopy with enhanced lateral resolution and depth of field, which can potentially benefit a many of biomedical applications.

Three-dimensional synthetic aperture focusing photoacoustic microscopy based on the acoustic simulation generated delay time and weighted factor.

Acoustic resolution photoacoustic microscopy (ARPAM) is a promising imaging tool in biomedical applications for its advantage of penetration over other optical imaging techniques. However, the lateral resolution of ARPAM deteriorates significantly in the out-of-focus region. The synthetic aperture focusing technique (SAFT) is required to restore this kind of focus-related imaging distortion. The conventional SAFT method is based on the virtual detector (VD) conception, in which the phase of the received photoacoustic (PA) signal is calculated by assuming the focus of the transducer as a VD. Nevertheless, the phase of the received PA signal is not only determined by the geometrical parameters of the transducer, but also by the transducer's electromechanic response and the original PA signal. Ignoring these two factors will reduce the quality of the imaging results. In this work, a new SAFT method, which is based on acoustic simulation, is proposed for ARPAM. The measured PA signal from a point target at the focus is employed to evaluate the convolution of the transducer's electromechanic response and the original PA signal. This measured signal is used as the excitation in an acoustic simulation. The simulation, which is based on the geometrical and acoustic parameters of the transducer, is employed to calculate the delay time and weighted coefficient for the SAFT calculation. The phantom experiments with point and line targets indicate that the proposed method obtains imaging results with better lateral resolution and improved signal-noise ratio compared with the widely used VD-based SAFT method.

Acoustic-resolution-based photoacoustic microscopy with non-coaxial arrangements and a multiple vertical scan for high lateral resolution in-depth.

In conventional acoustic-resolution-based photoacoustic microscopy (ARPAM), a focused ultrasound transducer is placed coaxially with the laser beam to obtain the generated ultrasound signals. The information from deep regions can be greatly affected by the shallow targets. More importantly, in ARPAM the irreconcilable conflict between the lateral resolution and depth of fields has always been a major factor that lowers the imaging quality. In this work, an ARPAM system was developed, in which a non-coaxial arrangement of light illumination and acoustic detection was adopted to alleviate the influence of the tissue surface on the deep targets, and a focal zone integral algorithm was applied with a multiple scanning scheme to improve the lateral resolution. The system can achieve a consistent high lateral resolution of 0.5 mm over a large range in the axial direction. Both the phantom experiment and the chicken embryo in vivo results indicate that the proposed method can provide more in-depth information compared with the conventional ARPAM method. With the development of high repetition lasers and the advancement of image scanning technologies, the proposed method may play an important role in cerebral vascular imaging, superficial tumor imaging, and other related biomedical imaging applications.

Back-projection algorithm in generalized form for circular-scanning-based photoacoustic tomography with improved tangential resolution.

BACKGROUND: The back-projection algorithm is the most common method for the reconstruction of circular-scanning-based photoacoustic tomography (CSPAT) due to its simplicity, computational efficiency, and robustness. It usually can be implemented in two models: one for ideal point detector, and the other for planar transducer with infinite element size. However, because most transducers in CSPAT are planar with a finite size, the off-center targets will be blurred in the tangential direction with these two reconstruction models. METHODS: Here in this paper, we put forward a new model of the back projection algorithm for the reconstruction of CSPAT with finite size planar transducer, in which the acoustic spatial temporal response of the employed finite size transducer is approximated with a virtual detector placed at an optimized distance behind the transducer, and the optimized distance is determined by a phase square difference minimization scheme. Notably, this proposed method can also be suitable for reconstruction with the ideal point detector and infinite planar detector, and thus is a generalized form of the back-projection algorithm. RESULTS: Compared with the two conventional models of the back-projection method and the modified back-projection method, the proposed method in this work can significantly improve the tangential resolution of off-center targets, thus improving the reconstructed image quality. These findings are validated with both simulations and experiments. CONCLUSIONS: We propose a generalized model of the back projection algorithm to restore the elongated tangential resolution in CSPAT in case of a planar transducer of finite size, which can also be applicable for point and large-size planar transducers. This proposed method may also guide the design of CSPAT scanning configurations for potential applications such as human breast imaging for cancer detection.