Ultrasound-assisted brain delivery of nanomedicines for brain tumor therapy: advance and prospect.

Nowadays, brain tumors are challenging problems, and the key of therapy is ensuring therapeutic drugs cross the blood-brain barrier (BBB) effectively. Although the efficiency of drug transport across the BBB can be increased by innovating and modifying nanomedicines, they exert insufficient therapeutic effects on brain tumors due to the complex environment of the brain. It is worth noting that ultrasound combined with the cavitation effect of microbubbles can assist BBB opening and enhance brain delivery of nanomedicines. This ultrasound-assisted brain delivery (UABD) technology with related nanomedicines (UABD nanomedicines) can safely open the BBB, facilitate the entry of drugs into the brain, and enhance the therapeutic effect on brain tumors. UABD nanomedicines, as the main component of UABD technology, have great potential in clinical application and have been an important area of interest in the field of brain tumor therapy. However, research on UABD nanomedicines is still in its early stages despite the fact that they have been associated with many disciplines, including material science, brain science, ultrasound, biology, and medicine. Some aspects of UABD theory and technology remain unclear, especially the mechanisms of BBB opening, relationship between materials of nanomedicines and UABD technology, cavitation and UABD nanomedicines design theories. This review introduces the research status of UABD nanomedicines, investigates their properties and applications of brain tumor therapy, discusses the advantages and drawbacks of UABD nanomedicines for the treatment of brain tumors, and offers their prospects. We hope to encourage researchers from various fields to participate in this area and collaborate on developing UABD nanomedicines into powerful tools for brain tumor therapy.

Dual ligand-capped gold nanoclusters for the smart detection of specific reactive oxygen species.

Quantitative detection of different types of reactive oxygen species (ROS) is vital for understanding the crucial roles of them in biological processes. However, few researches achieved the detection of multiple types of ROS with one probe until now. Given this, we designed and prepared fluorescent gold nanoclusters capped by dual ligand bovine serum albumin and lysozyme (BSA-LYS-AuNCs), which could detect 3 specific types of ROS based on its different fluorescent responses to H2O2, •OH and ClO-, respectively. The limit of detection (LOD) of H2O2, •OH, and ClO- was as low as 0.82 µM, 0.45 µM, and 0.62 µM. Moreover, as an important ROS type, ClO- was detected with high sensitivity and low LOD by BSA-LYS-AuNCs. It was also proved that the crosslinking of protein mainly contributed to the unique fluorescent characteristics of the probe exposing to ClO-. Furthermore, the fluorescent probe achieved the smart detection of hROS (including •OH and ClO-) and wROS (the form of H2O2) in the real sample, which could also been applied specifically to the detection of antioxidants, e.g. ascorbic acid. The gold nanoclusters developed have high potential for the smart detection of multiple ROS in the body fluid of organisms.

Multipotent miRNA Sponge-Loaded Magnetic Nanodroplets with Ultrasound/Magnet-Assisted Delivery for Hepatocellular Carcinoma Therapy.

Gene therapy is likely to be the most promising way to tackle cancer, while defects in molecular strategies and delivery systems have led to an impasse in clinical application. Here, it is found that onco-miRNAs of the miR-515 and -449 families were upregulated in hepatocellular carcinoma (HCC), and the sponge targeting miR-515 family had a significant probability to suppress cancer cell proliferation. Then, we constructed non-toxic sponge-loaded magnetic nanodroplets containing 20% C6F14 (SLMNDs-20%) that are incorporated with fluorinated superparamagnetic iron oxide nanoparticles enhancing external magnetism-assisted targeting and enabling a direct visualization of SLMNDs-20% distribution in vivo via magnetic resonance imaging monitoring. SLMNDs-20% could be vaporized by programmable focused ultrasound (FUS) activation, achieving ∼45% in vitro sponge delivery efficiency and significantly enhancing in vivo sponge delivery without a clear apoptosis. Moreover, the sponge-1-carrying SLMNDs-20% could effectively suppress proliferation of xenograft HCC after FUS exposure because sponge-1-suppressing onco-miR-515 enhanced the expression of anti-oncogenes (P21, CD22, TIMP1, NFKB, and E-cadherin) in cancer cells. The current results indicated that ultrasonic cavitation-inducing sonoporation enhanced the intracellular delivery of sponge-1 using SLMNDs-20% after magnetic-assisted accumulation, which was a therapeutic approach to inhibit HCC progression.

[An in vivo study of ultrasonic monitoring imaging of microwave ablation based on Nakagami statistic parameter].

This paper explored the feasibility of using ultrasonic Nakagami statistic parameter imaging to evaluate the thermal lesion induced by microwave ablation (MWA) in porcine models. In this paper, thermal lesions were induced in livers and kidneys in 5 swines using a clinical MWA system. During this treatment progress, ultrasonic radiofrequency (RF) data were collected. The dynamic changes of Nakagami parameter in the thermal lesion were calculated, and the ultrasonic B-mode images and Nakagami images were reconstructed simultaneously. The contrast-to-noise ratio (CNR) between the thermal lesion and the surrounding normal tissue was calculated over the MWA procedure. After MWA, a bright hyperechoic region appeared in the ultrasonic Nakagami image as an indicator of the thermal lesion and this bright spot enlarged with lesion development during MWA exposure. The mean value of Nakagami parameter in the liver and kidney increased from 0.78 and 0.79 before treatment to 0.91 and 0.92 after treatment, respectively. During MWA exposure, the mean values of CNR calculated from the Nakagami parameter increased from 0.49 to 1.13 in the porcine liver and increased from 0.51 to 0.85 in the kidney, which were both higher than those calculated from the B-mode images. This in vivo study on porcine models suggested that the ultrasonic Nakagami imaging may provide an alternative modality for monitoring MWA treatment.

In vivo monitoring of microwave ablation in a porcine model using ultrasonic differential attenuation coefficient intercept imaging.

In this study, the feasibility of using ultrasonic differential attenuation coefficient intercept (Δα0) imaging to evaluate thermal lesions induced by microwave ablation (MWA) was explored using an in vivo porcine model. The attenuation coefficient intercept (Δα0 is estimated by subtracting an initial value of Δα0 images. Receiver operating characteristic (ROC) curves and the area under ROC curve (AUC) were employed to statistically assess the predictability of ultrasonic imaging. Ultrasonic Δα0 values were approximately 0.13 dB/cm and 0.16 dB/cm in a normal liver and kidney, respectively, increasing to 2.9 dB/cm and 2.55 dB/cm in ablated regions after MWA. The CNR values of the ultrasonic Δα0 images (0.9 dB and 0.6 dB in the liver and kidney, respectively) were significantly higher (p < 0.05) than the values of B-mode images (0.6 dB and 0.3 dB). The AUC value of the ultrasonic Δα0 image was higher than the B-mode image value, 0.95 compared with 0.88. This in vivo study suggests that ultrasonic Δα0 imaging has the potential to evaluate thermal lesions with high accuracy and better image contrast for monitoring MWA.

Visualizing the mechanical wave of vocal fold tissue during phonation using electroglottogram-triggered ultrasonography.

In order to investigate the vibration pattern, especially the vibrational phase of tissue beneath the vocal fold mucosa, an imaging method called electroglottogram-triggered ultrasonography is proposed. The ultrasonic images of the vocal fold vibration are obtained in the coronal plane from five adult subjects during phonation. The velocity of the vocal fold tissue beneath the mucosal surface is obtained by using a motion estimation method. The results show that the vibration phase difference between tissues at different locations beneath the vocal fold mucosa results in a mechanical wave traveling upward at a speed of 720 to 1826 mm/s.

Visualizing the movement of the contact between vocal folds during vibration by using array-based transmission ultrasonic glottography.

For the purpose of noninvasively visualizing the dynamics of the contact between vibrating vocal fold medial surfaces, an ultrasonic imaging method which is referred to as array-based transmission ultrasonic glottography is proposed. An array of ultrasound transducers is used to detect the ultrasound wave transmitted from one side of the vocal folds to the other side through the small-sized contact between the vocal folds. A passive acoustic mapping method is employed to visualize and locate the contact. The results of the investigation using tissue-mimicking phantoms indicate that it is feasible to use the proposed method to visualize and locate the contact between soft tissues. Furthermore, the proposed method was used for investigating the movement of the contact between the vibrating vocal folds of excised canine larynges. The results indicate that the vertical movement of the contact can be visualized as a vertical movement of a high-intensity stripe in a series of images obtained by using the proposed method. Moreover, a visualization and analysis method, which is referred to as array-based ultrasonic kymography, is presented. The velocity of the vertical movement of the contact, which is estimated from the array-based ultrasonic kymogram, could reach 0.8 m/s during the vocal fold vibration.

High-contrast active cavitation imaging technique based on multiple bubble wavelet transform.

In this study, a unique method that combines the ultrafast active cavitation imaging technique with multiple bubble wavelet transform (MBWT) for improving cavitation detection contrast was presented. The bubble wavelet was constructed by the modified Keller-Miksis equation that considered the mutual effect among bubbles. A three-dimensional spatial model was applied to simulate the spatial distribution of multiple bubbles. The effects of four parameters on the signal-to-noise ratio (SNR) of cavitation images were evaluated, including the following: initial radii of bubbles, scale factor in the wavelet transform, number of bubbles, and the minimum inter-bubble distance. And the other two spatial models and cavitation bubble size distributions were introduced in the MBWT method. The results suggested that in the free-field experiments, the averaged SNR of images acquired by the MBWT method was improved by 7.16 ± 0.09 dB and 3.14 ± 0.14 dB compared with the values of images acquired by the B-mode and single bubble wavelet transform (SBWT) methods. In addition, in the tissue experiments, the averaged cavitation-to-tissue ratio of cavitation images acquired by the MBWT method was improved by 4.69 ± 0.25 dB and 1.74± 0.29 dB compared with that of images acquired by B-mode and SBWT methods.

Wavelet-transform-based active imaging of cavitation bubbles in tissues induced by high intensity focused ultrasound.

Cavitation detection and imaging are essential for monitoring high-intensity focused ultrasound (HIFU) therapies. In this paper, an active cavitation imaging method based on wavelet transform is proposed to enhance the contrast between the cavitation bubbles and surrounding tissues. The Yang-Church model, which is a combination of the Keller-Miksis equation with the Kelvin-Voigt equation for the pulsations of gas bubbles in simple linear viscoelastic solids, is utilized to construct the bubble wavelet. Experiments with porcine muscles demonstrate that image quality is associated with the initial radius of the bubble wavelet and the scale. Moreover, the Yang-Church model achieves a somewhat better performance compared with the Rayleigh-Plesset-Noltingk-Neppiras-Poritsky model. Furthermore, the pulse inversion (PI) technique is combined with bubble wavelet transform to achieve further improvement. The cavitation-to-tissue ratio (CTR) of the best tissue bubble wavelet transform (TBWT) mode image is improved by 5.1 dB compared with that of the B-mode image, while the CTR of the best PI-based TBWT mode image is improved by 7.9 dB compared with that of the PI-based B-mode image. This work will be useful for better monitoring of cavitation in HIFU-induced therapies.

Generalized LASSO with under-determined regularization matrices.

This paper studies the intrinsic connection between a generalized LASSO and a basic LASSO formulation. The former is the extended version of the latter by introducing a regularization matrix to the coefficients. We show that when the regularization matrix is even- or under-determined with full rank conditions, the generalized LASSO can be transformed into the LASSO form via the Lagrangian framework. In addition, we show that some published results of LASSO can be extended to the generalized LASSO, and some variants of LASSO, e.g., robust LASSO, can be rewritten into the generalized LASSO form and hence can be transformed into basic LASSO. Based on this connection, many existing results concerning LASSO, e.g., efficient LASSO solvers, can be used for generalized LASSO.

Microbubble embedded with upconversion nanoparticles as a bimodal contrast agent for fluorescence and ultrasound imaging.

Bimodal imaging offers additional imaging signal thus finds wide spread application in clinical diagnostic imaging. Fluorescence/ultrasound bimodal imaging contrast agent using fluorescent dyes or quantum dots for fluorescence signal has emerged as a promising method, which however requires visible light or UV irradiation resulting in photobleaching, photo blinking,auto-fluorescence and limited tissue penetration depth. To surmount these problems, we developed a novel bimodal contrast agent using layer-by-layer assembly of up conversion nanoparticles onto the surface of microbubbles. The resulting microbubbles with average size of 2 µm provide enhanced ultrasound echo for ultrasound imaging and upconversion emission upon near infrared irradiation for fluorescence imaging. The developed bimodal contrast agent holds great potential to be applied in ultrasound target technique for targeted diseases diagnostics and therapy.

Modeling photoacoustic cavitation nucleation and bubble dynamics with modified classical nucleation theory.

Photoacoustic cavitation (PAC) is the formation of bubbles in liquids using a focused laser and a pre-established ultrasound synchronously. The decreased threshold of each modality and the precise location of cavitation determined by the focused laser are both significant in the targeted theranostics. In this study, PAC nucleation was described using the modified classical nucleation theory by Kashchiev's scaling function. A two-stage model of the PAC bubble dynamics was presented based on the two different bubble behaviors. It was clarified that both negative acoustic pressure and laser-induced temperature rise, resulting in the decrease in critical radius and the increase in nucleation rate, and thereby contribute to the increase in nucleation probability in the confocal region. Ultrasound determined the whole PAC bubble dynamics with temperature-dependent parameters, while the laser mainly contributed to its initial conditions. Moreover, the effects of certain parameters on PAC were further discussed, including the relative acoustic phase when a laser is introduced (φ), laser pulse duration (τ(L)), laser focus radius (R(f)), and ultrasound amplitude (P(A)). The model would be helpful in understanding the PAC process and further in introducing PAC to potential targeted theranostics.

Spatial-temporal ultrasound imaging of residual cavitation bubbles around a fluid-tissue interface in histotripsy.

Cavitation is considered as the primary mechanism of soft tissue fragmentation (histotripsy) by pulsed high-intensity focused ultrasound. The residual cavitation bubbles have a dual influence on the histotripsy pulses: these serve as nuclei for easy generation of new cavitation, and act as strong scatterers causing energy "shadowing." To monitor the residual cavitation bubbles in histotripsy, an ultrafast active cavitation imaging method with relatively high signal-to-noise ratio and good spatial-temporal resolution was proposed in this paper, which combined plane wave transmission, minimum variance beamforming, and coherence factor weighting. The spatial-temporal evolutions of residual cavitation bubbles around a fluid-tissue interface in histotripsy under pulse duration (PD) of 10-40 µs and pulse repetition frequency (PRF) of 0.67-2 kHz were monitored by this method. The integrated bubble area curves inside the tissue interface were acquired from the bubble image sequence, and the formation process of histotripsy damage was estimated. It was observed that the histotripsy efficiency decreased with both longer PDs and higher PRFs. A direct relationship with a coefficient of 1.0365 between histotripsy lesion area and inner residual bubble area was found. These results can assist in monitoring and optimization of the histotripsy treatment further.

Ultrafast active cavitation imaging with enhanced cavitation to tissue ratio based on wavelet transform and pulse inversion.

The quality of ultrafast active cavitation imaging (UACI) using plane wave transmission is hindered by low transmission pressure, which is necessary to prevent bubble destruction. In this study, a UACI method that combined wavelet transform with pulse inversion (PI) was proposed to enhance the contrast between the cavitation bubbles and surrounding tissues. The main challenge in using wavelet transform is the selection of the optimum mother wavelet. A mother wavelet named "cavitation bubble wavelet" and constructed according to Rayleigh-Plesset-Noltingk-Neppiras-Poritsky model was expected to obtain a high correlation between the bubbles and beamformed echoes. The method was validated by in vitro experiments. Results showed that the image quality was associated with the initial radius of bubble and the scale. The signal-to-noise ratio (SNR) of the best optimum cavitation bubble wavelet transform (CBWT) mode image was improved by 3.2 dB compared with that of the B-mode image in free-field experiments. The cavitation-to-tissue ratio of the best optimum PI-based CBWT mode image was improved by 2.3 dB compared with that of the PI-based B-mode image in tissue experiments. Furthermore, the SNR versus initial radius curve had the potential to estimate the size distribution of cavitation bubbles.

Ultrafast 2-dimensional image monitoring and array-based passive cavitation detection for ultrasound contrast agent destruction in a variably sized region.

OBJECTIVES: A combined approach was proposed, based on programmable ultrasound equipment, to simultaneously monitor surviving microbubbles and detect cavitation activity during microbubble destruction in a variably sized region for use in ultrasound contrast agent (UCA)-enhanced therapeutic ultrasound applications. METHODS: A variably sized focal region wherein the acoustic pressure was above the UCA fragmentation threshold was synthesized at frequencies of 3, 4, 5, and 6 MHz with a linear broadband imaging probe. The UCAs' temporal and spatial distribution during the microbubbles' destruction was monitored in a 2-dimensional imaging plane at 5 MHz and a frame rate of 400 Hz, and simultaneously, broadband noise emissions during the microbubbles' fragmentation were extracted by using the backscattered signals produced by the focused release bursts (ie, destruction pulses) themselves. Afterward, the temporal evolution of broadband noise emission, the surviving microbubbles in a region of interest (ROI), and the destruction area in a static UCA suspension were computed. Then the inertial cavitation dose, destruction rate of microbubbles in the ROI, and area of the destruction region were determined. RESULTS: It was found that an increasing pulse length and a decreasing transmit aperture and excitation frequency were correlated with an increased inertial cavitation dose, microbubble destruction rate, and destruction area. Furthermore, it was obvious that the microbubble destruction rate was significantly correlated with the inertial cavitation dose (P < .05). In addition, the intensity decrease in the ROI was significantly correlated with the destruction area (P < .05). CONCLUSIONS: By the proposed strategy, microbubbles could be destroyed in a variably sized region, and destruction efficiency as well as the corresponding inertial cavitation dose could be regulated by manipulating the transmission parameters.

Enhanced lesion-to-bubble ratio on ultrasonic Nakagami imaging for monitoring of high-intensity focused ultrasound.

OBJECTIVES: This work explored the feasibility of using ultrasonic Nakagami imaging to enhance the contrast between thermal lesions and bubbles induced by high-intensity focused ultrasound (US) in a transparent tissue-mimicking phantom at different acoustic power levels. METHODS: The term "lesion-to-bubble ratio" was proposed and defined as the ratio of the scattered power from the thermal lesion to the scattered power from the bubbles calculated in the various monitoring of images for high-intensity focused US. Two-dimensional radiofrequency data backscattered from the exposed region were captured by a modified diagnostic US scanner to estimate the Nakagami statistical parameter, m, and reconstruct the ultrasonic B-mode images and Nakagami parameter images. The dynamic changes in the lesion-to-bubble ratio over the US exposure procedure were calculated simultaneously and compared among video photos, B-mode images, and Nakagami images for monitoring of high-intensity focused US. RESULTS: After a small thermal lesion was induced by high-intensity focused US in the phantom, the lesion-to-bubble ratio values corresponding to the video photo, B-mode image, and Nakagami image were 5.3, 1, and 9.8 dB, respectively. When a large thermal lesion appeared in the phantom, the ratio values increased to 7.2, 3, and 14 dB. During US exposure, the ratio values calculated for the video photo, B-mode image, and Nakagami image began to increase gradually and rose to peak values of 8.3, 2.9, and 14.8 dB at the end of the US exposure. CONCLUSIONS: This preliminary study on a tissue-mimicking phantom suggests that Nakagami imaging may have a potential use in enhancing the lesion-to-bubble ratio for monitoring high-intensity focused US. Further studies in vivo and in vitro will be needed to evaluate the potential applications for high-intensity focused US.

Measurement of the sound transmission characteristics of normal neck tissue using a reflectionless uniform tube.

Understanding the sound transmission of the neck tissue is necessary and important in areas such as vocal function evaluation and electrolarynx improvement. In this paper, a simple method using a reflectionless tube was proposed to measure the neck frequency response function (NFRF) of ten normal subjects (five males and five females) during Mandarin vowel production. The NFRFs across different subjects producing different vowels were measured at different neck positions and compared to confirm the effectiveness of the method, and determine the NFRF variations in normal subjects. The results showed that the proposed method offered an easy and effective way to obtain an accurate NFRF. For normal subjects, the neck tissue can be treated as a low-pass filter, with a maximum gain at 310 Hz and a roll-off at a slope of -8.4 dB/octave, flattening out above 2000 Hz. The measurement position on the neck did not influence the shape of the NFRF, but did change the overall gains of the NFRF. In addition, there was a significant gender difference in NFRFs at the low frequencies. Finally, some potential applications of this method and the results are suggested.

Classification of multi-feature fusion ultrasound images of breast tumor within category 4 using convolutional neural networks.

BACKGROUND: Breast tumor is a fatal threat to the health of women. Ultrasound (US) is a common and economical method for the diagnosis of breast cancer. Breast imaging reporting and data system (BI-RADS) category 4 has the highest false-positive value of about 30% among five categories. The classification task in BI-RADS category 4 is challenging and has not been fully studied. PURPOSE: This work aimed to use convolutional neural networks (CNNs) for breast tumor classification using B-mode images in category 4 to overcome the dependence on operator and artifacts. Additionally, this work intends to take full advantage of morphological and textural features in breast tumor US images to improve classification accuracy. METHODS: First, original US images coming directly from the hospital were cropped and resized. In 1385 B-mode US BI-RADS category 4 images, the biopsy eliminated 503 samples of benign tumor and left 882 of malignant. Then, K-means clustering algorithm and entropy of sliding windows of US images were conducted. Considering the diversity of different characteristic information of malignant and benign represented by original B-mode images, K-means clustering images and entropy images, they are fused in a three-channel form multi-feature fusion images dataset. The training, validation, and test sets are 969, 277, and 139. With transfer learning, 11 CNN models including DenseNet and ResNet were investigated. Finally, by comparing accuracy, precision, recall, F1-score, and area under curve (AUC) of the results, models which had better performance were selected. The normality of data was assessed by Shapiro-Wilk test. DeLong test and independent t-test were used to evaluate the significant difference of AUC and other values. False discovery rate was utilized to ultimately evaluate the advantages of CNN with highest evaluation metrics. In addition, the study of anti-log compression was conducted but no improvement has shown in CNNs classification results. RESULTS: With multi-feature fusion images, DenseNet121 has highest accuracy of 80.22 ± 1.45% compared to other CNNs, precision of 77.97 ± 2.89% and AUC of 0.82 ± 0.01. Multi-feature fusion improved accuracy of DenseNet121 by 1.87% from classification of original B-mode images (p < 0.05). CONCLUSION: The CNNs with multi-feature fusion show a good potential of reducing the false-positive rate within category 4. The work illustrated that CNNs and fusion images have the potential to reduce false-positive rate in breast tumor within US BI-RADS category 4, and make the diagnosis of category 4 breast tumors to be more accurate and precise.

Noninvasive assessment of pressure distribution and fractional flow in middle cerebral artery using microbubbles and plane wave in vitro.

Fractional flow has been proposed for quantifying the degree of functional stenosis in cerebral arteries. Herein, subharmonic aided pressure estimation (SHAPE) combined with plane wave (PW) transmission was employed to noninvasively estimate the pressure distribution and fractional flow in the middle cerebral artery (MCA) in vitro. Consequently, the effects of incident sound pressure (peak negative pressures of 86-653 kPa), pulse repetition frequency (PRF), number of pulses, and blood flow rate on the subharmonic pressure relationship were investigated. The radio frequency data were stored and beamformed offline, and the subharmonic amplitude over a 0.4 MHz bandwidth was extracted using a 12-cycle PW at 4 MHz. The optimal incident sound pressure was 217 kPa without skull (sensitivity = 0.09 dB/mmHg; r2 = 0.997) and 410 kPa with skull (median sensitivity = 0.06 dB/mmHg; median r2 = 0.981). The optimal PRF was 500 Hz, as this value affords the highest sensitivity (0.09 dB/mmHg; r2 = 0.976) and temporal resolution. In addition, the blood flow rate exhibited a lesser effect on the subharmonic pressure relationship in our experimental setup. Using the optimized parameters, the blood pressure distribution and fractional flow (FFs) were measured. As such, the FFs value was in high agreement with the value measured using the pressure sensor (FFm). The mean ± standard deviations of the FF difference (FFm - FFs) were 0.03 ± 0.06 without skull and 0.01 ± 0.05 with skull.

Transcranial ultrasound estimation of viscoelasticity and fluidity in brain tumors aided by transcranial shear waves.

Cerebral diseases, such as brain tumors, are intricately linked to the mechanical properties of brain tissues. Estimating the mechanical properties of brain tumors using transcranial ultrasound is a promising approach. However, the complexity of cranial features introduces challenges, such as ultrasound attenuation and interference from multidirectional transcranial shear waves induced by impact vibrations. To address these issues, this study proposes a transcranial ultrasound estimation method assisted by transcranial shear vibrations. Transcranial vibrations apply shear forces on the parietal bone, inducing unidirectional transcranial shear waves within brain tissue, as validated through simulations. Shear waves at different frequencies were captured via transcranial ultrasound, which were used to assess the viscoelasticity and fluidity of brain tumors. Transcranial experimental validations were conducted in 3D-printed models with tumor phantoms and ex vivo animal tumors. Vibration safety assessments were also performed. The results demonstrate that transcranial ultrasound can detect micron displacements induced by transcranial shear waves. In phantom and ex vivo animal experiments, speed distribution maps were employed to determine the size and location of one or two tumors enclosed in the skull model. The results revealed that the proposed approach could detect tumors with a minimum diameter of 0.8 cm and an inter-tumor distance of 0.8 cm. Notably, significant differences in viscoelasticity and fluidity between normal brain tissue and brain tumors were found (p<0.001). The maximum assessment errors for the elasticity, viscosity, and fluidity using transcranial ultrasound were 11.90%, 4.82%, and 0.73%, respectively, indicating that fluidity was more robust than viscoelasticity. The maximum accelerations of the skull were only 3.21 ms-2.