Microbubble Oscillation Research Articles

Enhanced neuronal activity in mouse motor cortex with microbubbles' oscillations by transcranial focused ultrasound stimulation.

Microbubbles (MBs) are known to serve as an amplifier of the mechanical effects of ultrasound, which combined with ultrasound are widely used in brain. The goal of this study is to investigate the effect of oscillating MBs on the neuronal activity in the central nervous system (CNS) of mammals. The motor cortex of mice brain was subjected to ultrasound stimulation with and without MBs, and evoked electromyogram signals were recorded. A c-fos immunofluorescence assay was performed to evaluate the neuronal activation in the region of ultrasound stimulation. BBB integrity during ultrasound stimulation with MBs was assessed in this study. Moreover, the safety of ultrasound stimulation with MBs was examined. Using ultrasound at 620 kHz, the injection of MBs significantly increased the success rate of motor response from 0.065 ± 0.06 to 0.28 ± 0.10 when stimulation was applied at 0.12 MPa and from 0.38 ± 0.09 to 0.77 ± 0.18 at 0.25 MPa (p < 0.001). The results of the c-fos immunofluorescence assay showed that the mean densities of c-fos+ cells were significantly increased from 15.67 ± 3.51 to 53.01 ± 9.54 at 0.12 MPa acoustic pressure. At 0.25 MPa, the mean density of c-fos + cells was 81 ± 10.97 without MBs and it significantly increased to 124.12 ± 25.71 with MBs (p < 0.05). Enhanced neuronal activities were observed with 0.12 MPa ultrasound stimulation with MBs, while the integrity of BBB was not compromised, but 0.25 MPa ultrasound stimulation with MBs resulted in BBB disruption. These findings reveal that the oscillations of MBs can enhance neuronal activity in the CNS of mammals, and may provide an insight into the application of MBs combined with ultrasound in brain.

Collective nonlinear behavior of interacting polydisperse microbubble clusters

Acoustically excited microbubbles (MBs) have shown to exhibit rich dynamics, enabling them to be employed in various applications ranging from chemistry to medicine. Exploiting the full potential of MBs for applications requires a good understanding of their complex dynamics. Improved understanding of MB oscillations can lead to further enhancement in optimizing their efficacy in many applications and also invent new ones. Oscillating MBs have been shown to generate secondary pressure waves that modify the dynamics of the MBs in their proximity. A modified Keller-Miksis equation is used to account for inter-bubble interactions. The oscillatory dynamics of each MB within clusters was computed by numerically solving the resulting system of coupled nonlinear second order differential equations in potential fluid flow. Frequency response analysis and bifurcation diagrams were employed to track the dynamics of interacting MBs. We start with investigating the effect of inter-bubble interactions for cases of three and four MBs over a wide range of acoustic and geometric parameters. Emergent collective behavior was observed which are dominated by the dynamics of the largest MB within the cluster. The emergent dynamics of smaller MBs within clusters can be characterized by constructive and destructive inter-bubble interactions. In constructive interactions, the radial oscillations of smaller MBs matched those of the largest MB and their oscillations are amplified. In destructive interactions, the oscillations of smaller bubbles are suppressed so that their oscillations match those of the largest MB. Furthermore, a special case of constructive interactions is presented where dominant MB (largest) can force smaller MBs into period doubling and subharmonic oscillations. The collective behavior is further investigated in large MB cluster and it is shown that largest MBs, even in small numbers can force smaller ones into period doubling and subharmonic oscillations.

Combined Confocal Microscope and Brandaris 128 Ultra-High-Speed Camera

Controlling microbubble-mediated drug delivery requires the underlying biological and physical mechanisms to be unraveled. To image both microbubble oscillation upon ultrasound insonification and the resulting cellular response, we developed an optical imaging system that can achieve the necessary nanosecond temporal and nanometer spatial resolutions. We coupled the Brandaris 128 ultra-high-speed camera (up to 25 million frames per second) to a custom-built Nikon A1R+ confocal microscope. The unique capabilities of this combined system are demonstrated with three experiments showing microbubble oscillation leading to either endothelial drug delivery, bacterial biofilm disruption, or structural changes in the microbubble coating. In conclusion, using this state-of-the-art optical imaging system, microbubble-mediated drug delivery can be studied with high temporal resolution to resolve microbubble oscillation and high spatial resolution and detector sensitivity to discern cellular response. Combining these two imaging technologies will substantially advance our knowledge on microbubble behavior and its role in drug delivery.

The in situ electrochemical detection of microbubble oscillations during motion through a channel.

Bubble oscillation has many applications, from driving local fluid motion to cleaning. However, in order to exploit their action, a full understanding of this motion, particularly in confined spaces (such as crevices etc. which are important in ultrasonic decontamination) is important. To this end, here we show how a Coulter counter can be used to characterize microbubbles produced through the ultrasonication of electrolytes. These microbubbles are shown to exist in relatively high concentrations while bubble activity is driven by ultrasound. Detection of these microbubbles, and their oscillatory behaviour, is achieved via translocation through a cylindrical glass microchannel (GMC). The microbubbles oscillate within the 40 μm channel employed and this behaviour is observed to change over the translocation period. This is attributed to the acoustic environment present or changes to the physical conditions in the interior of the chamber compared to the exterior. High-speed imaging confirms the presence of microbubbles as they move or 'skate' across the surface of the structures present before translocating through the channel. The observations are useful as they show that microbubble oscillation occurs within small structures, is preceded by surface confined bubbles and could be enhanced through pressure driven flow through a structure.

Closed Loop Spatial and Temporal Control of Cavitation Activity with Passive Acoustic Mapping.

Ultrasonically actuated microbubble oscillations hold great promise for minimally invasive therapeutic interventions. While several preclinical studies have demonstrated the potential of this technology, real-time methods to control the amplitude and type of microbubble oscillations (stable vs inertial acoustic cavitation) and ensure that cavitation occurs within the targeted region are needed for their successful translation to the clinic. In this paper, we propose a real-time nonlinear state controller that uses specific frequency bands of the microbubble acoustic emissions (harmonic, ultra-harmonic, etc.) to control cavitation activity (observer states). To attain both spatial and temporal control of cavitation activity with high signal to noise ratio, we implement a controller using fast frequency-selective passive acoustic mapping (PAM) based on the angular spectrum approach. The controller includes safety states based on the recorded broadband signal level and is able to reduce sensing inaccuracies with the inclusion of multiple frequency bands. In its simplest implementation the controller uses the peak intensity of the passive acoustic maps, reconstructed using the 3rd harmonic (4.896 × 0.019 MHz) of the excitation frequency. Our results show that the proposed real-time nonlinear state controller based on PAM is able to reach the targeted level of observer state (harmonic emissions) in less than 6 seconds and remain within 10 % of tolerance for the duration of the experiment (45 seconds). Similar response was observed using the acoustic emissions from single element passive cavitation detection, albeit with higher susceptibility to background noise and lack of spatial information. Importantly, the proposed PAM-based controller was able to control cavitation activity with spatial selectivity when cavitation existed simultaneously in multiple regions. The robustness of the controller is demonstrated using a range of controller parameters, multiple observer states concurrently (harmonic, ultra-harmonic, and broadband), noise levels (°6 to 12 dB SNR), and bubble concentrations (0.3 to 180 × 103 bubbles per microliter). More research in this direction under preclinical and clinical conditions is warranted.

Enhanced microbubble contrast agent oscillation following 250\u2009kHz insonation

Microbubble contrast agents are widely used in ultrasound imaging and therapy, typically with transmission center frequencies in the MHz range. Currently, an ultrasound center frequency near 250 kHz is proposed for clinical trials in which ultrasound combined with microbubble contrast agents is applied to open the blood brain barrier, since at this low frequency focusing through the human skull to a predetermined location can be performed with reduced distortion and attenuation compared to higher frequencies. However, the microbubble vibrational response has not yet been carefully evaluated at this low frequency (an order of magnitude below the resonance frequency of these contrast agents). In the past, it was assumed that encapsulated microbubble expansion is maximized near the resonance frequency and monotonically decreases with decreasing frequency. Our results indicated that microbubble expansion was enhanced for 250 kHz transmission as compared with the 1 MHz center frequency. Following 250 kHz insonation, microbubble expansion increased nonlinearly with increasing ultrasonic pressure, and was accurately predicted by either the modified Rayleigh–Plesset equation for a clean bubble or the Marmottant model of a lipid-shelled microbubble. The expansion ratio reached 30-fold with 250 kHz at a peak negative pressure of 400 kPa, as compared to a measured expansion ratio of 1.6 fold for 1 MHz transmission at a similar peak negative pressure. Further, the range of peak negative pressure yielding stable cavitation in vitro was narrow (~100 kPa) for the 250 kHz transmission frequency. Blood brain barrier opening using in vivo transcranial ultrasound in mice followed the same trend as the in vitro experiments, and the pressure range for safe and effective treatment was 75–150 kPa. For pressures above 150 kPa, inertial cavitation and hemorrhage occurred. Therefore, we conclude that (1) at this low frequency, and for the large oscillations, lipid-shelled microbubbles can be approximately modeled as clean gas microbubbles and (2) the development of safe and successful protocols for therapeutic delivery to the brain utilizing 250 kHz or a similar center frequency requires consideration of the narrow pressure window between stable and inertial cavitation.

Shape oscillation and stability of an encapsulated microbubble translating in an acoustic wave.

Encapsulated microbubbles (EMBs) are associated with a wide variety of important medical applications, including sonography, drug delivery, and sonoporation. The nonspherical oscillations, or shape modes, of EMBs strongly affect their stability and acoustic signature, and thus are an important factor to consider in the design and utilization of EMBs. Under acoustic forcing, EMBs often translate with significant velocity, which can excite shape modes, yet few studies have addressed the effect of translation on the shape stability of EMBs. In this work, the shape stability of an EMB subject to translation is investigated through development of an axisymmetric model for the case of small deformations. The potential flow in the bulk volume of the external flow is modeled using an asymptotic analysis. Viscous effects within the thin boundary layer at the interface are included, owing to the no-slip boundary condition, using Prosperetti's theory [Q. Appl. Math. 34, 339 (1977)]. In-plane stress and bending moment due to the encapsulation are incorporated into the model through the dynamic boundary condition at the interface. The evolution equations for radial oscillation, translation, and shape oscillation of an EMB are derived, which can be reduced to model an uncoated gas bubble by neglecting the encapsulation properties. These equations are solved numerically to analyze the shape mode stability of an EMB and a gas bubble subject to an acoustic, traveling plane wave. The findings demonstrate the counterintuitive result that translation has a more destabilizing effect on an EMB than on a gas bubble. The no-slip condition at the encapsulating membrane is the main factor responsible for mediating this interfacial instability due to translation.

Targeted microbubble opening of cell-cell junctions for vascular drug delivery elucidated with combined confocal microscopy and Brandaris 128 imaging

Ultrasound insonification of microbubbles enhances vascular drug delivery pathways, such as opening of cell-cell junctions and pore formation (sonoporation). However, the underlying mechanism remains unknown. The aim of our study was to elucidate the microbubble-cell interaction using the Brandaris 128 ultra-high speed camera (~17 Mfps), to visualize microbubble oscillation, coupled to a custom-build Nikon confocal microscope, to visualize cellular response. Confluent endothelial cells were evaluated for opening of cell-cell junctions with Cell Mask and for sonoporation with Propidium Iodide (PI). The cellular response of single targeted microbubbles (n = 168) was monitored up to 4 min after ultrasound insonification (2 MHz, 100–400kPa, 10-cycles). Cell-cell junctions opening occurred more often when cells were only partially attached to their neighbors (45%) than when fully attached (15%). Almost all fully attached cells showing cell-cell opening also showed PI uptake (92%). The mean microbubble excursion was larger when a cell was sonoporated (1.0μm) versus non-sonoporated (0.47μm). Additionally, larger microbubble excursion amplitudes correlated with larger pore size coefficients, obtained by fitting the PI uptake profiles to the Fan model [Fan, et al., PNAS, 2012]. In conclusion, using the state-of-the-art imaging system we can now elucidate the relationship between microbubble oscillation behavior and the drug delivery pathways.

Shape Oscillation of a Single Microbubble in an Ultrasound Field

The shape oscillation of a single two-dimensional nitrogen microbubble in an ultrasound field is numerically investigated. The Navier–Stokes equations are solved by using the finite-volume method combined with the volume-of-fluid model. The numerical results are in good accordance with experimental and theoretical results reported. According to the analyses of the shape oscillation process, the bubble deformation period is twice the driving acoustic pressure period and the shape oscillation is mainly caused by the change of interface velocity. The vortexes produced due to velocity variations lead to the deformation of the bubble interface.

Monodisperse Versus Polydisperse Ultrasound Contrast Agents: Non-Linear Response, Sensitivity, and Deep Tissue Imaging Potential

It has been proposed that monodisperse microbubble ultrasound contrast agents further increase the signal-to-noise ratio of contrast-enhanced ultrasound imaging. Here, the sensitivity of a polydisperse pre-clinical agent was compared experimentally with that of its size- and acoustically sorted derivatives by using narrowband pressure- and frequency-dependent scattering and attenuation measurements. The sorted monodisperse agents had up to a two-orders-of-magnitude increase in sensitivity, that is, in the average scattering cross section per bubble. Moreover, we found, for the first time, that the highly non-linear response of acoustically sorted microbubbles can be exploited to confine scattering and attenuation to the focal region of ultrasound fields used in clinical imaging. This property is a result of minimal pre-focal scattering and attenuation and can be used to minimize shadowing effects in deep tissue imaging. Moreover, it potentially allows for more localized therapy using microbubbles through the spatial control of resonant microbubble oscillations.

Numerical analyses of nonlinear behavior of microbubble contrast agents in ultrasound field and effective parameters.

This research aims to investigate the effects of some parameters on the nonlinear dynamics of an encapsulated microbubble. In the present study, the radial behavior of an encapsulated microbubble with modified Rayleigh-Plesset equation presented by Marmottant, van der Meer, Emmer, Versluis, de Jong, Hilgenfeldt, and Lohse [J. Acoust. Soc. Am. 118(6), 3499-3505 (2005)] is solved with matlab programming software. Radial dynamics of an individual microbubble for a free and coated state and effects of the added shell are also investigated. Results show that dilatational interfacial viscosity ( ks) of the shell and changes of surface tension have significant effects on the amplitude of oscillations, bubble dynamics, and bubble surface velocity. Regarding the fact that the velocity of the bubble surface has a significant role in stability and collapse of the bubble, it can be noted that this velocity is reduced considerably by adding the shell. Because of extensive usage of nonlinear microbubble oscillations in medical imaging techniques, the nonlinear response of a lipid-coated contrast agent called "compression-only" behavior is studied and effective parameters on this behavior are investigated. The results of bubble radius excursion reveal the fact that excitation frequency, pressure, and dilatational interfacial viscosity of the bubble affect the compression-only behavior.

On amplification of radial oscillations of microbubbles due to bubble-bubble interaction in polydisperse microbubble clusters under ultrasound excitation

Optimizing the performance of microbubbles (MBs) in applications not only requires a good understanding of the dynamics of individual MBs, but also knowledge of their interactions with each other within polydisperse clusters. However, the behavior of acoustically driven MB clusters is not well understood. Most studies have been limited to cases of a few interacting MBs for a limited range of acoustical parameters. We use a numerical method to simulate the dynamics of clusters of (20–50 MBs) randomly distributed MBs. MBs with the size distribution of 2–8 micron were sonicated with pressures between 1 and 250 kPa, frequencies between 0.5 and 10 MHz and concentrations between 2e3 and 2.5e6 MBs/mL. Bifurcation structures of radial oscillations of each MB within a cluster were studied. Results show that in a polydisperse MB cluster, larger MBs (even in small numbers) can amplify the radial oscillations of smaller MBs. Amplification occurs if the resonance peaks of larger MBs coincide with the resonance peaks of smaller MBs. Additionally, there is an optimum number density at which amplification is maximized. Results suggest that the presence of bigger MBs may enhance the superharmonic oscillations of the smaller MBs which can be applied in superhamonic ultrasound imaging using MBs.

Perspectives on cavitation enhanced endothelial layer permeability.

Traditional drug delivery systems, where pharmaceutical agents are conveyed to the target tissue through the blood circulation, suffer of poor therapeutic efficiency and limited selectivity largely due to the low permeability of the highly specialised biological interface represented by the endothelial layer. Examples concern cancer therapeutics or degenerative disorders where drug delivery is inhibited by the blood-brain barrier (BBB). Microbubbles injected into the bloodstream undergo volume oscillations under localised ultrasound irradiation and possibly collapse near the site of interest, with no effect on the rest of the endothelium. The resulting mechanical action induces a transient increase of the inter-cellular spaces and facilitates drug extravasation. This approach, already pursed in in vivo animal models, is extremely expensive and time-consuming. On the other hand in vitro studies using different kinds of microfluidic networks are firmly established in the pharmaceutical industry for drug delivery testing. The combination of the in vitro approach with ultrasound used to control microbubbles oscillations is expected to provide crucial information for developing cavitation enhanced drug delivery protocols and for screening the properties of the biological interface in presence of healthy or diseased tissues. Purpose of the present review is providing the state of the art in this rapidly growing field where cavitation is exploited as a viable technology to transiently modify the permeability of the biological interface. After describing current in vivo studies, particular emphasis will be placed on illustrating characteristics of micro-devices, biological functionalisation, properties of the artificial endothelium and ultrasound irradiation techniques.

Microbubble oscillation induced acoustic micromixing in microfluidic device

Microfluidic is of great significance for biomedical research and chemical engineering. The mixing of liquids is an essential and necessary procedure for the sample preparation. Due to the low Reynolds number, laminar flow is dominant in a microfluidic channel and it is difficult to mix the fluids in the microchannel quickly and effectively. To improve the mixing efficiency of the liquids in microfluidic channels, we develop an acoustic mixer based on single microbubble oscillation. By designing the cylinder structure on the bottom surface, when the fluid flows through cylinder structure with a diameter of 40 m, the microbubble can be generated by the surface tension of the liquid. The device is fabricated by using standard soft lithography and the replica moulding technique, ensuring the stability and repeatability of the mixing. A piezoelectric transducer (PZT) with a resonant frequency of 165 kHz is attached to the polydimethylsiloxane microfluidic device on the glass substrate by ultrasound coupling gel. When the microbubble is excited by the PZT at a resonant frequency of 165 kHz, microbubble oscillates immediately. To verify whether ultrasound can induce microbubble cavitation, a passive cavitation detection system is established. The results show that the higher harmonics can be detected, indicating that the stable cavitation occurs. The microstreaming induced by the oscillating microbubble disturbs the fluid dramatically, achieving the mixture of liquids. Particle image velocimetry method is utilized to characterize the microstreaming, and a pair of counter-rotating vortices in the microchannel is detected. Furthermore, to test the performance of the device, the deionized water and rhodamine B are injected into the Y-shape microchannel. Relative mixing index is used to quantitatively analyze the mixing performance by measuring the grayscale values of the optical images. The results indicate that with the increase of the input power, mixing time can be shortened correspondingly. When the input power is 14.76 W, the mixing process is ultrafast, within 37.5 ms the high mixing uniformity can be achieved to be 92.7%. With the advantages of simple design, high efficient and ultrafast mixing, and low power consumption, this oscillating microbubble-based acoustic micromixer may provide a powerful tool for various biochemical studies and applications.

Acoustic Characterization of the CLINIcell for Ultrasound Contrast Agent Studies.

Ultrasound contrast agents consist of gas-filled coated microbubbles that oscillate upon ultrasound insonification. Their characteristic oscillatory response provides contrast enhancement for imaging and has the potential to locally enhance drug delivery. Since microbubble response depends on the local acoustic pressure, an ultrasound compatible chamber is needed to study their behavior and the underlying drug delivery pathways. In this study, we determined the amplitude of the acoustic pressure in the CLINIcell, an optically transparent chamber suitable for cell culture. The pressure field was characterized based on microbubble response recorded using the Brandaris 128 ultrahigh-speed camera and an iterative processing method. The results were compared to a control experiment performed in an OptiCell, which is conventionally used in microbubble studies. Microbubbles in the CLINIcell responded in a controlled manner, comparable to those in the OptiCell. For frequencies from 1 to 4 MHz, the mean pressure amplitude was -5.4 dB with respect to the externally applied field. The predictable ultrasound pressure demonstrates the potential of the CLINIcell as an optical, ultrasound, and cell culture compatible device to study microbubble oscillation behavior and ultrasound-mediated drug delivery.

Dynamics of nonspherical microbubble oscillations above instability threshold.

Time-resolved dynamics of nonspherical oscillations of micrometer-sized bubbles are captured and analyzed using high-speed imaging. The axisymmetry of the bubble shape is ensured with certainty for the first time from the recordings of two synchronous high-speed cameras located at 90^{∘}. The temporal dynamics of finite-amplitude nonspherical oscillations are then analyzed for various acoustic pressures above the instability threshold. The experimental results are compared with recent theories accounting for nonlinearities and mode coupling, highlighting particular effects inherent to these mechanisms (saturation of the instability, triggering of nonparametric shape modes). Finally, the amplitude of the nonspherical oscillations is given as function of the driving pressure both for quadrupolar and octupolar bubbles.

Laser-driven resonance of dye-doped oil-coated microbubbles: Experimental study.

Photoacoustic (PA) imaging offers several attractive features as a biomedical imaging modality, including excellent spatial resolution and functional information such as tissue oxygenation. A key limitation, however, is the contrast to noise ratio that can be obtained from tissue depths greater than 1-2 mm. Microbubbles coated with an optically absorbing shell have been proposed as a possible contrast agent for PA imaging, offering greater signal amplification and improved biocompatibility compared to metallic nanoparticles. A theoretical description of the dynamics of a coated microbubble subject to laser irradiation has been developed previously. The aim of this study was to test the predictions of the model. Two different types of oil-coated microbubbles were fabricated and then exposed to both pulsed and continuous wave (CW) laser irradiation. Their response was characterized using ultra high-speed imaging. Although there was considerable variability across the population, good agreement was found between the experimental results and theoretical predictions in terms of the frequency and amplitude of microbubble oscillation following pulsed excitation. Under CW irradiation, highly nonlinear behavior was observed which may be of considerable interest for developing different PA imaging techniques with greatly improved contrast enhancement.

The use of a novel microfluidics system for in vitro ultrasound-mediated drug delivery

Ultrasound insonification of gas filled microbubbles can be used to locally enhance vascular drug delivery [1]. Understanding of the underlying mechanisms requires an in vitro endothelial cell model that includes 3D cell culture and flow. We propose to use the elaborate microchannel system in the OrganoPlate™ [2]. Since it has never been used with ultrasound before, we assessed the feasibility of acoustic transmission. The oscillation of microbubbles in the OrganoPlate™ was recorded during ultrasound insonification (50 kPa, 1-4 MHz, 8 cycles) using the Brandaris 128 ultra-high-speed camera at 17 Mfps. We compared these oscillations to measurements performed in an acoustically transparent OptiCell [3]. From 1 to 1.6 MHz, larger oscillation amplitudes were observed in the OrganoPlate™, resulting from pressure amplification in the microchannels. Finite element modeling of wave propagation using PZFlex supported our findings. Successful sonoporation of 3D cultured endothelial cells was achieved in preliminary experiments using CD31 targeted microbubbles. The obtained microbubble oscillations and successful sonoporation demonstrate the potential of the OrganoPlate™ for an ideal in vitro model to investigate ultrasound-mediated drug delivery. [1] Kooiman, et al., Adv. Drug Deliv. Rev., 2014. [2] Trietsch, et al., Lab Chip, 2013. [3] van Rooij, et al., Ultrasound Med. Biol., 2015.

Numerical investigation of the subharmonic response of a cloud of interacting microbubbles

Microbubbles (MBs) usually exist in polydisperse populations and often strongly interact with each other. Accurate investigation of the dynamics of the MBs requires considering the interaction between Microbubbles. We have developed an efficient method for numerically simulating N interacting MBs. The subharmonic (SH) responses of a polydispersions of 3-52 microbubbles with sizes between 2-5 microns, excited with ultrasound with a frequency and pressure of 1.8-8 MHz and 1-500 kPa were investigated. We show that if the frequency is set to the SH resonance of the larger MBs, the smaller MBs oscillations are controlled by the larger MB and the SH amplitude of the population of MBs increases. For small enough distances between MBs, one large MB may control the oscillations of the rest. If the excitation frequency is equal to the SH resonance of the smaller MBs, there exists two pressure regions. For lower pressures, the oscillations of the larger MB are out of phase with the smaller MBs and the resulting SH amplitude is smaller than the case without the bigger MB. As the pressure increases the oscillations of the larger MB becomes in phase with the smaller MBs and the SH response of the system is enhanced.

Passive acoustic mapping in aberrating media with the angular spectrum approach

The ability to localize and characterize ultrasound-induced microbubble oscillations through the intact skull with high spatial and temporal resolution holds significant promise for the diagnosis and treatment of brain diseases and disorders. In this study, we investigated the ability of angular spectrum (AS) method, a fast planar projection method, to perform passive acoustic mapping of microbubbles through an intact skull. Finite-difference time-domain numerical simulations were used to model microbubble emissions’ propagation through homogeneous, stratified, and 2D inhomogeneous (skull) environments approximately 80 mm by 160 mm. Reconstructions with the AS approach were performed with constant and effective sound speeds, as well as with multi-step propagation, to evaluate their ability to correct for induced aberrations and localize the microbubbles. We also investigated the impact of the receiver position on the localization accuracy. Results for skull simulations indicated that the multi-step AS method reduced the error in axial localization of the microbubbles by on the order of 50% compared with the effective sound speed method, while incurring approximately a 25% increase in computation time for each doubling of the number of propagation steps. Both AS methods were several orders of magnitude faster than time-domain reconstruction. Further investigation of the potential of this approach to correct skull aberrations is warranted.