Magnetic Microbubbles Research Articles

The behavior of magnetic microbubble in acoustic-magnetic field

A novel dynamic model of magnetic microbubble subjected to acoustic-magnetic field is developed by Lagrange method. Numerical works are effectively replaced by a non-magnetic microbubble immersed in highly magnetic fluid. Simulation shows that bubble’s pulsation and translation can be controlled by an applied uniform magnetic field. Depending on the coupled time scales between relaxation parameters, the oscillation of bubble can be improved or reduced by magnetic field. Besides, magnetic field significantly reduces bubble natural frequency due to the enhanced viscosity. Also, the properties of the magnetic fluid may affect bubble’s responses, such as viscosity and magnetic susceptibility. In the case of strong magnetic susceptibility and low viscosity, magnetic field has a remarkable effect on bubble manipulation. Finally, the larger bubble may have a better response to magnetic field. These results may be beneficial to the manipulation of magnetic microbubbles by a suitable magneto-acoustic field.

Magneto-sonothrombolysis with combination of magnetic microbubbles and nanodroplets

This paper reports a novel technique using the rotational magnetic field oscillation and low-intensity sub-megahertz ultrasound stimulation of magnetic microbubbles (MMBs) to promote the nanodroplets (NDs) phase transition and improve the permeation of NDs into the blood clot fibrin network to enhance the sonothrombolysis efficiency. In this study, the influence of different treatment methods with a combination of MMBs and NDs on the thrombolysis rate of both unretracted and retracted clots were investigated, including the stable and inertial cavitation, tPA effects, MMBs/NDs concentration ratio, sonication factors (input voltage, duty cycle) and rotational magnetic field factors (flux density, frequency). We demonstrated that tPA-mediated magneto-sonothrombolysis in combining NDs with MMBs could significantly enhance in vitro lysis of both unretracted clots (85 ± 8.3%) and retracted clots (57 ± 6.5%) in a flow model with 30 min treatment. The results showed that the combination of MMBs and NDs substantially improves in vitro lysis of blood clots with an unprecedented lysis rate.

Magnetic black phosphorus microbubbles for targeted tumor theranostics

Abstract Black phosphorus (BP) is attracting more and more interest for the biomedical application. The absorption in a wide spectral range and high photothermal conversion efficiency make BP suitable for photothermal therapy. However, BP alone is hard to realize the targeted therapy, which limits the precision and efficiency of the therapy. Magnetic microbubbles (MBs) are favored drug carriers because they can resist the sheer force of blood flow in a magnetic field, which improves the efficiency of MBs adhesion to the vascular wall for targeted ultrasound diagnosis and therapy. This study first optimized the magnetic MBs configurations through controlling the connecting polyethylene glycol (PEG) chain length. The magnetic MBs with PEG2000 have been chosen for targeted BP nanosheets delivery due to the better stability and magnetic responsiveness. The magnetic black phosphorus microbubbles (MBBPM) can realize the targeted tumor theranostics in vitro and in vivo. They could be applied for the targeted ultrasound imaging with an enhanced echogenicity by three times when accumulated at the target site where the magnetic field is applied. As the NIR laser irradiation was applied on the accumulated MBBPM, they dynamited and the temperature increased rapidly. It improved the cell membrane permeability, thus accelerating and enhancing a precision photothermal killing effect to the breast cancer cells, compared to BP alone.

Nonlinear acoustic characteristics of multilayer magnetic microbubbles

The combination of superparamagnetic iron oxide nanoparticles (SPIOs) with ultrasonic contrast agent (UCA) microbubble is called magnetic microbubble (MMB) and has been used to produce multimodal contrast agents to enhance medical ultrasound and magnetic resonance imaging. The nanoparticles are either covalently linked to the shell or physically entrapped into the shell. Considering the effect of the volume fraction of SPIOs on the shell density and viscosity, a nonlinear dynamic equation of magnetic microbubbles (MMBs) with multilayer membrane structure is constructed based on the basic theory of bubble dynamics. The influences of the driving sound pressure and frequency, particle volume fraction, shell thickness and surface tension on the acoustic-dynamics behavior of microbubbles are numerically analyzed. The results show that when the volume fraction of magnetic particles is small and <i>α</i> ≤ 0.1, the acoustic properties of magnetic microbubbles are similar to those of ordinary UCA microbubbles. The acoustic response of the microbubble depends on its initial size and driving pressure. The critical sound pressure of microbubble vibration instability is lowest when the driving sound field frequency is twice the magnetic microbubble resonance frequency <i>f</i><sub>0</sub> (<i>f</i> = 2<i>f</i><sub>0</sub>). The presence of magnetic particles inhibits the bubbles from expanding and contracting, but the inhibition effect is very limited. The surface tension parameter <i>K</i> of the outer film material and thickness of the shell also affect the vibration of the microbubble. When <i>K</i> and film thickness are 0.2–0.4 N/m and 50–150 nm respectively, it is observed that the bubble has an unstable vibration response region.

Ultrasound Imaging Based on Magnetic Lipid Microbubble Contrast Agent with Fe₃O₄ Nanoparticles.

To construct magnetic microbubbles with dual response characteristics of ultrasound and magnetic field. The surfactant-based microbubble ultrasound contrast agent (ST68) was prepared using acoustic cavitation. Magnetic Fe₃O₄ nanoparticles having a negative charge on the surface were prepared by the polyol method. The microbubbles were used as the template, and the magnetic microbubbles were prepared by alternating deposition of polyethyleneimine and magnetic Fe₃O₄ nanoparticles on the surface of microbubbles using electrostatic attraction for a layer-by-layer selfassembly. An in vitro ultrasound contrast device was set up to compare the ultrasound images of the silicone tube in the device before and after the injection of human magnetic microbubbles (3×10/M), and to observe the movement of the magnetic microbubbles after the magnetic field was applied to the silicone tube. To evaluate the contrast effect of magnetic microbubbles in vivo, we compared the renal ultrasound images of New Zealand white rabbits before and after injection of human magnetic microbubbles. The surface of Fe₃O₄ nanoparticles displayed a stable negative charge (-24.6±67 mV). More than 98% of the assembled magnetic microbubbles were smaller than 8 μm, which met the basic size requirement for an ultrasound contrast agent. There was no echo signal in the silicone tube before the injection of magnetic microbubbles. Following injection, a solid echo was detected in the silicone tube. After the application of the magnetic field, the magnetic microbubbles migrated in the direction of magnetic field. Contrast-enhanced ultrasound did not image the kidney before the injection of magnetic microbubbles, while the kidney shadow was clear following injection. Magnetic targeted microbubbles and contrast-enhanced ultrasound provide good imaging, which lays the foundation for further studies of magnetic targeted microbubble contrast agents in diagnosis and treatment.

Ultrasound Responsive Magnetic Mesoporous Silica Nanoparticle-Loaded Microbubbles for Efficient Gene Delivery

Purpose: Gene therapy is an important therapeutic strategy for cancer. Nanoparticles are used for noninvasive gene delivery, which has great potential in tumor therapy. However, it is a challenge to construct a targeted gene delivery vector with high gene delivery efficiency, good biocompatibility, and multiple functions. Method: Herein, we designed magnetic mesoporous silica nanoparticle loading microbubbles (M-MSN@MBs) for ultrasound-mediated imaging and gene transfection. The plasmid DNA (pDNA) was encapsulated into the pores of M-MSNs. Also, the pDNA-carrying M-MSNs were loaded in the lipid microbubbles. Results: The gene vector presented good biocompatibility, DNA binding stability, ultrasound imaging performance, and magnetic responsiveness. The polyethyleneimine (PEI)-modified M-MSNs effectively protected the loaded pDNA from enzyme degradation. The cytotoxicity of M-MSNs was significantly reduced via encapsulating in lipid microbubbles. Upon the magnetic field, M-MSN@MBs were attracted to the tumor area. Then, ultrasound-targeted microbubble destruction (UTMD) not only released loaded M-MSNs but also facilitated M-MSNs delivery to tumor tissue by opening blood-tumor barrier and increasing the cytomembrane permeability, and ultimately improved the pDNA delivery efficiency. Conclusion: Our findings suggested that the developed ultrasound-responsive gene delivery system was a promising platform for gene therapy, which could noninvasively enhance tumor gene transfection.

Magnetic microbubble mediated chemo-sonodynamic therapy using a combined magnetic-acoustic device

Recent pre-clinical studies have demonstrated the potential of combining chemotherapy and sonodynamic therapy for the treatment of pancreatic cancer. Oxygen-loaded magnetic microbubbles have been explored as a targeted delivery vehicle for this application. Despite preliminary positive results, a previous study identified a significant practical challenge regarding the co-alignment of the magnetic and ultrasound fields. The aim of this study was to determine whether this challenge could be addressed through the use of a magnetic-acoustic device (MAD) combining a magnetic array and ultrasound transducer in a single unit, to simultaneously concentrate and activate the microbubbles at the target site. in vitro experiments were performed in tissue phantoms and followed by in vivo treatment of xenograft pancreatic cancer (BxPC-3) tumours in a murine model. In vitro, a 1.4-fold (p < .01) increase in the deposition of a model therapeutic payload within the phantom was achieved using the MAD compared to separate magnetic and ultrasound devices. In vivo, tumours treated with the MAD had a 9% smaller mean volume 8 days after treatment, while tumours treated with separate devices or microbubbles alone were respectively 45% and 112% larger. This substantial and sustained decrease in tumour volume suggests that the proposed drug delivery approach has the potential to be an effective neoadjuvant therapy for pancreatic cancer patients.

Recent Advances in the Use of Focused Ultrasound for Magnetic Resonance Image-Guided Therapeutic Nanoparticle Delivery to the Central Nervous System.

Targeting systemically-administered drugs and genes to specific regions of the central nervous system (CNS) remains a challenge. With applications extending into numerous disorders and cancers, there is an obvious need for approaches that facilitate the delivery of therapeutics across the impervious blood-brain barrier (BBB). Focused ultrasound (FUS) is an emerging treatment method that leverages acoustic energy to oscillate simultaneously administered contrast agent microbubbles. This FUS-mediated technique temporarily disrupts the BBB, allowing ordinarily impenetrable agents to diffuse and/or convect into the CNS. Under magnetic resonance image guidance, FUS and microbubbles enable regional targeting—limiting the large, and potentially toxic, dosage that is often characteristic of systemically-administered therapies. Subsequent to delivery across the BBB, therapeutics face yet another challenge: penetrating the electrostatically-charged, mesh-like brain parenchyma. Non-bioadhesive, encapsulated nanoparticles can help overcome this additional barrier to promote widespread treatment in selected target areas. Furthermore, nanoparticles offer significant advantages over conventional systemically-administered therapeutics. Surface modifications of nanoparticles can be engineered to enhance targeted cellular uptake, and nanoparticle formulations can be tailored to control many pharmacokinetic properties such as rate of drug liberation, distribution, and excretion. For instance, nanoparticles loaded with gene plasmids foster relatively stable transfection, thus obviating the need for multiple, successive treatments. As the formulations and applications of these nanoparticles can vary greatly, this review article provides an overview of FUS coupled with polymeric or lipid-based nanoparticles currently utilized for drug delivery, diagnosis, and assessment of function in the CNS.

Preparation of Magnetic Targeting Microbubble Ultrasound Contrast Material and Its Performance in Myocardial Infarction

Preparation of Magnetic Targeting Microbubble Ultrasound Contrast Material and Its Performance in Myocardial Infarction

Sonothrombolysis with magnetic microbubbles under a rotational magnetic field

Thrombosis is an extremely critical clinical condition where a clot forms inside a blood vessel which blocks the blood flow through the cardiovascular system. Previous sonothrombolysis methods using ultrasound and microbubbles (MBs) often have a relatively low lysis rate due to the low microbubbles concentration at clot region caused by blood flow in the vessel. To solve this problem, the magnetic microbubbles (MMBs) that can be retained by an outer magnetic field against blood flow are used in this study. Here we report the development of a new method using the rotational magnetic field to trap and vibrate magnetic microbubbles at target clot region and then using an intravascular forward-looking ultrasound transducer to activate them acoustically. In this study, we investigated the influence of different blood flow conditions, vessel occlusion conditions (partial and fully occluded), clot ages (fresh, retracted), ultrasound parameters (input voltage, duty cycle) and rotational magnetic field parameters (amplitude, frequency) on the thrombolysis rate. The results showed that the additional use of magnetic microbubbles significantly enhances in vitro lysis of blood clot.

Sonothrombolysis with Magnetically Targeted Microbubbles

Microbubble-enhanced sonothrombolysis is a promising approach to increasing the tolerability and efficacy of current pharmacological treatments for ischemic stroke. Maintaining therapeutic concentrations of microbubbles and drugs at the clot site, however, poses a challenge. The objective of this study was to investigate the effect of magnetic microbubble targeting upon clot lysis rates in vitro. Retracted whole porcine blood clots were placed in a flow phantom of a partially occluded middle cerebral artery. The clots were treated with a combination of tissue plasminogen activator (0.75 µg/mL), magnetic microbubbles (∼107 microbubbles/mL) and ultrasound (0.5 MHz, 630-kPa peak rarefactional pressure, 0.2-Hz pulse repetition frequency, 2% duty cycle). Magnetic targeting was achieved using a single permanent magnet (0.08–0.38 T and 12-140 T/m in the region of the clot). The change in clot diameter was measured optically over the course of the experiment. Magnetic targeting produced a threefold average increase in lysis rates, and linear correlation was observed between lysis rate and total energy of acoustic emissions.

Magnetic and Acoustically Active Microbubbles Loaded with Nucleic Acids for Gene Delivery.

Targeted gene or drug delivery aims to locally accumulate the active agent and achieve the maximum local therapeutic effect at the target site while reducing unwanted effects at nontarget sites. A further development of the magnetic drug-targeting concept is combining it with an ultrasound-triggered delivery using magnetic microbubbles as a carrier for gene or drug delivery. For this purpose, selected magnetic nanoparticles (MNPs), phospholipids, and nucleic acid are assembled in the presence of perfluorocarbon gas into flexible formulations of magnetic lipospheres or microbubbles. This chapter describes the protocols for preparation of magnetic lipospheres and microbubbles for nucleic acid delivery, and it also describes the procedures for labeling the components of the bubbles (lipids, MNPs, and nucleic acids) for the visualization of the vectors and their characterization, such as magnetic responsiveness and ultrasound contrast effects. Protocols are given for the transfection procedure in adherent cells, evaluation of the association of the magnetic vectors with the cells, reporter gene expression analysis, and cell viability assessment.

Comparing Strategies for Magnetic Functionalization of Microbubbles.

The advancement of ultrasound-mediated therapy has stimulated the development of drug-loaded microbubble agents that can be targeted to a region of interest through an applied magnetic field prior to ultrasound activation. However, the need to incorporate therapeutic molecules while optimizing the responsiveness to both magnetic and acoustic fields and maintaining adequate stability poses a considerable challenge for microbubble synthesis. The aim of this study was to evaluate three different methods for incorporating iron oxide nanoparticles (IONPs) into phospholipid-coated microbubbles using (1) hydrophobic IONPs within an oil layer below the microbubble shell, (2) phospholipid-stabilized IONPs within the shell, or (3) hydrophilic IONPs noncovalently bound to the surface of the microbubble. All microbubbles exhibited similar acoustic response at both 1 and 7 MHz. The half-life of the microbubbles was more than doubled by the addition of IONPs by using both surface and phospholipid-mediated loading methods, provided the lipid used to coat the IONPs was the same as that constituting the microbubble shell. The highest loading of IONPs per microbubble was also achieved with the surface loading method, and these microbubbles were the most responsive to an applied magnetic field, showing a 3-fold increase in the number of retained microbubbles compared to other groups. For the purpose of drug delivery, surface loading of IONPs could restrict the attachment of hydrophilic drugs to the microbubble shell, but hydrophobic drugs could still be incorporated. In contrast, although the incorporation of phospholipid IONPs produced more weakly magnetic microbubbles, it would not interfere with hydrophilic drug loading on the surface of the microbubble.

Prototypical madness: Design and demonstration of a magnetic-acoustic targeted drug delivery system

Ultrasound, microbubbles, and magnetic nanoparticles have been used both separately and in varying combinations for targeted drug delivery. Recent studies have demonstrated the therapeutic benefit of magnetic microbubble (MMB) retention and acoustic targeting using separate devices. As a developmental step towards clinical implementation, a magnetic-acoustic device (MAD) was designed for the purpose of generating co-aligned magnetic and acoustic fields with a single hand-held enclosure. This paper presents in vitro characterization and in vivo demonstration of a targeted therapeutic system wherein the MAD non-invasively retains and activates drug-loaded MMBs. Free field experiments were conducted in order to characterize the magnetic field and its gradient for MMB capture, and to quantify acoustic field strength and directivity. Flow phantom experiments were used to quantify MMB retention and illustrate the resulting enhancement of cavitation activity. Murine experiments then demonstrated therapeutic efficacy in a pancreatic cancer model, showing a significant benefit in comparison to the use of separate magnetic and ultrasonic devices.

The enhanced HIFU-induced thermal effect via magnetic ultrasound contrast agent microbubbles

High intensity focused ultrasound (HIFU) has been regarded as a promising technology for treating cancer and other severe diseases noninvasively. In the present study, dual modality magnetic ultrasound contrast agent microbubbles (MBs) were synthesized by loading the super paramagnetic iron oxide nanoparticles (SPIOs) into the albumin-shelled MBs (referred as SPIO-albumin MBs). Then, both experimental measurements and numerical simulations were performed to evaluate the ability of SPIO-albumin MBs of enhancing HIFU-induced thermal effect. The results indicated that, comparing with regular albumin-shelled MBs, the SPIO-albumin MBs would lead to quicker temperature elevation rate and higher peak temperature. This phenomenon could be explained by the changes in MBs’ physical and thermal properties induced by the integration of SPIOs into MB shell materials. In addition, more experimental results demonstrated that the enhancement effect on HIFU-induced temperature elevation could be further strengthened with more SPIOs combined with albumin-shell MBs. These observations suggested that more violent cavitation behaviors might be activated by ultrasound exposures with the presence of SPIOs, which in turn amplified ultrasound-stimulated thermal effect. Based on the present studies, it is reasonable to expect that, with the help of properly designed dual-modality magnetic MBs, the efficiency of HIFU-induced thermal effect could be further improved to achieve better therapeutic outcomes.

Circulating Magnetic Microbubbles for Localized Real-Time Control of Drug Delivery by Ultrasonography-Guided Magnetic Targeting and Ultrasound.

Image-guided and target-selective modulation of drug delivery by external physical triggers at the site of pathology has the potential to enable tailored control of drug targeting. Magnetic microbubbles that are responsive to magnetic and acoustic modulation and visible to ultrasonography have been proposed as a means to realize this drug targeting strategy. To comply with this strategy in vivo, magnetic microbubbles must circulate systemically and evade deposition in pulmonary capillaries, while also preserving magnetic and acoustic activities in circulation over time. Unfortunately, challenges in fabricating magnetic microbubbles with such characteristics have limited progress in this field. In this report, we develop magnetic microbubbles (MagMB) that display strong magnetic and acoustic activities, while also preserving the ability to circulate systemically and evade pulmonary entrapment.Methods: We systematically evaluated the characteristics of MagMB including their pharmacokinetics, biodistribution, visibility to ultrasonography and amenability to magneto-acoustic modulation in tumor-bearing mice. We further assessed the applicability of MagMB for ultrasonography-guided control of drug targeting.Results: Following intravenous injection, MagMB exhibited a 17- to 90-fold lower pulmonary entrapment compared to previously reported magnetic microbubbles and mimicked circulation persistence of the clinically utilized Definity microbubbles (>10 min). In addition, MagMB could be accumulated in tumor vasculature by magnetic targeting, monitored by ultrasonography and collapsed by focused ultrasound on demand to activate drug deposition at the target. Furthermore, drug delivery to target tumors could be enhanced by adjusting the magneto-acoustic modulation based on ultrasonographic monitoring of MagMB in real-time.Conclusions: Circulating MagMB in conjunction with ultrasonography-guided magneto-acoustic modulation may provide a strategy for tailored minimally-invasive control over drug delivery to target tissues.

A novel technique for waste sludge solubilization using a combined magnetic field and CO2 injection as a pretreatment prior anaerobic digestion

In this study, the effect of combined magnetic field and CO2 microbubble technology on the solubilization rate and performance of municipal waste activated sludge (WAS) was investigated. Four numerical variables (CO2 injection, initial pH, magnetic field, and retention time) were selected to analyze and optimize the process. The region of exploration for the process was taken as the area enclosed by CO2 flow rate (0–1 L/min), initial pH (3–11), magnetic field (0–40 mT) and retention time (20–180 min) boundaries. In order to analyze the process, three dependent parameters as the process responses were studied. The results showed that the disintegration performance of WAS was effectively improved in the presence of magnetic field and CO2 microbubble. The sCOD, sTKN and PO43− concentrations in sludge supernatant increased to 48%, 40% and 47% respectively, with increasing CO2 flow rate from 0 to 1 L/min and magnetic field from 0 to 40 mT. This study showed that the initial pH was a key factor affecting the process performance, cell lysis and disintegration. The result showed that acid and base range of pH caused an increase in the WAS degradation. It was also observed that the sludge settleability was improved about 43% and oxygen uptake rate decreased by 30%. In conclusion, the combined magnetic field and CO2 microbubble pretreatment is an effective method to disintegrate the waste activated sludge.

Magnetic targeting to enhance microbubble delivery in an occluded microarterial bifurcation

Ultrasound and microbubbles have been shown to accelerate the breakdown of blood clots both in vitro and in vivo. Clinical translation of this technology is still limited, however, in part by inefficient microbubble delivery to the thrombus. This study examines the obstacles to delivery posed by fluid dynamic conditions in occluded vasculature and investigates whether magnetic targeting can improve microbubble delivery. A 2D computational fluid dynamic model of a fully occluded Y-shaped microarterial bifurcation was developed to determine: (i) the fluid dynamic field in the vessel with inlet velocities from 1–100 mm s−1 (corresponding to Reynolds numbers 0.25–25); (ii) the transport dynamics of fibrinolytic drugs; and (iii) the flow behavior of microbubbles with diameters in the clinically-relevant range (0.6–5 µm). In vitro experiments were carried out in a custom-built microfluidic device. The flow field was characterized using tracer particles, and fibrinolytic drug transport was assessed using fluorescence microscopy. Lipid-shelled magnetic microbubbles were fluorescently labelled to determine their spatial distribution within the microvascular model. In both the simulations and experiments, the formation of laminar vortices and an abrupt reduction of fluid velocity were observed in the occluded branch of the bifurcation, severely limiting drug transport towards the occlusion. In the absence of a magnetic field, no microbubbles reached the occlusion, remaining trapped in the first vortex, within 350 µm from the bifurcation center. The number of microbubbles trapped within the vortex decreased as the inlet velocity increased, but was independent of microbubble size. Application of a magnetic field (magnetic flux density of 76 mT, magnetic flux density gradient of 10.90 T m−1 at the centre of the bifurcation) enabled delivery of microbubbles to the occlusion and the number of microbubbles delivered increased with bubble size and with decreasing inlet velocity.

基于磁性质的药物递送系统

There has been unprecedented progress in the development of biomedical nanotechnology and nanomaterials over the past few decades, and nanoparticle-based drug delivery systems (DDSs) have great potential for clinical applications. Among these, magnetic drug delivery systems (MDDSs) based on magnetic nanoparticles (MNPs) are attracting increasing attention owing to their favorable biocompatibility and excellent multifunctional loading capability. MDDSs primarily have a solid core of superparamagnetic maghemite (γ-Fe2O3) or magnetite (Fe3O4) nanoparticles ranging in size from 10 to 100 nm. Their surface can be functionalized by organic and/or inorganic modification. Further conjugation with targeting ligands, drug loading, and MNP assembly can provide complex magnetic delivery systems with improved targeting efficacy and reduced toxicity. Owing to their sensitive response to external magnetic fields, MNPs and their assemblies have been developed as novel smart delivery systems. In this review, we first summarize the basic physicochemical and magnetic properties of desirable MDDSs that fulfill the requirements for specific clinical applications. Secondly, we discuss the surface modifications and functionalization issues that arise when designing elaborate MDDSs for future clinical uses. Finally, we highlight recent progress in the design and fabrication of MNPs, magnetic assemblies, and magnetic microbubbles and liposomes as MDDSs for cancer diagnosis and therapy. Recently, researchers have focused on enhanced targeting efficacy and theranostics by applying step-by-step sequential treatment, and by magnetically modulating dosing regimens, which are the current challenges for clinical applications.

Coating microbubbles with nanoparticles for medical imaging and drug delivery.

Coating microbubbles with nanoparticles for medical imaging and drug delivery.