Investigation of an Active Measurement Method to Detect Inertial Cavitation and the Presence of Potential Drug Carriers

Drug carriers, such as nanoparticles, are capable of releasing pharmaceutically active ingredients, which can be initiated by focused ultrasound via the effect of inertial cavitation. This effect of inertial cavitation is often verified by passive measurement methods that rely on the analysis of emitted acoustic signals caused by the implosion of bubbles. However, a major issue of such methods is their inability to detect the presence of potential drugs in human vessels, complicating the implementation of a closed loop control for future medical therapies. Therefore, this contribution introduces an active measurement method to determine both inertial cavitation and the presence of potential drug carriers in a tissue mimicking phantom

Investigation of Inertial Cavitation of Sonosensitive and Biocompatible Nanoparticles in Flow - Through Tissue- Mimicking Phantoms Employing Focused Ultrasound

A promising approach to drug delivery applications for chemotherapeutics is the use of drug carriers to reduce the total amount of cytostatics, minimizing side effects. In addition, the carriers, loaded with the drug, can be guided to the tumorous tissue via the vascular system, which enables a local drug release (LDR). In our case, LDR is activated due to the sonosensitive behavior of the nanocapsules by inertial cavitation (IC) caused by focused ultrasound (FUS). Thereby, IC is excited by employing sound pressures within the recommended limit allowed for diagnostic ultrasound. In order to verify this drug delivery approach for its clinical suitability, a tissue-mimicking flow -through phantom, containing a small vessel, is used. Investigations have shown that the drug releasing cavitation effect associated with the sonosensitive and biocompatible nanocapsules also occurs in fine vessel structures, even in the case of moving particles and vessel diameters dc smaller than the wavelength λ.

Cavitation Dynamics and Inertial Cavitation Threshold of Lipid Coated Microbubbles in Viscoelastic Media with Bubble–Bubble Interactions

Encapsulated microbubbles combined with ultrasound have been widely utilized in various biomedical applications; however, the bubble dynamics in viscoelastic medium have not been completely understood. It involves complex interactions of coated microbubbles with ultrasound, nearby microbubbles and surrounding medium. Here, a comprehensive model capable of simulating the complex bubble dynamics was developed via taking the nonlinear viscoelastic behaviors of the shells, the bubble–bubble interactions and the viscoelasticity of the surrounding medium into account simultaneously. For two interacting lipid-coated bubbles with different initial radii in viscoelastic media, it exemplified that the encapsulating shell, the inter-bubble interactions and the medium viscoelasticity would noticeably suppress bubble oscillations. The inter-bubble interactions exerted a much stronger suppressing effect on the small bubble within the parameters examined in this paper, which might result from a larger radiated pressure acting on the small bubble due to the inter-bubble interactions. The lipid shells make the microbubbles exhibit two typical asymmetric dynamic behaviors (i.e., compression or expansion dominated oscillations), which are determined by the initial surface tension of the bubbles. Accordingly, the inertial cavitation threshold decreases as the initial surface tension increases, but increases as the shell elasticity and viscosity increases. Moreover, with the distance between bubbles decreasing and/or the initial radius of the large bubble increasing, the oscillations of the small bubble decrease and the inertial cavitation threshold increases gradually due to the stronger suppression effects caused by the enhanced bubble–bubble interactions. Additionally, increasing the elasticity and/or viscosity of the surrounding medium would also dampen bubble oscillations and result in a significant increase in the inertial cavitation threshold. This study may contribute to both encapsulated microbubble-associated ultrasound diagnostic and emerging therapeutic applications.

On the Acoustic Response of Ultrasonically - stimulated microbubbles and Enhanced Intracellular Uptake of a Fluorescent Molecule

Effectiveness of ultrasound-and-microbubble mediated therapy depends on the acoustic response of microbubbles. In this study, the acoustic response of microbubbles in the absence and presence of cells is measured using integrated cavitation dose (ICD) over harmonics/ultraharmonics/broadband, and correlated with intracellular uptake of a fluorescent marker for varying peak-negative-pressures (PNPs). The ICD was independent of presence of cells. A PNP-threshold of 0.64 MPa was observed for microbubble’s inertial cavitation; stable cavitation (PNPs<0.64MPa) and inertial cavitation (PNPs≥0.64MPa) regimes were identified. Within inertial cavitation regime, a stronger correlation (R2>0.9) was observed between the ICD and FITC-positive cells, whereas, a weaker correlation, ranging from R2=0.59 at 3rd ultra-harmonic to R2 = 0.85 at 2nd ultra-harmonic, was observed under stable cavitation regime. The intracellular uptake, ICD and their correlation is dependent on microbubbles cavitation regime, indicating that ICD shows potential to predict bio-effects induced not only by inertial cavitation but also by stable cavitation of MBs.

On the Acoustic Response of Ultrasonically - stimulated microbubbles and Enhanced Intracellular Uptake of a Fluorescent Molecule

Effectiveness of ultrasound-and-microbubble mediated therapy depends on the acoustic response of microbubbles. In this study, the acoustic response of microbubbles in the absence and presence of cells is measured using integrated cavitation dose (ICD) over harmonics/ultraharmonics/broadband, and correlated with intracellular uptake of a fluorescent marker for varying peak-negative-pressures (PNPs). The ICD was independent of presence of cells. A PNP-threshold of 0.64 MPa was observed for microbubble’s inertial cavitation; stable cavitation (PNPs<0.64MPa) and inertial cavitation (PNPs≥0.64MPa) regimes were identified. Within inertial cavitation regime, a stronger correlation (R2>0.9) was observed between the ICD and FITC-positive cells, whereas, a weaker correlation, ranging from R2=0.59 at 3rd ultra-harmonic to R2 = 0.85 at 2nd ultra-harmonic, was observed under stable cavitation regime. The intracellular uptake, ICD and their correlation is dependent on microbubbles cavitation regime, indicating that ICD shows potential to predict bio-effects induced not only by inertial cavitation but also by stable cavitation of MBs.

On the acoustic response of ultrasound and induced cell death

Ultrasonically-stimulated microbubbles can enhance cell membrane permeability and decrease cell viability where the underlying acoustic mechanism has been associated with both non-inertial and inertial cavitation. In this study, breast cancer cells (MDA-MB-231) were exposed to 0.5MHz ultrasound pulses of 16μs duration at varying peak negative pressures (PNP: 218kPa, 335kPa and 908kPa) and pulse repetition period (PRP 10ms and 100ms) in the presence of Definity microbubbles (3.3% v/v). The acoustic response of microbubbles was measured using passive cavitation detection with 2.25MHz transducer, and characterized by their frequency a cavitation dose (CD). Results show that the number of non-viable cells and integrated cavitation dose (ICD) significantly increases with PNP, whereas no significant differences were found between 10ms and 100ms PRPs. In this study, no correlation was found between (ICD) and cell non-viability.

On the acoustic response of ultrasound and induced cell death

Ultrasonically-stimulated microbubbles can enhance cell membrane permeability and decrease cell viability where the underlying acoustic mechanism has been associated with both non-inertial and inertial cavitation. In this study, breast cancer cells (MDA-MB-231) were exposed to 0.5MHz ultrasound pulses of 16μs duration at varying peak negative pressures (PNP: 218kPa, 335kPa and 908kPa) and pulse repetition period (PRP 10ms and 100ms) in the presence of Definity microbubbles (3.3% v/v). The acoustic response of microbubbles was measured using passive cavitation detection with 2.25MHz transducer, and characterized by their frequency a cavitation dose (CD). Results show that the number of non-viable cells and integrated cavitation dose (ICD) significantly increases with PNP, whereas no significant differences were found between 10ms and 100ms PRPs. In this study, no correlation was found between (ICD) and cell non-viability.