Electrical stimulation is a fundamental tool in studying neural circuits, treating neurological diseases, and advancing regenerative medicine. Injectable, free-standing piezoelectric particle systems ...have emerged as non-genetic and wireless alternatives for electrode-based tethered stimulation systems. However, achieving cell-specific and high-frequency piezoelectric neural stimulation remains challenging due to high-intensity thresholds, non-specific diffusion, and internalization of particles. Here, we develop cell-sized 20 μm-diameter silica-based piezoelectric magnetic Janus microparticles (PEMPs), enabling clinically-relevant high-frequency neural stimulation of primary neurons under low-intensity focused ultrasound. Owing to its functionally anisotropic design, half of the PEMP acts as a piezoelectric electrode via conjugated barium titanate nanoparticles to induce electrical stimulation, while the nickel-gold nanofilm-coated magnetic half provides spatial and orientational control on neural stimulation via external uniform rotating magnetic fields. Furthermore, surface functionalization with targeting antibodies enables cell-specific binding/targeting and stimulation of dopaminergic neurons. Taking advantage of such functionalities, the PEMP design offers unique features towards wireless neural stimulation for minimally invasive treatment of neurological diseases.
Controlled drug delivery (CDD) technologies have received extensive attention recently. Despite recent efforts, drug releasing systems still face major challenges in practice, including low ...efficiency in releasing the pharmaceutical compounds at the targeted location with a controlled time rate. We present an experimentally-validated acoustic-thermoelastic mathematical framework for modeling the focused ultrasound (FU)-induced thermal actuation of shape memory polymers (SMPs). This paper also investigates the feasibility of using SMPs stimulated by FU for designing CDD systems. SMPs represent a new class of materials that have gained increased attention for designing biocompatible devices. These polymers have the ability of storing a temporary shape and returning to their permanent or original shape when subjected to external stimuli such as heat. In this work, FU is used as a trigger for noninvasively stimulating SMP-based systems. FU has a superior capability to localize the heating effect, thus initiating the shape recovery process only in selected parts of the polymer. The multiphysics model optimizes the design of a SMP-based CDD system through analysis of a filament as a constituting base-structure and quantifies its activation under FU. Experimental validations are performed using a SMP filament submerged in water coupled with the acoustic waves generated by a FU transducer. The modeling results are used to examine and optimize parameters such as medium properties, input power and frequency, location, geometry and chemical composition of the SMP to achieve favorable shape recovery of a potential drug delivery system.
Venous thromboembolism is a significant source of morbidity and mortality worldwide. Catheter-directed thrombolytics is the primary treatment used to relieve critical obstructions, though its ...efficacy varies based on the thrombus composition. Non-responsive portions of the specimen often remain in situ, which prohibits mechanistic investigation of lytic resistance or the development of diagnostic indicators for treatment outcomes. In this study, thrombus samples extracted from venous thromboembolism patients were analyzed ex vivo to determine their histological properties, susceptibility to lytic therapy, and imaging characteristics. A wide range of thrombus morphologies were observed, with a dependence on age and etymology of the specimen. Fibrinolytic inhibitors including PAI-1, alpha 2-antiplasmin, and TAFI were present in samples, which may contribute to the response venous thrombi to catheter-directed thrombolytics. Finally, a weak but significant correlation was observed between the response of the sample to lytic drug and its magnetic microstructure assessed with a quantitative MRI sequence. These findings highlight the myriad of changes in venous thrombi that may promote lytic resistance, and imaging metrics that correlate with treatment outcomes.
Deep vein thrombosis is a major source of morbidity and mortality worldwide. For acute proximal deep vein thrombosis, catheter-directed thrombolytic therapy is an accepted method for vessel ...recanalization. Thrombolytic therapy is not without risk, including the potential for hemorrhagic bleeding that increases with lytic dose. Histotripsy is a focused ultrasound therapy that generates bubble clouds spontaneously in tissue at depth. The mechanical activity of histotripsy increases the efficacy of thrombolytic therapy at doses consistent with current pharmacomechanical treatments for venous thrombosis. The objective of this study was to determine the influence of lytic dose on histotripsy-enhanced fibrinolysis. Human whole blood clots formed in vitro were exposed to histotripsy and a thrombolytic agent (recombinant tissue plasminogen activator, rt-PA) in a venous flow model perfused with plasma. Lytic was administered into the clot via an infusion catheter at concentrations ranging from 0 (control) to 4.54 μg/mL (a common clinical dose for catheter-directed thrombolysis). Following treatment, perfusate samples were assayed for markers of fibrinolysis, hemolysis, and intact red blood cells and platelets. Fibrinolysis was equivalent between the common clinical dose of rt-PA (4.54 μg/mL) and rt-PA at a reduction to one-twentieth of the common clinical dose (0.23 μg/mL) when combined with histotripsy. Minimal changes were observed in hemolysis for treatment arms with or without histotripsy, potentially due to clot damage from insertion of the infusion catheter. Likewise, histotripsy did not increase the concentration of red blood cells or platelets in the perfusate following treatment compared to rt-PA alone. At the highest lytic dose, a refined histotripsy exposure scheme was implemented to cover larger areas of the clot. The updated exposure scheme improved clot mass loss and fibrinolysis relative to administration of lytic alone. Overall, the data collected in this study indicate the rt-PA dose can be reduced by more than a factor of ten and still promote fibrinolysis when combined with histotripsy.
Contactless ultrasound power transfer (UPT) has emerged as one of the promising techniques for wireless power transfer. Physical processes supporting UPT include the vibrations at a ...transmitting/acoustic source element, acoustic wave propagation, piezoelectric transduction of elastic vibrations at a receiving element, and acoustic-structure interactions at the surfaces of the transmitting and receiving elements. A novel mechanism using a high-intensity focused ultrasound (HIFU) transmitter is proposed for enhanced power transfer in UPT systems. The HIFU source is used for actuating a finite-size piezoelectric disk receiver. The underlying physics of the proposed system includes the coupling of the nonlinear acoustic field with structural responses of the receiver, which leads to spatial resonances and the appearance of higher harmonics during wave propagation in a medium. Acoustic nonlinearity due to wave kinematics in the HIFU-UPT system is modeled by taking into account the effects of diffraction, absorption, and nonlinearity in the medium. Experimentally-validated acoustic-structure interaction formulation is employed in a finite element based multiphysics model. The results show that the HIFU high-level excitation can cause disproportionately large responses in the piezoelectric receiver if the frequency components in the nonlinear acoustic field coincide with the resonant frequencies of the receiver.
Histotripsy is a form of focused ultrasound therapy that uses the mechanical activity of bubbles to ablate tissue. While histotripsy alone degrades the cellular content of tissue, recent studies have ...demonstrated it effectively disrupts the extracellular structure of pathologic conditions such as venous thrombosis when combined with a thrombolytic drug. Rather than relying on standard administration methods, associating thrombolytic drugs with an ultrasound-triggered echogenic liposome vesicle will enable targeted, systemic drug delivery. To date, histotripsy has primarily relied on nano-nuclei inherent to the medium for bubble cloud generation, and microbubbles associated with echogenic liposomes may alter the histotripsy bubble dynamics. The objective of this work was to investigate the interaction of histotripsy pulse with echogenic liposomes.
Bubble clouds were generated using a focused source in an
model of venous flow. Acoustic emissions generated during the insonation were passively acquired to assess the mechanical activity of the bubble cloud. High frame rate, pulse inversion imaging was used to track the change in echogenicity of the liposomes following histotripsy exposure.
For peak negative pressures less than 20 MPa, acoustic emissions indicative of stable and inertial bubble activity were observed. As the peak negative pressure of the histotripsy excitation increased, harmonics of the excitation were observed in OFP t-ELIP solutions and plasma alone. Additional observations with high frame rate imaging indicated a transition of bubble behavior as the pulse pressure transitioned to shock wave formation.
These observations suggest that a complex interaction between histotripsy pulses and echogenic liposomes that may be exploited for combination treatment approaches.
Deep vein thrombosis is a major source of morbidity and mortality worldwide. For acute proximal deep vein thrombosis, catheter-directed thrombolytic therapy is an accepted method for vessel ...recanalization. Thrombolytic therapy is not without risk, including the potential for hemorrhagic bleeding that increases with lytic dose. Histotripsy is a focused ultrasound therapy that generates bubble clouds spontaneously in tissue at depth. The mechanical activity of histotripsy increases the efficacy of thrombolytic therapy at doses consistent with current pharmacomechanical treatments for venous thrombosis. The objective of this study was to determine the influence of lytic dose on histotripsy-enhanced fibrinolysis. Human whole blood clots formed in vitro were exposed to histotripsy and a thrombolytic agent (recombinant tissue plasminogen activator, rt-PA) in a venous flow model perfused with plasma. Lytic was administered into the clot via an infusion catheter at concentrations ranging from 0 (control) to 4.54 μg/mL (a common clinical dose for catheter-directed thrombolysis). Following treatment, perfusate samples were assayed for markers of fibrinolysis, hemolysis, and intact red blood cells and platelets. Fibrinolysis was equivalent between the common clinical dose of rt-PA (4.54 μg/mL) and rt-PA at a reduction to one-twentieth of the common clinical dose (0.23 μg/mL) when combined with histotripsy. Minimal changes were observed in hemolysis for treatment arms with or without histotripsy, potentially due to clot damage from insertion of the infusion catheter. Likewise, histotripsy did not increase the concentration of red blood cells or platelets in the perfusate following treatment compared to rt-PA alone. At the highest lytic dose, a refined histotripsy exposure scheme was implemented to cover larger areas of the clot. The updated exposure scheme improved clot mass loss and fibrinolysis relative to administration of lytic alone. Overall, the data collected in this study indicate the rt-PA dose can be reduced by more than a factor of ten and still promote fibrinolysis when combined with histotripsy.
Controlled drug delivery (CDD) technologies have received extensive attention recently. Despite recent efforts, drug releasing systems still face major challenges in practice, including low ...efficiency in releasing the pharmaceutical compounds at the targeted location with a controlled time rate. We present an experimentally-validated acoustic-thermoelastic mathematical framework for modeling the focused ultrasound (FU)-induced thermal actuation of shape memory polymers (SMPs). This paper also investigates the feasibility of using SMPs stimulated by FU for designing CDD systems. SMPs represent a new class of materials that have gained increased attention for designing biocompatible devices. These polymers have the ability of storing a temporary shape and returning to their permanent or original shape when subjected to external stimuli such as heat. In this work, FU is used as a trigger for noninvasively stimulating SMP-based systems. FU has a superior capability to localize the heating effect, thus initiating the shape recovery process only in selected parts of the polymer. The multiphysics model optimizes the design of a SMP-based CDD system through analysis of a filament as a constituting base-structure and quantifies its activation under FU. Experimental validations are performed using a SMP filament submerged in water coupled with the acoustic waves generated by a FU transducer. The modeling results are used to examine and optimize parameters such as medium properties, input power and frequency, location, geometry and chemical composition of the SMP to achieve favorable shape recovery of a potential drug delivery system.
Controlled drug delivery (CDD) technologies have received extensive attention recently.
Contactless ultrasound power transfer (UPT) has emerged as one of the promising techniques for wireless power transfer due to several advantages over other known techniques. Physical processes ...supporting UPT include the vibrations at a transmitting/acoustic source element, piezoelectric transduction of elastic vibrations at a receiving element, acoustic wave propagation, and acoustic-structure interactions at the surfaces of the transmitting and receiving elements. In this paper, a novel mechanism using a high-intensity focused ultrasound (HIFU) transmitter is proposed for enhanced power transfer in UPT systems. By focusing the transmitted energy, the HIFU strongly excites a finite-size piezoelectric receiver with dramatically reduced levels of energy input to the source, in comparison to the case of unfocused power transmission. The underlying physics of the proposed system includes the coupling of the nonlinear acoustic field with structural responses of the receiver, which lead to spatial resonances and the appearance of higher harmonics during wave propagation in a nonlinear dispersive medium. Acoustic nonlinearity due to wave kinematics in the HIFU-UPT system is modeled by considering the effects of diffraction, absorption, and nonlinearity in the medium. The experimentally-validated acoustic-structure interaction formulation is employed in a finite element based multiphysics model. The results show that the existence of the HIFU high-level excitation can cause disproportionately large responses in the piezoelectric receiver if the frequency components in the nonlinear acoustic field coincide with the resonant frequencies of the receiver. This research aims to give a comprehensive view of modeling and to serve as a basis for designing UPT systems where piezoelectric disks of finite aspect ratios are operating in a nonlinear acoustic field.
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