Localized micro‐scale disruption of cells using laser‐generated focused ultrasound

We utilize laser‐generated focused ultrasound (LGFU) to create targeted mechanical disturbance on a few cells. The LGFU is transmitted through an optoacoustic lens that converts laser pulses into focused ultrasound. The tight focusing (<100 µm) and high peak pressure of the LGFU produces cavitational disturbances at a localized spot with micro‐jetting and secondary shock‐waves arising from micro‐bubble collapse. We demonstrate that LGFU can be used as a non‐contact, non‐ionizing, high‐precision tool to selectively detach a single cell from its culture substrate. Furthermore, we explore the possibility of biomolecule delivery in a small population of cells targeted by LGFU at pressure amplitudes below and above the cavitation threshold. We experimentally confirm that cavitational disruption is required for delivery of propidium iodide, a membrane‐impermeable nucleic acid‐binding dye, into cells. (© 2013 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102202/1/jbio_201200247_sm_miscellaneous_information.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/102202/2/905_ftp.pd

Applications of acoustics and cavitation to noninvasive therapy and drug delivery

Biomedical acoustics is rapidly evolving from a diagnostic modality into a therapeutic tool, and acoustic cavitation is often the common denominator in a wide range of new therapeutic applications. High-intensity focused ultrasound (HIFU) waves generated outside the body can be used to deposit heat deep within the body. Through a quantitative analysis of heat deposition by ultrasound, it is shown that inertial cavitation can help address some of the major challenges of HIFU therapy by providing a means of enhancing and monitoring treatment noninvasively. In the context of drug delivery, both inertial and stable cavitation play roles in enhancing drug activity and uptake. In particular, shape oscillations arising during stable cavitation provide an effective micropumping mechanism for enhanced mass transport across inaccessible interfaces

Nucleation, mapping and control of cavitation for drug delivery

Acoustically driven bubbles produce a range of mechanical, thermal and chemical effects that can be exploited in drug delivery applications. Significant improvements in the targeting, distribution and efficacy of both current and emerging therapeutics can be achieved, from small molecules to biologics and nucleic-acid-based drugs. This Review describes how specially designed cavitation nuclei in the form of solid, liquid or gas particles can enable the triggered release of drugs, promote the permeabiliziation of challenging biological barriers and enhance drug delivery through tissue regions where diffusion alone is inadequate. Scalable strategies for mapping and controlling cavitation activity to harness its therapeutic potential at depth within the body are discussed, alongside current and emerging applications for the treatment of diseases, including cancer and stroke

Broadband ultrasonic attenuation estimation and compensation with passive acoustic mapping

Several active and passive techniques have been developed to detect, localize and quantify cavitation activity during therapeutic ultrasound procedures. Much of the prior cavitation monitoring research has been conducted using lossless in vitro systems or small animal models in which path attenuation effects were minimal. However, the performance of these techniques may be substantially degraded by attenuation between the internal therapeutic target and the external monitoring system. As a further step towards clinical application of passive acoustic mapping (PAM), this paper presents methods for attenuation estimation and compensation based on broadband cavitation data measured with a linear ultrasound array. Soft tissue phantom experiment results are used to illustrate: 1) the impact of realistic attenuation on PAM images, 2) the possibility of estimating attenuation from cavitation data, 3) cavitation source energy estimation following attenuation compensation, and 4) the impact of sound speed uncertainty on PAM-related processing. Cavitation-based estimates of attenuation were within 1.5-6.2 % of the values found from conventional through-transmission measurements. Tissue phantom attenuation reduced the PAM energy estimate by an order of magnitude, but array data compensation using the cavitation-based attenuation spectrum enabled recovery of the PAM energy estimate to within 2.9-5.9% of the values computed in the absence of the phantom. Sound speed uncertainties were found to modestly impact attenuation-compensated PAM energies, inducing errors no larger than 28% for a 40 m/s path-averaged speed error. Together, the results indicate the potential to significantly enhance the quantitative capabilities of PAM for ensuring therapeutic safety and efficacy

Cavitation-mediated immunomodulation and its use with checkpoint inhibitors

The promotion of anti-tumour immune responses can be an effective route to the complete remission of primary and metastatic tumours in a small proportion of patients. Hence, researchers are currently investigating various methods to further characterise and enhance such responses to achieve a beneficial impact across a wider range of patients. Due to its non-invasive, non-ionising, and targetable nature, the application of ultrasound-mediated cavitation has proven to be a popular method to enhance the delivery and activity of immune checkpoint inhibitors. However, to optimise this approach, it is important to understand the biological and physical mechanisms by which cavitation may promote anti-tumour immune responses. Here, the published literature relating to the role that cavitation may play in modulating anti-tumour immunity is therefore assessed

Diffraction effects and compensation in passive acoustic mapping

Over the last decade, a variety of noninvasive techniques has been developed to monitor therapeutic ultrasound procedures in support of safety or efficacy assessments. One class of methods employs diagnostic ultrasound arrays to sense acoustic emissions, thereby providing a means to passively detect, localize and quantify the strength of nonlinear sources, including cavitation. Real array element diffraction patterns may differ substantially from those presumed in existing beamforming algorithms. However, diffraction compensation has received limited treatment in passive and active imaging, and measured diffraction data has yet to be used for array response correction. The objectives of this work were to identify differences between ideal and real element diffraction patterns, and to quantify the impact of diffraction correction on cavitation mapping beamformer performance. These objectives were addressed by performing calibration measurements on a diagnostic linear array, using the results to calculate diffraction correction terms, and applying the corrections to cavitation emission data collected from soft tissue phantom experiments. Measured diffraction patterns were found to differ significantly from those of ideal element forms, particularly at higher frequencies and shorter distances from the array. Diffraction compensation of array data resulted in cavitation energy estimates elevated by as much as a factor of five, accompanied by the elimination of a substantial bias between two established beamforming algorithms. These results illustrate the importance of using measured array responses to validate analytical field models and to minimize observation biases in imaging applications where quantitative analyses are critical for assessment of therapeutic safety and efficacy

Sound speed and attenuation of human pancreas and pancreatic tumors and their influence on focused ultrasound thermal and mechanical therapies

Background There is increasing interest in using ultrasound for thermal ablation, histotripsy, and thermal or cavitational enhancement of drug delivery for the treatment of pancreatic cancer. Ultrasonic and thermal modelling conducted as part of the treatment planning process requires acoustic property values for all constituent tissues, but the literature contains no data for the human pancreas. Purpose This study presents the first acoustic property measurements of human pancreatic samples and provides examples of how these properties impact a broad range of ultrasound therapies. Methods Data were collected on human pancreatic tissue samples at physiological temperature from 23 consented patients in cooperation with a hospital pathology laboratory. Propagation of ultrasound over the 2.1–4.5 MHz frequency range through samples of various thicknesses and pathologies was measured using a set of custom-built ultrasonic calipers, with the data processed to estimate sound speed and attenuation. The results were used in acoustic and thermal simulations to illustrate the impacts on extracorporeal ultrasound therapies for mild hyperthermia, thermal ablation, and histotripsy implemented with a CE-marked clinical system operating at 0.96 MHz. Results The mean sound speed and attenuation coefficient values for human samples were well below the range of values in the literature for non-human pancreata, while the human attenuation power law exponents were substantially higher. The simulated impacts on ultrasound mediated therapies for the pancreas indicated that when using the human data instead of the literature average, there was a 30% reduction in median temperature elevation in the treatment volume for mild hyperthermia and 43% smaller volume within a 60°C contour for thermal ablation, all driven by attenuation. By comparison, impacts on boiling and intrinsic threshold histotripsy were minor, with peak pressures changing by less than 15% (positive) and 1% (negative) as a consequence of the counteracting effects of attenuation and sound speed. Conclusion This study provides the most complete set of speed of sound and attenuation data available for the human pancreas, and it reiterates the importance of acoustic material properties in the planning and conduct of ultrasound-mediated procedures, particularly thermal therapies

Thermosensitive liposomes: a promising step toward localised chemotherapy

Introduction Many small molecules and biologic therapeutics have been developed for solid tumor therapy. However, the unique physiology of tumors makes the actual delivery of these drugs into the tumor mass inefficient. Such delivery requires transport from blood vessels, across the vasculature and into and through interstitial space within a tumor. This transportation is dependent on the physiochemical properties of the therapeutic agent and the biological properties of the tumor. It was hoped the application of nanoscale drug carrier systems would solve this problem. However, issues with poor tumor accumulation and limited drug release have impeded clinical impact. In response, these carrier systems have been redesigned to be paired with targetable external mechanical stimuli which can trigger much enhanced drug release and deposition. Areas covered The pre-clinical and clinical progress of thermolabile drug carrier systems and the modalities used to trigger the release of their cargo are assessed. Expert opinion Combined application of mild hyperthermia and heat-responsive liposomal drug carriers has great potential utility. Clinical trials continue to progress this approach and serve to refine the technologies, dosing regimens and exposure parameters that will provide optimal patient benefit