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Focused ultrasound (FUS) offers an attractive tool for non-invasive neuromodulation, addressing a clinical need to develop more minimally invasive approaches that are safer, more tolerable and versatile. In combination with a cavitation agent, the effects of ultrasound can be amplified and localized for therapy. Using c-Fos expression mapping, we show how ultrasound-sensitive nanodroplets can be used to induce either neurosuppression or neurostimulation, without disrupting the blood-brain barrier in rats. By repurposing a commercial ultrasound contrast agent, Definity, lipid-shell decafluorobutane-core nanodroplets of 212.5 ± 2.0 nm were fabricated and loaded with or without pentobarbital. FUS was delivered with an atlas-based targeting system at 1.66 MHz to the motor cortex of rats, using a feedback-controller to detect successful nanodroplet vaporization and drug release. Neuromodulation was quantified through changes in sensorimotor function and c-Fos expression. Following FUS-triggered delivery, sham nanodroplets induced a 22.6 ± 21% increase in local c-Fos expression, whereas pentobarbital-loaded nanodroplets induced a 21.7 ± 13% decrease (n = 6). Nanodroplets, combined with FUS, offer an adaptable tool for neuromodulation, through local delivery of small molecule anesthetics or targeted mechanical effects.

In sonodynamic therapy, cellular toxicity from sonosensitizer drugs, such as 5-aminolevulinic acid hydrochloride (5-ALA), may be triggered with focused ultrasound through the production of reactive oxygen species (ROS). Here we show that by increasing local oxygen during treatment, using oxygen-loaded perfluorocarbon nanodroplets (250 +/- 8 nm), we can increase the damage induced by 5-ALA, and monitor the severity by recording acoustic emissions in the brain. To achieve this, we sonicated the right striatum of 16 healthy rats after an intravenous dose of 5-ALA (200 mg/kg), followed by saline, nanodroplets, or oxygen-loaded nanodroplets. We assessed haemorrhage, edema and cell apoptosis immediately following, 24 hr, and 48 hr after focused ultrasound treatment. The localized volume of damaged tissue was significantly enhanced by the presence of oxygen-loaded nanodroplets, compared to ultrasound with unloaded nanodroplets (3-fold increase), and ultrasound alone (40-fold increase). Sonicating 1 hr following 5-ALA injection was found to be more potent than 2 hr following 5-ALA injection (2-fold increase), and the severity of tissue damage corresponded to the acoustic emissions from droplet vaporization. Enhancing the local damage from 5-ALA with monitored cavitation activity and additional oxygen could have significant implications in the treatment of atherosclerosis and non-invasive ablative surgeries.

While current neuromodulation techniques are invasive, inaccurate, and/or unable to penetrate deeply, focused ultrasound (FUS) offers a way to study and treat the nervous system that is non-invasive, precise, and able to reach targets deep within the brain. Using ultrasound to trigger the delivery of pharmaceuticals from nanodroplets combines the spatial precision of FUS with the temporal control of psychoactive drugs. Here, I will present our work developing ultrasound-responsive nanodroplets to deliver anesthetics in the brain for neuromodulation. This work has shown how nanodroplets, loaded with pentobarbital, can be vaporized with FUS and inhibit activity in specific brain regions. This platform is now being investigated for the treatment of several neurological and psychiatric disorders, including agitation and aggression in a model of Alzheimer’s disease.

Pharmaceuticals currently used for reducing blood pressure prove ineffective for many patients. As well, although hypertension is the most common disorder in pregnancy, many anti-hypertension drugs pose significant risks associated with restricted fetal growth, decreased uteroplacental blood flow, and fetal loss. Deep brain stimulation of the periaqueductal gray (PAG) region has shown promise in treating drug-resistant hypertension in patients. However, a non-invasive approach would carry far fewer risks, particularly during pregnancy. Our work has explored the potential of focused ultrasound (FUS), targeted to the PAG region, to reduce blood pressure. In a rodent model of hypertension, FUS delivered to the PAG successfully reduced high blood pressure to within the normal range. By comparing treatment regimes, we have also investigated the mechanisms underlying this reduction in blood pressure and ways to prolong the effect. This approach could point towards a new treatment for hypertension that has greater safety and broader applicability for vulnerable patient populations.

Focused ultrasound (FUS) is an emerging modality for performing incisionless neurosurgical procedures including thermoablation and blood-brain barrier (BBB) modulation. Emerging evidence suggests that low intensity FUS can also be used for neuromodulation with several benefits, including high spatial precision and the possibility of targeting deep brain regions. Here we review the existing data regarding the biological mechanisms of FUS neuromodulation, the characteristics of neuronal activity altered by FUS, emerging indications for FUS neuromodulation, as well as the strengths and limitations of this approach.

The last two decades have seen the development of acoustically activated droplets, also known as phase-change emulsions, from a diagnostic tool to a therapeutic agent. Through bubble effects and triggered drug release, these superheated agents have found potential applications from oncology to neuromodulation. The aim of this review is to summarise the key developments in therapeutic droplet design and use, to discuss the current challenges slowing clinical translation, and to highlight the new frontiers progressing towards clinical implementation. The literature is summarised by addressing the droplet design criteria and by carrying out a multiparametric study of a range of droplet formulations and their associated vaporisation thresholds.

Drug-loaded nanoscale cavitation agents, called nanodroplets, are an attractive solution to enhance and localize drug delivery, offering increased stability and prolonged half-life in circulation compared to microbubbles. However, the spatial precision with which drug can be released and delivered into brain tissue from such agents has not been directly mapped. Decafluorobutane lipid-shell droplets (206 +/− 6 nm) were loaded with a fluorescent blood-brain barrier (BBB)-penetrating dye (Nile Blue) and vaporized with ultrasound (1.66 MHz, 10 ms pulse length, 1 Hz pulse repetition frequency), generating transient echogenic microbubbles and delivering the encapsulated dye. The distribution and intensity of released fluorophore was mapped in a tissue-mimicking phantom, and in the brain of rats (Sprague Dawley, N = 4, n = 16). The release and distribution of dye was found to be pressure-dependent (0.2–3.5 MPa) and to occur only above the vaporization threshold of the nanodroplets (1.5 +/− 0.25 MPa in vitro, 2.4 +/− 0.05 MPa in vivo). Dye delivery was achieved with sub-millimetre spatial precision, covering an area of 0.4 to 1.5 mm in diameter, determined by the sonication pressure. The distribution and intensity of dye released at depth in the brain followed the axial pressure profile of the ultrasound beam. Nile Blue (354 Da, LogP 2.7) was compared to Nile Red (318 Da, LogP 3.8) and Quantum Dots (CdSe/ZnS, 5 nm diameter) to visualize the role of molecule size and lipophilicity in crossing the intact BBB following triggered release. Acoustic emissions were shown to predict the successful delivery of the BBB-penetrating dye and the extent of the distribution, demonstrating the theranostic capabilities of nanoscale droplets to precisely localize drug delivery in the brain.

Focused ultrasound (FUS) is an emerging modality for performing incisionless neurosurgical procedures including thermoablation and blood-brain barrier (BBB) modulation. Emerging evidence suggests that low intensity FUS can also be used for neuromodulation with several benefits, including high spatial precision and the possibility of targeting deep brain regions. Here we review the existing data regarding the biological mechanisms of FUS neuromodulation, the characteristics of neuronal activity altered by FUS, emerging indications for FUS neuromodulation, as well as the strengths and limitations of this approach.

High-resolution imaging of microvasculature is important for diagnostic and therapeutic applications. Here, the utility of a multi-frequency large-aperture hemispherical phased array in the context of vasculature imaging via passive beamforming and super-resolution techniques was explored at various receive frequencies, to investigate the capability of mapping the emissions of lipid coated phase-change nanodroplets flowing through tube phantoms as well as rabbit renal and cerebral vasculatures in-vivo. With super-resolution techniques, the mean lateral (axial) full-width-at-half-maximum image intensity was estimated to be 16 ± 3 (32 ± 6) μm and 7 ± 1 (15 ± 2) μ m, corresponding to approximately 1/85 of normal resolution when received with the subarrays at 612 and 1224 kHz, respectively. The mean positional uncertainties were approximately 1/350 (lateral) and 1/180 (axial) of the receive wavelength in water. The renal and cerebral vasculatures of rabbits were partially visualized. A correlation between transmit pulse and nanodroplet vaporization is observed, demonstrating potentials for nanodroplet vaporization modulation and signal-to-noise ratio enhancement. This study demonstrates the feasibility of mapping vaporized nanodroplets with passive beamforming and super-resolution imaging techniques. It may provide means to map complete vasculature pre- or post-treatment with therapeutic focused ultrasound in organs that can be surrounded by the hemispherical array.

The blood-brain barrier, while fundamental in maintaining homeostasis in the central nervous system, is a bottleneck to achieving efficacy for numerous therapeutics. Improved brain penetration is also desirable for reduced dose, cost, and systemic side effects. Transient disruption of the blood-brain barrier with focused ultrasound (FUS) can facilitate drug delivery noninvasively with precise spatial and temporal specificity. FUS technology is transcranial and effective without further drug modifications, key advantages that will accelerate adoption and translation of existing therapeutic pipelines. In this review, we performed a comprehensive literature search to build a database and provide a synthesis of ultrasound parameters and drug characteristics that influence the safety and efficacy profile of FUS to enhance drug delivery.

A significant barrier to successful drug delivery is the limited penetration of nanoscale therapeutics beyond the vasculature. Building on recent in vivo findings in the context of cancer drug delivery, the current study investigates whether modification of nanoparticle drug-carriers to increase their density can be used to enhance their penetration into viscoelastic materials under ultrasound exposure. A computational model is first presented to predict the transport of identically sized nanoparticles of different densities in an ultrasonic field in the presence of an oscillating microbubble, by a combination of primary and secondary acoustic radiation forces, acoustic streaming and microstreaming. Experiments are then described in which near monodisperse (polydispersity index 0.2) nanoparticles of approximate mean diameter 200 nm and densities ranging from 1.01 g cm

New strategies are required to enhance the penetration and tumor-wide distribution of cancer therapeutics, including viruses, antibodies, and oligonucleotides. We have shown previously that increasing the density of a nanoparticle can enhance its ultrasound-mediated transport, particularly when exposed to microstreaming. The current study investigates how the physical characteristics and dynamics of different cavitation nucleation agents affect the cavitation-mediated transport of therapeutics not directly bound to the gas nuclei. SonoVue (Bracco, Milan, Italy) microbubble contrast agent (with 3 μm mean initial bubble diameter) and polymeric gas-entrapping nanoparticles (with 260 nm mean initial bubble diameter) were first compared in terms of inertial cavitation threshold and cavitation persistence. Under the same ultrasound exposure conditions (centre frequencies of either 0.5 MHz or 1.6 MHz, and peak negative pressures from 0.2 MPa to 3.5 MPa) their respective cavitation emissions were found to differ ...

Rate-adaptive pacemakers make use of sensors in order to automatically adjust the pacing rate according to the metabolic needs of the patient, thus overcoming the limitation of fixed-rate pacemakers that cannot ensure an adequate heart beat in cases of varying physical, mental or emotional activity. This feature significantly improves the quality of life of patients with chronotropic incompetence, i.e. Whose heart is unable to increase its rate as the activity increases. We develop a formal model of a rate-adaptive pacemaker based on hybrid automata that explicitly includes sensors for rate control. In particular, we model the VVIR pacemaker with a QT interval sensor, a highly specific metabolic sensor that can sense the exercise activity level, based on the fact that physical (and mental) stresses shorten the QT interval, in turn requiring an increased heart rate. We implement the QT interval sensor through a runtime ECG detection algorithm and validate our model with patient data, showing that the simulated VVIR pacemaker is able to successfully regulate a bradycardia ECG signal and produce a correctly paced heart. The validated rate-adaptive pacemaker is plugged into the model-based framework introduced in Chen et al. (2014), which enables rigorous and quantitative verification of closed-loop patient-device systems described as hybrid automata, and supports multiple heart and pacemaker models in a modular way. We demonstrate the usefulness of the framework by performing in silico experiments to demonstrate the correct functioning of rate modulation under different activity levels. Our framework has the potential to reduce the need for exercise testing with real patients.

For effective cancer therapy, therapeutic agents must extravasate from the blood stream into the tumour mass, then overcome the elevated intratumoural pressure and dense extracellular matrix to reach each and every cancer cell. Several recent studies have suggested that inertial cavitation in the absence or presence of artificial cavitation nuclei can significantly enhance the delivery, penetration, and distribution of small-molecule or nanoparticulate therapeutic agents into tumors. We first present a comparison of the reported enhancements in delivery achieved for a range of frequencies and therapeutic sizes without or with pre-seeding of cavitation, with particular emphasis on the potential role of cavitation persistence and spatial distribution. With microstreaming hypothesized to be the dominant transport mechanism for drug delivery, the likely benefit of using sub-micron cavitation nucleation agents capable of extravasating alongside the therapeutic, rather than microbubbles confined to the blood po...

A significant barrier to successful drug delivery in cancer therapy is the limited penetration of nanoscale therapeutics deep into tumors. Ultrasound mediated cavitation has been shown to promote nanoparticle transport, but achieving tumor wide distribution still represents a considerable challenge. The current study investigates the way in which nanoparticle drug-carriers may be designed to enhance penetration under ultrasound exposure. A computational model has been developed to predict the transport of a nanoparticle in an ultrasonic field in the presence of an oscillating microbubble, by a combination of primary and secondary acoustic radiation forces, acoustic streaming, and microstreaming. Experimental investigations were also performed in a tissue-mimicking phantom to study the transport of different types of particle, in the presence or absence of a microbubble ultrasound contrast agent, at ultrasound frequencies of 0.5 MHz and 1.6 MHz with peak pressures in the range of 0–2.0 MPa. Micro- and nanoparticles with contrasting density cores ranging from 1.0 g/cm3 to 19.3 g/cm3 were used for the study. Both the theoretical and experimental results showed that the denser particles exhibit significantly greater ultrasound-mediated transport than their lower density counterparts, indicating that this is a key consideration in the design of nanoscale therapeutics.