More than 1,500 researchers from around the world attended the IEEE International Ultrasonics Symposium (IUS) October 22-25 in Kobe, Japan. The topics on focused ultrasound therapy include ultrasound-mediated drug delivery, neurostimulation, monitoring techniques, microbubble and cavitation in ultrasound therapy, and new technologies to enhance ultrasound therapy. Highlights include:
  • IEEE IUSNeurostimulation continues to be an area of high research interest, with multiple specialized sessions. Preclinical studies continue to demonstrate ultrasound neurostimulation in Parkinson’s, epilepsy, and cancer models. Researchers from Shenzhen Institute of Advanced Technology Chinese Academy of Science presented early evidence of neurostimulation in human temporal lobe epilepsy.
  • Researchers from Imperial College London presented a novel sequence for ultrasound-mediated drug delivery through blood-brain barrier (BBB) opening. Using a rapid short-pulse (RaSP) sequence, they achieved more uniform drug distribution through the BBB as compared to conventional long-pulses, and this sequence deposited 150 times less acoustic energy into the brain. This new ultrasound sequence has the potential to improve the safety of ultrasound-mediated BBB opening.

  • Researchers from the University of Washington and University of Kansas combined focused ultrasound with laser to lower the acoustic cavitation threshold for cavitational ultrasound therapy, such as ultrasound-mediated clot lysis, to be performed within the FDA safety limit of diagnostic ultrasound.

The Foundation thanks Zhen Xu, PhD, from the University of Michigan, for sending this meeting report.

Focused Ultrasound Abstracts Presented at IEEE IUS

Bi-modal modulation of neuronal excitability by ultrasound stimulation in human temporal lobe epilepsy
Zhengrong Lin1, Lili Niu1, Long Meng1, Wei Zhou1, Xiaowei Huang2, Hairong Zheng1

Paul C. Lauterbur Research Center for Biomedical Imaging, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China, CA, China, People's Republic of
2Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China, People's Republic of China

Background, Motivation, and Objective: Temporal lobe epilepsy (TLE) is a prevalent neurological disorder resulting in disruptive seizures and often associated with pharmaco-resistance. Ultrasound stimulation as an emerging non-invasive neuro-stimulation technique has shown its effectiveness in suppressing the epileptic seizures in rodent animal models (Neuroimage 56, 1267-1275, 2011; BMC Neuroscience 12, 23, 2011; Epilepsy Behavior 49, 26-32, 2015). The effect of ultrasound stimulation on the seizures of human temporal lobe epilepsy (TLE) have been little addressed. In this study, we aimed to determine whether ultrasound stimulation was capable of inhibiting single neuronal excitability in brain slices of the temporal lobe from TLE patients.

Statement of Contribution/Methods: A biopsy specimen was removed from a TLE patient and the spontaneous activity of the neurons in the TLE slice was recorded using electrophysiological technique. Low-intensity pulsed ultrasound (frequency: 28 MHz, pressure: 0.25 MPa) was delivered into human TLE slices generated by the ultrasound stimulation system. The following pulsed ultrasound parameters were chosen and used in the present study: (1) single 5ms ultrasound pulse containing 140000 acoustic cycles of 28MHz at pulse repetition frequency (PRF) of 100Hz and (2) single 0.5ms ultrasound pulses containing 14000 acoustic cycles were repeated at PRF of 1000Hz.

Results/Discussion: Ultrasound stimulation could be bi-modal modulation of the burst discharge of ‘epileptic neurons.’ Single 5ms ultrasound pulse containing 140000 acoustic cycles of 28MHz at pulse repetition frequency (PRF) of 100Hz could effectively inhibit the burst discharge. A population of 13 neurons showed that the relative frequency rapidly decreased several-fold. Interestingly, another parameter with single 0.5ms ultrasound pulses containing 14000 acoustic cycles were repeated at PRF of 1000Hz showed a completely different effect on the burst discharge. A total of 7 neurons showed that the relative frequency rapidly increased several-fold. This suggests that ultrasound stimulation may be a valuable treatment modality for patients with epilepsy.

Improved performance and safety of drug delivery to the brain in vivo with Rapid Short-Pulse (RaSP) sequences
Sophie V. Morse1, Tiffany G. Chan2, Matthew J. Copping1, Antonios Pouliopoulos1, Nicholas J. Long2, James J. Choi1

1Bioengineering, Imperial College London, London, United Kingdom
2Chemistry, Imperial College London, United Kingdom

Background, Motivation, and Objective: Focused ultrasound and microbubbles can locally and noninvasively enhance the blood-brain barrier permeability for drugs. Although clinical results have been encouraging for glioblastoma treatment in adults, there are concerns for more sensitive patients - the elderly with dementia and children with brain cancer. With current ultrasound methods, drugs are delivered inefficiently to diseased regions and safety relies on a long healing process. Side effects include unpredictable drug distributions, high drug concentrations along vessels and red blood cell extravasation. Our group has developed a Rapid Short-Pulse (RaSP) sequence designed to improve cavitation distribution. Here, we evaluated the ability of RaSP to improve drug delivery performance and safety, by comparing the drug dose and distribution and the extent of morphological changes and red blood cell extravasation compared to conventional long-pulses.

Statement of Contribution/Methods: We tested a RaSP sequence in vivo that had a low-energy pulse (PL: 5 cycles, P: 350 kPapk-neg) and compared it to a long-pulse sequence that had a high-energy pulse (PL: 10,000 cycles, P: 350 kPapk-neg) in mice at 1 MHz. RaSP pulses were emitted at a rapid pulse and slow burst rate (PRF: 1.25 kHz, BRF: 0.5 Hz) while long-pulses were emitted at a slow pulse rate (PRF: 0.5 Hz). Fluorescent 3 kDa dextran and SonoVue® microbubbles were injected with emissions captured by a 7.5 MHz passive cavitation detector. Brains were imaged by fluorescence microscopy and stained with H&E to check for any damage and red blood cell extravasation.

Results/Discussion: Despite depositing 150 times less acoustic energy into the brain, RaSP sequences delivered a more uniform drug distribution with a similar dose to conventional long-pulses. Such improvement is thought to be due to a better spatiotemporal distribution of cavitation. Neuronal uptake was higher with RaSP and less dextran was observed within glial cells which are linked to a tissue response to damage. No red blood cell extravasation or morphological damage was observed with RaSP, while with long-pulses, one brain had haemorrhage and microvacuolations. These results indicate that low-pressure RaSP sequences could be used to deliver drugs with improved performance and safety to treat sensitive neurological diseases, such as neurodegenerative diseases and paediatric brain cancers.

Antivascular photo-mediated ultrasound therapy for neovascularization in the eye
Xinmai Yang1, Xinyi Xie2, Yu Qin2, Shuying Li2, Wei Zhang2, Yannis Paulus2, Xueding Wang2 

1University of Kansas, Lawrence, KS, United States
2University of Michigan, Ann Arbor, MI, United States 

Background, Motivation, and Objective: Neovascularization and pathologic microvasculature are common in several eye diseases, including corneal neovascularization, diabetic retinopathy, and macular degeneration. Current treatments, such as laser photocoagulation, photodynamic therapy (PDT), and anti-vascular endothelial growth factor (VEGF) therapy, impose significant burdens on patients, their families, and our health care system because of frequent administration, high cost, and their destructive nature. We developed a novel treatment, termed photo-mediated ultrasound therapy (PUT), that uses a combination of a low intensity nanosecond laser concurrently with ultrasound. PUT can remove microvessels noninvasively without damaging surrounding tissue in the eye. We present the first evaluation of PUT on a disease model of corneal neovascularization on rabbits.

Statement of Contribution/Methods: An integrated therapeutic ultrasound and laser treatment system was devised. Laser pulses, produced by a pulsed (Nd:YAG) laser at 532 nm with 5-ns pulse duration and 10-Hz repetition rate, synchronized with millisecond ultrasound bursts. New Zealand white rabbits were used. Corneal neovascularization was induced using an established animal model placing pro-inflammatory silk sutures in the cornea. The outcome of PUT treatment was evaluated by using imaging techniques such as photography, optical coherence tomography (OCT), fluorescein angiography, and photoacoustic microscopy (PAM). Imaging was performed before, after, and weekly following PUT treatment for 1 month.

Results/Discussion: Treatment with laser- or ultrasound-only resulted in no changes to the corneal neovascularization. PUT treatment with concurrent laser and ultrasound was able to remove the corneal neovascularization. The optimal parameters were 0.5 MPa ultrasound + 32 mJ/cm2 laser. By 1 week, neovascularization in the region of treatment was greatly retreated (Figure 1). Quantified results from OCT indicated significant decrease in neovascularization. In conclusion, PUT holds significant promise as a novel non-invasive method to precisely remove microvessels in neovascular eye diseases by more selectively treating vasculature with minimized side-effects and no systemic photosensitizing dye.

Sono-Photoacoustic Vaporization of Polypyrrole coated Perfluorocarbon Droplets for Clot Lysis
David Li1,2, Kacper Lachowski1, Ivan Pelivanov2, Thomas Matula3, Matthew O'Donnell4, Lilo Pozzo4

1Department of Chemical Engineering, University of Washington, Seattle, WA, United States
2Department of Bioengineering, University of Washington, Seattle, WA, United States
3Center of Industrial and Medical Ultrasound, University of Washington, Seattle, WA, United States
4University of Washington, Seattle, WA, United States

Background, Motivation, and Objective: Theranostic strategies to destroy clots using photoacoustic (PA) imaging in combination with photothermal heating or cavitation have previously been demonstrated. However, poor light penetration into tissue has restricted photoacoustic theranostic applications to superficial sites. Phase-change contrast agents (PCCAs) can be effective alternatives to conventional dye or particle-based PA contrast agents. The threshold-based vaporization of PCCAs and large displacements generated from vaporizing nanodroplets to form microbubbles enables PCCAs to be effective theranostic agents. However, PA thresholds for vaporizing droplets still require a minimum optical fluence of 10 mJ/cm2, making them unsuitable for deep tissue imaging and therapy.

Statement of Contribution/Methods: Sono-photoacoustic imaging is a non-linear imaging modality using simultaneous optical and acoustic activation of PCCAs. Using combined optical and acoustic sources to initiate vaporization, greater penetration depths can be achieved than by either source alone at optical fluences and acoustic pressures within FDA and ANSI limits. In this study, sono-photoacoustic vaporization of targeted polypyrrole coated liquid perfluorocarbon core agents for clot lysis is presented.

Results/Discussion: Using the ouzo method to spontaneously nucleate the droplet in solution, agents can be easily synthesized with diameters <200 nm, making them well suited for extravascular imaging and theranostics. These agents have been shown to have no adverse effects on cell viability and can be functionalized for targeted delivery. Preliminary studies on sono-photoacoustic clot lysis show that agents can penetrate into fibrin clots (Figure 1). Once delivered, sono-photoacoustic cavitation of the agents can be used to disrupt the fibrin clot to restore blood flow.



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