The Foundation is pleased to announce that five new research projects have been selected for funding in the third quarter of 2017. The scientific topics include experiments designed to test a variety of focused ultrasound mechanisms. Applications range from temporal lobe epilepsy to chronic wound healing to drug delivery for pancreatic cancer and bladder disorders. One research team will combine two mechanisms as they examine a potential role for shock wave histotripsy in improving thermal ablation.Nicholas Ellens, PhD, Johns Hopkins University
Project: Focused ultrasound – mediated drug delivery across the urothelium
The bladder wall is tough and relatively impermeable which protects the body but also prevents drugs and other therapeutics from crossing from the bladder into surrounding tissues. Focused ultrasound mediated sonoporation may increase the permeability of the bladder without damaging it, allowing for a novel means of bladder therapy with minimal side effects.
Vera Khokhlova, University of Washington
Project: Use of shock-wave exposures for accelerating thermal ablation of targeted tissue volumes
In high-intensity focused ultrasound (HIFU) applications, nonlinear acoustic propagation effects can result in the formation of high-amplitude shock fronts at the focus, with amplitudes exceeding 100 MPa. The presence of such shocks leads to increased tissue heating, which can be beneficial for HIFU thermal therapy. Our preliminary simulation data shows that shock-enhanced exposures provide significantly higher ablation rates at target sites with less heat diffusion to the surrounding tissues in comparison with conventional HIFU treatments. Such exposures may benefit thermal HIFU by shortening both sonication and treatment time, reducing heating of near-field and surrounding tissues, mitigating diffusion and perfusion effects, and providing sharper lesion margins. The goal of the experiment is to test the shock-enhanced thermal HIFU method and to evaluate the efficacy of different shock-wave exposures to accelerate thermal ablation of tissue volumes while enabling safer conditions for intervening tissues. Specifically, our goals are:
- Refine 3D nonlinear acoustic model combined with the bio-heat equation for simulating shock-enhanced thermal ablation of clinically relevant tissue volumes;
- Validate high-power acoustic modeling results against measurements in water using a fiber optic hydrophone in MR- and US-guided HIFU systems;
- Determine most effective focus trajectories and compare ablation rates and lesion margins using nonlinear simulations of volumetric tissue ablation at different power levels of the two systems;
- Evaluate the efficacy of shock-wave exposures developed in simulations by comparing temperature fields and lesion volumes predicted by the model and measured in an MR-guided system.
Kevin S. Lee, University of Virginia
Project: Use of low-intensity focused ultrasound for the noninvasive, focal disconnection of brain circuitry in the treatment of neurological disorders
Disturbances in the function of neuronal circuitry contribute to many neurological disorders. As knowledge of the brain's connectome continues to improve, a more refined understanding of the role of specific circuits in pathological states will also evolve. Tools capable of intervening in a targeted and restricted manner will be essential not only to expand our understanding of the functional roles of such circuits, but also to therapeutically disconnect critical pathways contributing to neurological disease. This project will test a novel strategy for producing focal, non-ablative, neuronal lesions in the central nervous system. This strategy is termed Precise Intracerebral Noninvasive Guided surgery (PING). This proposal will test the therapeutic ability of PING to attenuate seizure activity in a model of temporal lobe epilepsy. Guiding hypothesis: Targeted disconnection of dysfunctional brain circuitry can be achieved in a precise, conformal, and noninvasive manner, and this strategy can be implemented to control seizures in Drug Resistant Epilepsy. The project will take advantage of the ability of low-intensity, magnetic resonance-guided focused ultrasound (MRgFUS) to transiently disrupt the blood brain barrier (BBB) in order to deliver to the brain parenchyma a neurotoxin with poor BBB permeability. This represents a targeted, noninvasive, nonablative strategy for precise destruction of neurons. Our preliminary findings provide the first evidence of noninvasive, focal destruction of neurons in a targeted brain area that spares non-targeted structures. Our proposed study is the first test-of-concept of the therapeutic efficacy of PING for treating a biomedical disorder.
Ashish Ranjan, Oklahoma State University
Project: Wound healing in client-owned dogs
Nonhealing wounds caused by biofilm-forming bacteria are hard to treat, and often require long duration antimicrobial treatment, extensive surgical debridement, and, in many cases, limb amputations. To overcome these barriers, this project will investigate the enhancement of antimicrobial delivery and sensitization using focused ultrasound in client-owned dogs with chronic nonhealing wounds. Successful demonstration and translation of our proposed technology will enhance antimicrobial treatment responses, sensitize drug resistant pathogens, and reduce the need for extensive surgical interventions and follow-up care.
Sarah White, MD, Medical College of Wisconsin
Project: Focused ultrasound driven drug release from theranostic nanoparticles for the treatment of pancreatic cancer
Pancreatic cancer shows extreme resistance to chemotherapy and radiotherapy. Most pancreatic cancer patients will die within the first year of diagnosis. Insufficient perfusion of pancreatic tumors results in limited delivery of therapeutics into the tumor parenchyma. Therefore, improved drug delivery efficiency, coupled with suppression of drug resistance, is a priority in pancreatic cancer treatment. Focused ultrasound (FUS) is an effective therapy; however, it is limited by adjacent structures. We aim to develop and characterize a theranostic nanoparticle-based drug platform that can be triggered by acoustic changes induced by ultrasound for gemcitabine release in cells, and, in a pre-clinical rodent pancreatic cancer model, to achieve targeted chemohyperthermia. We hypothesize that we can significantly improve "kill" zones by combining local delivery of targeted novel drug platforms with FUS for the treatment of pancreatic cancer. To do this, a nanomaterial-based platform will be synthesized and tested in vitro for the ultrasound-mediated release of gemcitabine. Later, these nanoparticles will be infused in a rodent orthotopic pancreatic tumor model to assess feasibility, triggered release, noninvasive imaging, pathological changes, and survival benefit. Our goal is to achieve image-guided, targeted triggered release of cytotoxic doses of gemcitabine to treat pancreatic tumors, thereby alleviating resistance, systemic toxicity, and off-target delivery.