Ultrasound (US)-mediated gene delivery (UMGD) of nonviral vectors was demonstrated in this study to be an effective method to transfer genes into the livers of large animals via a minimally invasive approach. We developed a transhepatic venous nonviral gene delivery protocol in combination with transcutaneous, therapeutic US (tUS) to facilitate significant gene transfer in pig livers. A balloon catheter was inserted into the pig hepatic veins of the target liver lobes via jugular vein access under fluoroscopic guidance. tUS exposure was continuously applied to the lobe with simultaneous infusion of pGL4 plasmid (encoding a luciferase reporter gene) and microbubbles. tUS was delivered via an unfocused, two-element disc transducer (H105) or a novel focused, single-element transducer (H114). We found applying transcutaneous US using H114 and H105 with longer pulses and reduced acoustic pressures resulted in an over 100-fold increase in luciferase activity relative to untreated lobes. We also showed effective UMGD by achieving focal regions of >10
5
relative light units (RLUs)/mg protein with minimal tissue damage, demonstrating the feasibility for clinical translation of this technique to treat patients with genetic diseases.
Focused ultrasound (FUS) is becoming widely researched for medical therapies due to its high penetration depth, spatial resolution, and affordability. Applications of FUS range from high intensity focused ultrasound (HIFU) for the ablation of cancerous tumors to low intensity focused ultrasound (LIFU) for the treatment of neurological conditions like essential tremors. A key step in developing these treatments and their corresponding FUS devices is characterizing the emitted ultrasound from the proposed transducer. However, a bottleneck exists at this verification and validation stage; current characterization techniques lack the robustness of reliably recording below a 5μm resolution. This level of accuracy is needed to adequately design devices which can target cells like astrocytes or other desired target tissues at this scale. Our Acoustic Measurement Platform for Localizing and Implementing Therapeutic Ultrasound Devices and Equipment (AMPLITUDE) is a solution which enables engineers, scientists, and clinicians to confidently characterize their equipment in a benchtop setting. It achieves this resolution by utilizing an all-in-one water conditioning unit, linear stepper motors with a theoretical step size of 1 μm and a 1% standard deviation on repetitive experiments, as well as signal processing techniques. This system can be used throughout the product timeline including prototyping, verifying efficacy, FDA testing, and routine check-ups during clinical use.
Therapeutic ultrasound is proving to be viable in the clinic and is producing a high level of commercial activity in Therapeutic Ultrasound Systems globally across a wide variety of clinical indications. Recently there has been an increased level of commercial interest in systems delivering lower intensity ultrasound. Some examples of clinical indications include modulating nerves, sonodynamic therapy, or combining ultrasound with drugs to lower the threshold of required intensities. Regardless of the acoustic intensity required, new product inception will adopt an effective bio-acoustic result to match a clinical indication, creating a gap in product development. Sonic Concepts provides transmit ultrasound development services to fill this gap through a phased development program, accelerating first-in-man and time to market. Sonic Concepts has co-developed 30 + clinical systems, servicing customers with more than 100 years of accumulated experience, creative design techniques, and a spectrum of products and intellectual property to leverage. Examples of co-developed clinical systems will be presented, detailing the process from initial concept to first-in-man while using pre-clinical systems, HIFUPlex™ and NeuroFUS® to fast-track development.
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