Ultrasound Shear Wave Gene Delivery via Sonoactive Agents
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing ultrasound-based gene therapy techniques, such as those using high-intensity focused ultrasound (HIFU), face challenges including low transfection rates, insufficient gene expression, and safety concerns due to thermal and cavitation effects. Additionally, lower intensity ultrasound methods struggle with achieving high levels of gene expression, uniform tissue biodistribution, and tissue penetration in large regions.
Innovation Solution
The method employs an acoustic radiation force generated by ultrasound to deliver an exogenous payload to cells in a tissue, using shear waves and stable vibrational and inertial cavitation of sonoactive agents to enhance payload delivery and gene expression. This approach is highly effective in transfecting cells throughout the target organ, even those remote from the ultrasound energy source, while minimizing risk to the subject.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If high-intensity focused ultrasound (HIFU) is used to enhance payload delivery, then gene expression levels improve, but tissue ablation and cell death occur due to thermal and cavitation effects
Solution Approach 1:
The patent changes the ultrasound intensity parameter from high-intensity (HIFU) to intermediate intensity levels, and modifies the duty cycle to pulsed modes with specific on/off ratios. This parameter optimization allows sufficient acoustic radiation force generation for payload delivery while preventing excessive thermal accumulation that causes tissue ablation
Solution Approach 2:
The patent employs pulsed ultrasound delivery with specific duty cycles (e.g., 10% duty cycle with 10ms on/90ms off patterns) rather than continuous high-intensity exposure. This periodic action allows tissue cooling intervals between pulses, preventing thermal damage while maintaining cumulative acoustic radiation force effects for effective gene delivery
2Object-affected harmful factors
If lower intensity ultrasound is used to minimize tissue damage, then safety improves, but gene expression levels and tissue penetration remain insufficient
Solution Approach 1:
The patent administers sonoactive agents (microbubbles or nanoparticles) to the tissue before ultrasound application. These agents accumulate at the target site and serve as cavitation nuclei that amplify the acoustic radiation force effect at lower ultrasound intensities, enabling effective payload delivery without requiring high-power ultrasound that would cause tissue damage
Solution Approach 2:
The patent introduces sonoactive agents as intermediary substances that mediate between the ultrasound field and the target cells. These agents convert acoustic energy into localized mechanical effects (cavitation and shear waves) that enhance payload delivery efficiency, allowing lower intensity ultrasound to achieve effects previously requiring high-intensity exposure
3Stability of the object's composition
If high-intensity ultrasound is applied to achieve uniform biodistribution, then payload distribution improves, but thermal effects and tissue ablation increase
Solution Approach 1:
The patent uses pulsed ultrasound with duty cycles optimized to allow thermal dissipation between pulses. The periodic on/off pattern maintains cumulative mechanical effects for uniform biodistribution while providing cooling intervals that prevent excessive temperature rise and thermal damage in the tissue
Solution Approach 2:
The patent divides the ultrasound delivery into multiple low-intensity pulses rather than one high-intensity continuous exposure. This segmentation of the energy delivery in time allows the tissue to dissipate heat between pulses while still accumulating the mechanical effects needed for uniform payload distribution across the target organ
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The method achieves significant enhancement in payload delivery and gene expression compared to low intensity ultrasound techniques, with uniform biodistribution throughout the target organ and minimal adverse effects on the tissue, allowing for a safe and repeatable procedure.
Implementation Method 1
an acoustic radiation force generated when applying ultrasound which is highly effective at transfecting cells throughout in the target organ
Implementation Method 2
inducing displacing the tissue of the subject with an acoustic radiation force to induce propagation of shear waves throughout the tissue of the target organ
Implementation Method 3
inducing stable vibrational and inertial cavitation of substantially all of the sonoactive agents in the treated organ
Implementation Method 4
cavitation effects due to interaction of HIFU with sonoactive agents
Data Source
AI summary
Provided are systems and methods of delivering an exogenous payload to a cell in a tissue of a subject, including: administering an exogenous payload to the subject; administering a sonoactive agent to the subject, and applying an acoustic radiation force (ARF) to the subject, thereby generating shear waves in the tissue of the subject, wherein the acoustic radiation force enhances delivery of the exogenous payload to the cell in the tissue of an organ of the subject.