Asymmetric Bipolar Waveforms for Controlled Electroporation
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Solution Overview
Problem
Existing electroporation techniques face challenges in controlling the ratio of reversible to irreversible effects, leading to undesired side-effects such as tissue damage and irregular ablations, particularly in cancer treatment and gene therapy applications.
Innovation Solution
The use of asymmetric waveforms with selected positive and negative pulse widths allows for controlled delivery of electrical pulses to tune the ratio of reversible to irreversible electroporation, minimizing muscle contractions and achieving more uniform and predictable ablation volumes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If long duration monopolar IRE pulses are used, then complete cell killing and ablation volume are achieved, but muscle contractions and irregular shaped ablations occur
Solution Approach 1:
The patent applies periodic action by using bursts of alternating polarity pulses (H-FIRE protocol) instead of continuous monopolar pulses. The alternating polarity reverses the direction of electrostriction forces between pulses, preventing sustained muscle contractions while maintaining cumulative electroporation effects for complete cell killing.
Solution Approach 2:
The patent employs asymmetric pulse widths within the alternating polarity bursts, where positive and negative pulses have different durations. This asymmetry allows optimization of the electroporation effect while balancing the mechanical forces on tissue, achieving uniform ablation shapes without the irregularities caused by symmetric monopolar pulses.
2Volume of stationary object
If long duration monopolar IRE pulses are used, then ablation volume is achieved, but ablation shape irregularity occurs
Solution Approach 1:
The periodic alternating polarity pulses create uniform electroporation distribution throughout the target volume. The reversal of field direction between pulses ensures consistent energy deposition and pore formation patterns, leading to spherical and uniform ablation zones rather than irregular shapes.
Solution Approach 2:
The patent changes the waveform parameters from monopolar to alternating polarity with asymmetric pulse widths. This parameter modification optimizes the electric field distribution in heterogeneous tissue, producing predictable and uniform ablation volumes that are less sensitive to tissue property variations.
3Reliability
If high intensity electrical pulses are used for IRE, then cell death is achieved, but reversible electroporation overlap causes tissue damage
Solution Approach 1:
The patent uses multiple bursts of alternating polarity pulses where each burst delivers partial electroporation stress. The cumulative effect of multiple partial actions achieves complete cell killing while allowing tissue recovery between bursts, preventing uncontrolled damage that would result from single excessive monopolar pulses.
Solution Approach 2:
The periodic alternation between positive and negative pulses creates controlled stress cycles on cell membranes. This periodic action allows cumulative pore formation leading to cell death while the alternating nature prevents sustained mechanical damage, enabling selective cell killing without excessive tissue harm.
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
This approach enables the production of larger ablations with reduced lethal thresholds, enhancing drug or gene delivery while minimizing cell killing, and improving the precision of tumor ablation and gene transfection efficiency.
Implementation Method 1
Electroporation involves application of external electric fields to tissue, increasing the voltage drop across cell membranes. When this potential reaches a critical potential (approximately 0.5-1 V) the molecules in the cell membrane deform in an attempt to minimize the energy in the system. This results in the formation of nanoscale defects (electro-pores) which are either transient and do not affect cell viability (reversible electroporation), or permanent and result in cell death (irreversible electroporation).
Data Source
AI summary
A ratio of reversible electroporation and irreversible electroporation may be controlled by selecting a symmetric waveform or asymmetric waveform to either minimize or enhance irreversible effects on cells in the target tissue. Combined reversible and irreversible electroporation includes inserting one or more therapeutic electrodes into a target tissue, introducing an electroporation compound into the target tissue, selecting a pulse waveform that is either 1) asymmetric bipolar that has positive and negative pulses with different durations, or 2) symmetric bipolar that has positive and negative pulses with the same duration, and delivering to the target tissue a series of electrical pulses having the selected pulse waveform.