Dual-Nanopore Sensing With Feedback-Controlled Molecule Delivery
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Solution Overview
Problem
Nanopore sequencing faces challenges in achieving single-nucleotide sensitivity and controlling the delivery rate of nucleotides due to the lack of effective methods that do not rely on enzymes or optics, leading to compromised sensor functionality.
Innovation Solution
A dual-nanopore device with switchable sensing and control circuitry, where one nanopore uses a sensor circuitry for constant voltage measurement and the other uses a control circuitry with dynamic voltage feedback to regulate molecule delivery and enhance sensing accuracy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If a single nanopore is used for sensing, then the device structure is simple, but the delivery rate of nucleotides cannot be controlled and single-nucleotide sensitivity is insufficient
Solution Approach 1:
The device is divided into two separate nanopores: a first nanopore for sensing nucleotide identity and a second nanopore for controlling delivery rate. This segmentation allows each pore to be optimized for its specific function, resolving the contradiction between measurement precision and device complexity by distributing functions across multiple components rather than attempting to combine them in a single pore.
Solution Approach 2:
The second nanopore acts as an intermediary control element that regulates the delivery of nucleotides to the first nanopore. By introducing this intermediate control pore, the system achieves precise delivery rate control without compromising the sensing capability of the first nanopore, thus improving measurement precision while maintaining manageable device complexity.
2Measurement precision
If DNA traverses the sensor rapidly, then productivity is high, but the sensor function is compromised due to insufficient sensitivity
Solution Approach 1:
By separating the sensing function (first nanopore) from the delivery control function (second nanopore), the system can independently optimize each function. The first nanopore can be designed for maximum sensitivity to accurately identify nucleotides, while the second nanopore controls the delivery rate to match the sensing capability, thus resolving the contradiction between measurement precision and productivity.
Solution Approach 2:
The system uses feedback control where the sensing output from the first nanopore informs the delivery rate control at the second nanopore. This feedback mechanism allows the system to adjust the delivery rate dynamically based on sensing performance, ensuring that nucleotides are delivered at an optimal rate that maintains both high identification accuracy and efficient sequencing throughput.
3Ease of operation
If enzymes or optics are used to control delivery rate, then delivery control is achieved, but device complexity and cost increase
Solution Approach 1:
The invention replaces complex enzymatic or optical control mechanisms with a simpler solid-state nanopore-based electrical control system. The second nanopore uses voltage control to regulate ion flow and thereby control nucleotide delivery rate, eliminating the need for enzymes or optical components while achieving the desired delivery control functionality with reduced device complexity.
Solution Approach 2:
The system controls delivery rate by changing electrical parameters (voltage, current) across the second nanopore rather than using complex mechanical or biochemical mechanisms. By adjusting the electrical potential applied to the second nanopore, the delivery rate of nucleotides to the first nanopore can be precisely controlled through simple parameter changes, reducing device complexity while maintaining ease of operation.
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 dual-nanopore device enables precise control over molecule delivery and repeated sensing, improving nucleotide identification accuracy and reducing signal noise, thereby enhancing genome sequencing efficiency.
Implementation Method 1
The first circuitry that incorporates a nanopore, hereafter referred to as the sensor circuitry, comprises a sensing voltage clamp or patch clamp amplifier circuit. When the first circuitry that incorporates a nanopore is used, the nanopore serves as an 'ionic current sensing' nanopore.
Implementation Method 2
The second circuitry, hereafter referred to as the control circuitry, comprises customized circuitry that controls the magnitude and direction of the field forces across a nanopore incorporated within the second circuitry.
Implementation Method 3
The control circuitry also has access to information from the first circuitry (e.g., a measured current) that is used for feedback voltage-control.
Data Source
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AI summary
Two pore devices and method for sequencing are described. A two pore device can include first chamber, a second chamber, and a third chamber, wherein the first chamber is in communication with the second chamber through a first nanopore, and wherein the second chamber is in communication with the third chamber through a second nanopore. The device can also include sensing circuitry for measuring electrical signals associated with a target at a nanopore, and control circuitry for controlling motion of the target at a nanopore. The device can include and/or switch between sensing and control modes for each of the first nanopore and the second nanopore. Sequencing methods can implement a two pore device in relation to translocation of a target through one or more nanopores, switching between sensing and control modes as appropriate, and measuring aspects of the target using in sensing modes.