Nanopore Array Resistive Openings Crosstalk Reduction
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Solution Overview
Problem
Current nanopore-based DNA and RNA sequencing technologies face challenges in achieving accurate and reliable high-speed sequencing at single-nucleotide resolution, and there is a need for devices capable of manufacturing arrays of nanopores and sequencing molecules with nanoscale dimensions effectively.
Innovation Solution
A device comprising an array of nanopores on a semiconductor substrate with integrated electronic circuitry, where each nanopore is fluidically connected to upper and lower fluidic regions, and includes resistive openings to minimize electrical crosstalk, allowing for high-resolution sequencing of polymers by measuring current modulations as they pass through the nanopores.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If multiple nanopores are used to increase sequencing throughput, then productivity is improved, but electrical crosstalk between nanopores increases causing measurement precision to deteriorate
Solution Approach 1:
The device divides the sequencing function into multiple independent nanopores arranged in an array, with each nanopore processed separately through fluidic regions and resistive openings. This segmentation allows parallel sequencing operations while maintaining electrical isolation between individual measurement sites, resolving the contradiction between throughput and precision.
Solution Approach 2:
Resistive openings serve as intermediary elements between the nanopores and the measurement circuitry. These openings with controlled resistance values act as electrical buffers that prevent crosstalk between adjacent nanopores while still allowing ionic current flow, enabling both high throughput and single-nucleotide resolution simultaneously.
2Productivity
If nanopore arrays are fabricated to improve productivity, then device complexity increases making manufacturing more difficult
Solution Approach 1:
The patent combines multiple functional elements (nanopores, fluidic regions, resistive openings, and electronic circuitry) into an integrated device structure. By merging these components into a unified array architecture, the device achieves high throughput while simplifying manufacturing through standardized fabrication processes that can be scaled.
Solution Approach 2:
The device utilizes parameter changes in the resistive openings (controlled resistance values) to optimize performance across different nanopore configurations. By adjusting these electrical parameters during fabrication, the device can be tuned for optimal signal-to-noise ratio and crosstalk suppression without requiring complex structural modifications, easing manufacturing.
3Productivity
If high-speed sequencing is implemented to improve productivity, then sequencing speed increases but measurement precision at single-nucleotide resolution deteriorates
Solution Approach 1:
The sequencing process utilizes periodic translocation of DNA molecules through the nanopores, with each nanopore sequentially analyzing nucleotides as they pass through. This periodic action allows high-speed processing while maintaining precision by ensuring that each nucleotide is measured at optimal detection conditions before moving to the next position.
Solution Approach 2:
The device replaces traditional mechanical sequencing methods with electrical measurement through nanopores. By using ionic current modulation detected by electrodes, the system achieves both high speed and single-nucleotide resolution without mechanical limitations, as electrical signals can be processed rapidly with high precision.
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 solution enables accurate and reliable high-speed sequencing of nucleic acids by reducing cross-talk between nanopores and allowing for the precise determination of polymer sequences, improving the resolution and efficiency of DNA and RNA sequencing.
Implementation Method 1
The signal can, for example, be detected as a modulation of the ionic current by the passage of a DNA molecule through the nanopore
Implementation Method 2
each upper fluidic region is fluidically connected through an upper resistive opening to an upper liquid volume
Data Source
AI summary
The invention relates to methods for nanopore sequencing. A substrate such as a semiconductor is provided having a nanopore or an array of nanopores connecting an upper solution with a lower solution. A polymerase-nucleic acid complex comprising a strand displacing DNA polymerase and a circular nucleic acid template and components required for DNA synthesis are provided. The polymerase produces a nascent DNA strand complementary to the circular nucleic acid template and this nascent strand is translocated through the nanopore while it is being produced by a polymerase-nucleic acid complex comprising a strand displacing DNA polymerase and a circular nucleic acid template and providing the components required for DNA synthesis whereby the polymerase produces a nascent DNA strand which is translocated through the nanopore while the nascent DNA strand is being produced. The sequence of the nascent DNA strand is determined while it translates through the pore using the measured current over time. The polymerase proceeds around the circular template and continues to produce the nascent DNA strand such that a sequence in the nascent strand corresponding a sequence in the circular template is determined more than once. Determining the sequence of corresponding to the circular template more than once can provide for greater accuracy.