Nanotrain Single-Molecule Detection via Nanopore Current Modulation
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Solution Overview
Problem
Current methods for multiplexed detection of biomarkers, such as microarrays and nanopore technologies, face limitations in sensitivity, specificity, and cost, particularly in clinical diagnostics, as they often rely on ensemble-average signal readouts and require trained personnel, and are inefficient for charged molecules without uniform charge distribution.
Innovation Solution
A one-dimensional water-soluble nanoarray, or nanotrain, composed of single-stranded DNA carriages with unique sequences, flexible linkers, and affinity molecules, which translocates through a nanopore to detect multiplexed protein markers and other targets by causing ionic current fluctuations, allowing for single-molecule detection and analysis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If nanopore technology is used for single-molecule detection, then detection sensitivity is improved, but the method becomes inefficient for charged molecules without uniform charge distribution
Solution Approach 1:
The patent introduces a carrier molecule as an intermediary that binds to uncharged or poorly charged analytes and delivers them to the nanopore. This carrier acts as a mediator that enables detection of molecules that would otherwise be inefficient at translocating through the nanopore on their own, thus resolving the contradiction between high detection sensitivity and efficiency for charged molecules.
Solution Approach 2:
The detection system is segmented into functional components: the nanopore sensor, the carrier molecule, and the analyte. This segmentation allows each component to be optimized independently - the nanopore for sensitivity, the carrier for interaction with diverse analytes including those without uniform charge distribution.
2Measurement precision
If AFM is used for single-molecule detection, then measurement precision is improved, but the cost and time increase and require well-trained personnel
Solution Approach 1:
The patent replaces the mechanical scanning probe microscopy (AFM) system with an electrochemical nanopore detection system. This substitution eliminates the need for complex mechanical scanning, trained personnel operation, and expensive equipment maintenance, while maintaining single-molecule detection precision through electrical signal measurement.
Solution Approach 2:
The nanopore detection system performs self-service through automated signal acquisition and analysis. The system automatically detects molecular translocation events through ionic current modulation, eliminating the need for manual operation and interpretation required by AFM, thus reducing cost and time while maintaining precision.
3Productivity
If microarrays are used for multiplexed detection, then productivity is improved, but signal readout relies on ensemble-average level reducing detection precision
Solution Approach 1:
The patent segments the detection approach into single-molecule events rather than ensemble averages. Each molecular binding event is detected as an individual translocation through the nanopore, allowing precise measurement of individual molecule properties while maintaining the ability to detect multiple molecules through multiplexed carrier molecules.
Solution Approach 2:
The patent changes the detection parameter from ensemble-average signal intensity to single-molecule translocation timing and current modulation. This parameter change enables both high productivity through multiplexed detection and high precision through single-event analysis, as each molecule's translocation provides a discrete, measurable signal.
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 nanotrain system enables high-throughput, sensitive, and specific detection of biomarkers and other molecules by recording current fluctuations, improving diagnostic accuracy and reducing costs compared to existing technologies.
Implementation Method 1
When a charged molecule is driven to pass through the nanopore electrophoretically, it modulates the ionic current by partially obstructing ionic flow.
Implementation Method 2
it modulates the ionic current by partially obstructing ionic flow. As a result, the current blockade signals are recorded
Implementation Method 3
the current blockade signals are recorded and are used to identify the molecule and even its structural subunits
Data Source
AI summary
Provided herein, in one aspect, is an improved nanotrain for use in connection with a nanopore device for single-molecule detection. Methods for making and using the same are also provided.