Nanonozzle Arrays for Single-Molecule Sequencing
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Solution Overview
Problem
Current technologies for DNA and RNA sequencing are expensive and inefficient, particularly for large-scale genomic analysis, and struggle to achieve true single-molecule sequencing of long biological polymers due to limitations in nanopore design and integration with semiconductor processes.
Innovation Solution
The development of nanochannels with constrictions that physically constrain and linearize macromolecules, allowing for their transportation and analysis by monitoring signals as they pass through the constriction, enabling the characterization of features such as sequence and epigenetic markers.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If biological nanopores are used for sequencing, then single-molecule sequencing capability is achieved, but sensitivity to pH, temperature and electric fields limits reliability
Solution Approach 1:
The patent replaces sensitive biological nanopores with durable solid-state nanopores fabricated from semiconductor materials. The solid-state nanopores are integrated with on-chip electronics and can be mass-produced using standard semiconductor fabrication processes, providing a stable, reusable alternative to disposable biological pores while maintaining single-molecule sequencing capability.
Solution Approach 2:
The patent substitutes biological systems with solid-state mechanical structures. The biological nanopore is replaced by a solid-state nanopore formed in a semiconductor membrane, eliminating sensitivity to pH, temperature, and electric fields while preserving the core function of detecting single-molecule translocation through ionic current measurements.
2Ease of manufacture
If solid state nanopores are fabricated, then integration with semiconductor processes is achieved, but only pores in membranes are produced not longer channels needed for long polymers
Solution Approach 1:
The patent creates a nested structure where a long nanochannel is formed within the bulk semiconductor material, and a shorter nanopore opening is created at the surface. The nanochannel extends deep into the substrate, providing sufficient length for long polymer translocation, while the nanopore opening remains accessible for sample introduction. This nested configuration allows integration with semiconductor processes while achieving the required channel length.
Solution Approach 2:
The patent transitions from two-dimensional membrane pores to three-dimensional bulk nanochannels. By etching channels into the depth of the semiconductor substrate rather than merely through a thin membrane, the patent achieves long channel lengths compatible with long polymer sequencing while maintaining compatibility with standard semiconductor fabrication techniques.
3Loss of information
If extensive sequencing coverage is performed, then genomic analysis capability is improved, but cost remains too expensive for large population analysis
Solution Approach 1:
The patent divides the sequencing task into independent parallel operations by integrating multiple nanopore sensors on a single chip. Each nanopore can independently sequence individual DNA molecules simultaneously, enabling high-throughput parallel sequencing. This segmentation of the sequencing function across multiple sensors dramatically increases throughput and reduces the cost per genome by enabling analysis of many samples in parallel rather than sequentially.
Solution Approach 2:
The patent creates a universal sequencing platform that can analyze various types of nucleic acid samples (genomic DNA, RNA, etc.) using the same solid-state nanopore device. The platform is designed to handle diverse sequencing applications and sample types, making it suitable for large-scale population studies across different genomic analyses without requiring specialized equipment for each application.
4Stability of the object's composition
If macromolecules are analyzed in native state, then biological relevance is maintained, but macromolecules tend to collapse into random coils not suitable for sequencing
Solution Approach 1:
The patent applies preliminary linearizing forces to macromolecules before they enter the nanopore. Electric fields or other forces are applied to extend and linearize the macromolecules in advance of their translocation through the nanopore. This preliminary action ensures that the macromolecules are in the appropriate linear conformation for sequencing while minimizing the time they spend in the folded state, thereby maintaining biological relevance during the actual sequencing process.
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 cost-effective, high-throughput analysis of long biological polymers like DNA and RNA, facilitating rapid determination of genomic and epigenomic information, even from small sample amounts, thereby advancing disease monitoring and understanding.
Implementation Method 1
at least a portion of the nanochannel being capable of physically constraining at least a portion of the macromolecule so as to maintain in linear form that portion of the macromolecule
Implementation Method 2
applying a gradient to the macromolecule, the gradient giving rise to at least a portion of the linearized macromolecule being transported within at least a portion of the nanochannel
Implementation Method 3
monitoring at least one signal arising in connection with the macromolecule passing through the constriction; and correlating the at least one signal to one or more features of the macromolecule
Data Source
Figure 1(a)~1(c)
Figure 2(a)~2(c)
Figure 3(a)~3(c)
AI summary
Constricted nanochannel devices suitable for use in analysis of macromolecular structure, including DNA sequencing, are disclosed. Also disclosed are methods for fabricating such devices and for analyzing macromolecules using such devices.