Nanofluidic Polymer Sequencing With SERS Signal Enhancement
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Solution Overview
Problem
Current DNA sequencing technologies face challenges in achieving long reads without amplification, accurately identifying epigenetic variations, and providing spatial resolution at the molecular scale, particularly due to limitations in Raman scattering techniques.
Innovation Solution
Incorporating engineered SERS enhancement structures into nanochannels within a nanofluidic chip to enhance Raman scattering signals, controlling polymer motion with electric fields, and using porous materials to manage velocity, allowing for single nucleotide sensitivity and spatial resolution.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If traditional Raman scattering is performed on bulk samples, then the signal is sufficient for detection, but the spatial resolution is limited by diffraction and much larger than individual nucleotides
Solution Approach 1:
The patent introduces SERS enhancement structures (metallic nanostructures) that create localized regions of enhanced electromagnetic fields at specific positions where nucleotides pass through. This local field enhancement provides both the necessary signal amplification and the spatial resolution to distinguish individual nucleotides, resolving the contradiction between signal strength and spatial resolution.
2Measurement precision
If template amplification is performed to improve sequencing signal, then detection sensitivity is enhanced, but copying errors, sequence dependent biases, information loss and added time and complexity occur
Solution Approach 1:
The patent enables direct detection of native DNA molecules through SERS without requiring template amplification. The enhanced Raman scattering signal from individual nucleotides provides sufficient detection sensitivity, allowing the system to 'self-service' by directly reading the native DNA sequence and epigenetic modifications without introducing amplification-related errors or information loss.
3Reliability
If native DNA sequencing without amplification is implemented, then epigenetic information is preserved, but the signal from individual nucleotides is too weak for detection
Solution Approach 1:
The patent changes the physical parameters of the detection system by introducing metallic nanostructures that dramatically enhance the local electromagnetic field strength. This parameter change in field intensity (by 10- to 1000-times) enables detection of the inherently weak Raman signal from individual nucleotides in native DNA, preserving epigenetic information while overcoming signal weakness.
4Productivity
If long reads are pursued to reduce sequencing complexity, then fewer reads are needed for reconstruction, but maintaining single nucleotide accuracy over long distances becomes more difficult
Solution Approach 1:
The patent enables continuous, real-time detection of nucleotides as they pass through the SERS enhancement region. The polymerase synthesizes DNA continuously while the SERS signal is continuously monitored, providing uninterrupted detection over long read lengths while maintaining single nucleotide accuracy through the persistent field enhancement effect.
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
Enables accurate, long-read sequencing of DNA with epigenetic information without amplification, achieving high throughput and single nucleotide sensitivity through surface-enhanced Raman scattering.
Implementation Method 1
Surface-enhanced Raman scattering (SERS) eases these problems. SERS is a local 'antenna' effect that 1) provides large enhancements (109 to 1011); and 2) dramatically improves spatial resolution as a result of near-field effects associated with metallic nanostructures.
Implementation Method 2
In some embodiments, low frequency (dc to ̃GHz) electric fields are applied along the channel structure (i.e., longitudinally) to assist in stretching the polymer in the nanochannels and to control the movement of (e.g., advance or reverse) the polymer past the ES.
Implementation Method 3
The apparatus comprises: a source laser; a dichroic beam splitter for separating the reflected pump laser beam and the Raman signals
Data Source
AI summary
The systems disclosed herein may a nanoscale chip. The chip includes a nanochannel with two nanoscale transverse dimensions and a SERS enhancement structure therein, alignment marks for enabling positioning of a laser excitation beam onto the enhancement structure, and a structural element for controlling the positioning of a polymer within the nanofluidic chip relative to the enhancement structure. The system may further comprise a reader for analyzing polymers on the chip. The disclosure also relates to methods of fabricating the chip and sequencing a polymer using the chip and reader.