Nanopore Sequencing with Plasmonic Structures for Single Base Resolution
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Solution Overview
Problem
Current sequencing technologies struggle to completely sequence a human genome due to limitations in read length, phase insensitivity, and the inability to resolve complex structural variants and repetitive regions, which hinders the identification of haplotypes and their association with diseases.
Innovation Solution
The development of long read, label-free, optical nanopore sequencing technology using nanochannels with tortuous nanopores and engineered plasmonic/polaritonic structures for single base resolution, enabling massively parallel sequencing without the need for labeling.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If short read sequencing technologies are used, then sequencing coverage can be achieved, but the ability to resolve repetitive regions and complex structural variants is lost
Solution Approach 1:
The patent replaces traditional mechanical/optical detection systems with nanopore-based detection. DNA molecules pass through nanopores, and changes in ionic current are measured to detect base sequences. This substitution enables long-read sequencing capability while maintaining sequencing coverage, resolving the contradiction between read length and sequencing effectiveness.
2Measurement precision
If reference genome-based assembly is used, then assembly quality improves, but the ability to perform de novo assembly and identify novel variants is reduced
Solution Approach 1:
The patent changes the fundamental parameter of read length from short (100-300 bp) to long (kilobase to megabase scale). This parameter change enables both high-quality reference-based assembly and robust de novo assembly, as well as the detection of novel structural variants that cannot be identified with short reads alone.
3Quantity of substance
If current sequencing technologies are used, then cost has decreased, but complete genome sequencing including all polymorphisms and structural variants remains impossible
Solution Approach 1:
The patent segments the genome into individual DNA molecules that are sequenced independently as they pass through nanopores. This segmentation approach, combined with long-read capability, allows complete genome sequencing including all polymorphisms and structural variants at reduced cost, as each molecule provides information about its entire length without requiring complex assembly of many short reads.
4Ease of operation
If haplotype information is not resolved, then sequencing simplicity is maintained, but the ability to assign polymorphisms to specific chromosomes and determine cis/trans relationships is lost
Solution Approach 1:
The patent maintains continuous sequencing of long DNA molecules that span multiple polymorphic sites and extend across chromosome boundaries. This continuity preserves haplotype information and enables determination of cis/trans relationships while maintaining operational simplicity through direct nanopore detection without requiring additional processing steps.
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 technology achieves single base resolution and long read lengths, allowing for the sequencing of a full human genome in under a day at a cost of approximately $100, while providing the necessary spatial localization for accurate haplotype determination.
Implementation Method 1
nanochannels to deliver single long-chain molecules with widely spaced (>wavelength), ∼1-nm aperture 'tortuous' nanopores that slow translocation sufficiently
Implementation Method 2
engineered plasmonic/polaritonic structures allow for single base resolution using optical techniques
Implementation Method 3
Surface Enhanced Coherent Anti-Stokes Raman Spectroscopy (SECARS) is one such technique
Data Source
AI summary
Methods and apparatus for long read, label-free, optical nanopore long chain molecule sequencing. In general, the present disclosure describes a novel sequencing technology based on the integration of nanochannels to deliver single long-chain molecules with widely spaced (>wavelength), ˜1-nm aperture “tortuous” nanopores that slow translocation sufficiently to provide massively parallel, single base resolution using optical techniques. A novel, directed self-assembly nanofabrication scheme using simple colloidal nanoparticles is used to form the nanopore arrays atop nanochannels that unfold the long chain molecules. At the surface of the nanoparticle array, strongly localized electromagnetic fields in engineered plasmonic/polaritonic structures allow for single base resolution using optical techniques.