Densely packed analyte layers for sub-diffraction sequencing
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Solution Overview
Problem
Current sequencing technologies face challenges in achieving high-density DNA packing on biochips due to the diffraction limit of optical signals, limiting cost reduction and efficiency in sequencing, especially for applications like large population sequencing and single-cell analysis.
Innovation Solution
The method involves densely packing DNA molecules on a substrate with a minimum effective pitch below the diffraction limit, using super-resolution imaging and advanced optical distribution models to resolve optical signals, allowing for 100-fold increase in data per unit area and 100-fold reduction in reagent usage, enabling sub-diffraction limited imaging and accurate analyte detection.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If DNA molecules are densely packed on a biochip to increase data per unit area, then sequencing cost is reduced, but optical signals from densely packed molecules cannot be resolved due to the diffraction limit of light
Solution Approach 1:
The patent changes the physical parameters of the optical system by using super-resolution imaging techniques that achieve resolution beyond the conventional diffraction limit. This allows densely packed DNA molecules to be imaged with sufficient separation to resolve individual optical signals, thereby enabling high-density packing without sacrificing measurement precision.
Solution Approach 2:
The patent replaces conventional optical imaging systems with super-resolution imaging systems that use advanced optical distribution models and computational methods to resolve signals from densely packed molecules. This substitution enables the system to overcome the physical diffraction limit and achieve the required resolution at high densities.
2Device complexity
If conventional optical imaging is used to sequence DNA molecules, then the system is simpler and lower cost, but the diffraction limit prevents high-density packing and 100-fold cost reduction
Solution Approach 1:
The patent changes the resolution parameter of the imaging system by implementing super-resolution techniques. This allows the system to achieve 100-fold increase in data per unit area while managing complexity through the use of advanced optical distribution models and computational resolution methods.
3Measurement precision
If DNA molecules are spaced at larger pitch to ensure optical signal resolution, then imaging is easier, but the amount of data per chip unit area decreases, preventing 100-fold cost reduction
Solution Approach 1:
The patent changes the effective pitch parameter by using super-resolution imaging that can resolve signals at much smaller separations than the conventional diffraction limit. This allows DNA molecules to be packed at high density (100-fold increase) while maintaining sufficient signal resolution through advanced optical distribution modeling and computational methods.
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 significantly reduces sequencing costs, enabling the economical sequencing of every newborn and facilitating deep sequencing and single-cell analysis by increasing data density and reducing reagent consumption, thereby achieving a $10 genome price point.
Implementation Method 1
The method comprises providing a substrate comprising a surface, wherein the surface comprises a plurality of analytes disposed on the surface... performing a plurality of cycles of probe binding to the plurality of analytes... imaging a field of the surface with an optical system to detect an optical signal from each probe
Data Source
AI summary
Disclosed herein are methods and systems for detection and discrimination of optical signals from a densely packed substrate. These have broad applications for biomolecule detection near or below the diffraction limit of optical systems, including in improving the efficiency and accuracy of polynucleotide sequencing applications.