3D Nucleic Acid Matrix for Spatial Sequencing
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Solution Overview
Problem
Current methods for analyzing nucleic acids require extraction from their native environment, which disrupts their spatial orientation and makes it impossible to identify their cellular origin.
Innovation Solution
A three-dimensional matrix of nucleic acids is created by covalently binding nucleic acids to a matrix material, allowing for in situ amplification and sequencing while preserving the spatial orientation of the nucleic acids.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If nucleic acids are extracted from their native environment for analysis, then amplification and sequencing can be performed, but spatial orientation and cellular origin information are lost
Solution Approach 1:
The patent transitions from traditional two-dimensional flat arrays to a three-dimensional matrix structure. Nucleic acids are covalently bound within a 3D matrix material, preserving their spatial coordinates (x, y, z) while enabling in situ amplification and sequencing. This dimensional change allows simultaneous preservation of spatial information and maintenance of analytical capabilities.
Solution Approach 2:
The patent introduces a matrix material as an intermediary between the nucleic acids and the sequencing process. This matrix serves as both a structural support that preserves spatial orientation and a medium that allows diffusion of reagents for amplification and sequencing reactions, resolving the contradiction between preserving spatial information and enabling analytical processing.
2Productivity
If nucleic acids are placed on a flat array surface or beads, then high-throughput sequencing is enabled, but three-dimensional spatial information is lost
Solution Approach 1:
The patent explicitly moves from 2D flat arrays to 3D matrix structures. The matrix material creates a three-dimensional environment where nucleic acids maintain their x, y, z spatial coordinates while still allowing high-throughput sequencing through in situ amplification and reagent diffusion, thus preserving spatial information without sacrificing productivity.
Solution Approach 2:
The matrix material is designed with porous or mesh-like structures that allow diffusion of amplification reagents and sequencing chemicals throughout the 3D structure. This porosity enables high-throughput processing while maintaining the three-dimensional spatial arrangement of nucleic acids, preventing information loss.
3Reliability
If nucleic acids are covalently bound to a matrix material, then spatial orientation is preserved, but accessibility for amplification and sequencing may be reduced
Solution Approach 1:
The matrix material employs a porous or mesh-like structure with controlled pore sizes that balance two competing requirements: maintaining the three-dimensional spatial arrangement of nucleic acids while allowing sufficient diffusion of amplification reagents and sequencing chemicals. The porosity ensures reagent accessibility without compromising spatial orientation preservation.
Solution Approach 2:
The matrix material exhibits local variations in density and porosity to optimize different functions in different regions. Areas with nucleic acids have appropriate porosity for reagent access, while maintaining overall 3D spatial structure. This local optimization resolves the contradiction between reliability of spatial preservation and ease of operation for amplification.
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 method enables the preservation and analysis of nucleic acid spatial information within cells or tissues, allowing for high-throughput sequencing and prolonged information storage with minimal degradation.
Implementation Method 1
nucleic acids covalently bound into a matrix or into or to a matrix material
Implementation Method 2
The nucleic acids may be co-polymerized with the matrix material
Implementation Method 3
The nucleic acids may then be amplified and sequenced in situ, i.e. within the matrix
Implementation Method 4
Each of the plurality of nucleic acids includes a fluorescent label
Data Source
AI summary
Methods of selectively sequencing amplicons in a biological sample are provided.