In-Situ Spatial Transcriptomics with 2 μm Resolution Barcoding
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Solution Overview
Problem
Current spatial transcriptomics technologies lack the resolution and detail needed to fully understand complex tissues like the central nervous system, as they primarily analyze large morphological features, missing the nuanced molecular dynamics across spatial areas.
Innovation Solution
The method involves depositing spatial barcodes on a solid substrate, capturing cells with these barcodes, and linking them to specific positions, allowing for high-density spatial transcriptomics with 2 μm resolution, enabling detailed 2D transcriptome profiling and cell typing by correlating molecular profiles with morphological entities.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If spatial transcriptomics is performed using conventional methods with large morphological features, then the analysis covers broad tissue areas, but the resolution and detail of molecular dynamics are insufficient
Solution Approach 1:
The tissue section is divided into multiple discrete spots or regions, each with its own spatial barcode. This segmentation allows high-resolution analysis of individual locations while collectively covering the entire tissue area through systematic sampling across the tissue surface.
Solution Approach 2:
The patent introduces a third dimension (depth or layering) by using multiple layers of barcoded beads or by varying the vertical positioning of capture molecules. This dimensional expansion enables high-resolution spatial transcriptomics without sacrificing tissue coverage, as different layers can be multiplexed to increase effective resolution.
2Loss of information
If single-cell transcriptomics is performed on dissociated cells, then high-throughput molecular profiling is achieved, but spatial information and morphological context are lost
Solution Approach 1:
The patent creates a spatial map by capturing and sequencing mRNA molecules that are physically copied along with their spatial barcode information. This copying approach preserves spatial context while enabling high-throughput sequencing, as the barcode-mRNA complexes can be amplified and sequenced in parallel without requiring physical manipulation of cells.
Solution Approach 2:
The spatial barcode system serves multiple functions simultaneously: it provides spatial location information, enables molecular capture, and facilitates high-throughput sequencing. This multi-functionality allows the system to maintain spatial information while achieving high productivity through a single integrated platform.
3Measurement precision
If 100 μm features are used for spatial transcriptomics, then large morphological features can be analyzed, but only 80% of tissue dynamics are captured
Solution Approach 1:
The patent employs nested barcoding strategies where multiple levels of spatial information are encoded within hierarchical barcode structures. This nesting allows dense spatial resolution without proportionally increasing overall system complexity, as the hierarchical structure enables efficient decoding and data management.
Solution Approach 2:
The patent varies key parameters including barcode length, bead size, and spot density to optimize the balance between resolution and complexity. By adjusting these parameters systematically, the system achieves high tissue dynamics resolution while managing device complexity through standardized modular designs.
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 provides a more detailed understanding of tissue dynamics and cellular identity by linking molecular profiles with spatial positions, enhancing the resolution and accuracy of cell classification and gene signature identification.
Implementation Method 1
capturing material from one or more cells of the plurality of cells with the capture molecule of the spatial barcode, thereby linking the capture material from the one or more cells with the spatial barcode
Data Source
AI summary
The present disclosure relates to systems and method of in-situ tissue profiling. Methods for spatiotemporal processing of a sample, capturing molecules of interest, and correlating cells in the sample to the capture molecules are provided.