Spatial Barcode Sequencing for Cellular Resolution
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Solution Overview
Problem
Current methods for assessing spatial heterogeneity in biological tissues struggle to provide spatially resolved measurements at cellular and sub-cellular resolution, failing to correlate analyte data with specific spatial locations within a biological sample.
Innovation Solution
The method involves a spatial array with features having spatial barcodes, where sequencing probes with labels are hybridized to determine the sequence of the barcode, allowing features to be associated with specific locations, enabling the correlation of analyte data with spatial positions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If spatially resolved measurements are performed to assess spatial heterogeneity, then measurement precision is improved, but device complexity increases due to the difficulty of correlating captured analytes with specific spatial locations
Solution Approach 1:
The spatial barcode is divided into multiple segments, each recognized by a different sequencing probe. Each probe binds to a specific segment of the barcode and carries a label indicating its binding position. This segmentation allows the complex task of spatial correlation to be broken down into simpler, parallel probe-binding operations, reducing overall system complexity while maintaining high spatial resolution.
Solution Approach 2:
Sequencing probes act as intermediaries between the spatial barcodes on the substrate and the detection system. Each probe carries information about its binding location through its label, serving as a mediator that translates spatial position into detectable signal. This intermediary approach simplifies the correlation process by decoupling the spatial encoding from the direct detection mechanism.
2Measurement precision
If multiple sequencing probes are used to determine the complete spatial barcode sequence, then measurement precision is improved, but the number of operation steps increases
Solution Approach 1:
Multiple sequencing probes that recognize different segments of the spatial barcode are combined in a single hybridization reaction mixture. All probes simultaneously bind to their respective target segments on the barcodes during one incubation step. This merging of multiple sequencing operations into a single parallel reaction dramatically reduces the total time required while maintaining complete sequence accuracy.
Solution Approach 2:
The sequencing process maintains continuity by having all sequencing probes active and binding simultaneously in a single continuous hybridization step, rather than sequentially processing each probe separately. This continuous parallel action eliminates idle time between probing operations while ensuring complete barcode sequence determination.
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 allows for the precise determination of analyte locations within a biological sample, providing detailed spatial information on analyte distribution and function, enhancing the understanding of tissue morphology and behavior.
Implementation Method 1
hybridizing a first sequencing probe to the spatial barcode, where the first sequencing probe has a first label and a first nucleotide sequence
Data Source
AI summary
Methods for determining a location of a feature in a spatial array of features include: providing a spatial array including a plurality of features on a substrate, where a feature of the plurality of features has a capture probe, and where the capture probe has a spatial barcode and a constant sequence; hybridizing a first sequencing probe to the spatial barcode, where the first sequencing probe has a first label and a first nucleotide sequence; obtaining a first image of the first label with the first sequencing probe hybridized to the spatial barcode; determining, based on the first image, a first portion of a sequence of the spatial barcode; and associating the feature with a location in the spatial array based on a location of the first label in the first image.