Spatial Tissue Sampling With DNA Barcoding for Single-Cell Mapping
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Solution Overview
Problem
Current methods for preparing single cells and nuclei from solid tissues are laborious, require skilled technicians, and often lead to variability in quality and gene expression changes, limiting scalability and integration with downstream Next Generation Sequencing (NGS) analysis.
Innovation Solution
A Spatial Sequencing system that automates the processing of solid tissues into single cells or nuclei with spatial registration, using a disposable cartridge and encoding biomolecules with DNA barcodes or mass tags to preserve spatial information, compatible with existing NGS infrastructure.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Extent of automation
If manual methods are used to prepare single cells and nuclei from solid tissues, then processing can be performed with existing equipment, but the process is laborious and requires skilled technicians
Solution Approach 1:
The patent introduces an intermediary automated processing system that mediates between the tissue sample and the analysis equipment. This system includes automated tissue sectioning, cell dissociation, and spatial encoding modules that handle the complex processing steps without requiring skilled technicians, thereby resolving the contradiction between automation and system complexity by providing a turnkey solution.
Solution Approach 2:
The patent employs disposable cartridges containing pre-loaded reagents and processing components. These single-use cartridges eliminate the need for complex cleaning and preparation procedures, reducing the operational complexity while maintaining high automation. The disposable nature ensures consistent quality without requiring skilled technicians for setup and maintenance.
2Reliability
If manual processing methods are used, then equipment requirements are minimal, but quality variability and gene expression changes occur
Solution Approach 1:
The patent implements preliminary action by pre-programming the automated processing parameters and pre-loading reagents into disposable cartridges before sample processing. This ensures that each processing step is performed with optimal, pre-determined conditions, eliminating variability introduced by manual operations. The system maintains reliability while managing complexity through standardized pre-prepared protocols.
Solution Approach 2:
The patent incorporates feedback mechanisms through quality control sensors and real-time monitoring during the automated processing steps. The system automatically adjusts parameters to maintain consistent quality output, and provides feedback on sample integrity and gene expression preservation. This feedback loop ensures reliable, repeatable results while the automation handles the complexity of maintaining these standards.
3Loss of information
If spatial information is not encoded, then processing steps are simpler, but spatial relationships between cells are lost
Solution Approach 1:
The patent replaces complex mechanical tracking systems with a molecular encoding approach. Instead of using mechanical coordinates or imaging systems to track spatial position, the system uses DNA barcodes or mass tags that are chemically attached to cells at their original spatial locations. This substitution dramatically simplifies the overall system complexity while perfectly preserving spatial information through the molecular tags.
Solution Approach 2:
The patent transitions from three-dimensional spatial coordinates to a one-dimensional molecular sequence dimension for encoding spatial information. By converting physical position data into DNA barcode sequences or mass tag patterns, the system preserves spatial relationships in a format that is easily stored, processed, and analyzed by existing sequencing infrastructure, reducing complexity while maintaining information fidelity.
4Productivity
If high-throughput processing is implemented, then productivity increases, but integration with downstream NGS analysis becomes more difficult
Solution Approach 1:
The patent designs the automated processing system with universal output formats that are compatible with multiple downstream analysis platforms including NGS, mass spectrometry, and other high-throughput technologies. The spatial encoding using DNA barcodes serves multiple functions: preserving spatial information, enabling high-throughput processing, and ensuring compatibility with existing sequencing workflows. This multi-functionality resolves the contradiction by making the system universally integrable without increasing complexity.
Data Source
AI summary
Provided herein is a system comprising: a) spatial sampler system configured to collect and transmit one or a plurality of cells or nuclei from a tissue specimen, the system comprising: i) a lower carrier having an array of conduits passing therethrough, each conduit comprising an opening on a first side and communicating with an opening on a second side, wherein the opening on the second side either (1) terminates in a capillary or (2) opens onto a well of a multiwell plate; ii) positioned, above the lower carrier, a perforated specimen holder configured to support a frozen tissue specimen, wherein the specimen holder comprises a plurality of perforations having a size sufficient to permit the passage of single cells or nuclei; and iii) positioned, above the specimen holder, a multifunctional head comprising an upper array of upper conduits, optionally, each aligned with a conduit opening of the lower carrier.