Spatially Tagged Nuclei for Single-Cell Spatial Genomics

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Solution Overview

Problem

Current spatially-resolved genomics tools struggle with low resolution, incomplete cell capture, and limited multiplexing, especially in single-cell profiling, and require laborious methods with low spatial resolution.

Innovation Solution

A method involving spatially tagged nuclei using sequence-verified arrays with cleavable linkers and spatial barcodes, allowing for high-resolution spatial profiling by delivering spatial barcodes to nuclei in a tissue sample, followed by isolating tagged nuclei for single-cell genomics sequencing.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Measurement precision

If traditional histological approaches or in situ techniques are used for spatial monitoring, then spatial information can be obtained, but the resolution is low (approximately 100-200 μm) and the process is laborious with high technical difficulty

Engineering Contradiction:

Improvespatial resolutionVSAvoidtechnical difficulty

Core Design Contradiction:

Measurement precisionVSEase of operation

Solution Approach 1:

The patent introduces spatial barcodes as intermediary molecules that mediate between the tissue sample and the sequencing platform. These barcodes are delivered to nuclei via permeabilization and diffusion, serving as a bridge that enables high-resolution spatial mapping without requiring complex in situ sequencing or imaging procedures. This intermediary approach simplifies the workflow while achieving superior spatial resolution.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent replaces mechanical histological sectioning and staining procedures with a molecular diffusion-based barcode delivery system. Instead of physically sectioning tissue and performing manual staining, the system uses chemical permeabilization followed by passive diffusion of spatial barcodes into nuclei, thereby substituting labor-intensive mechanical operations with a simplified biochemical protocol.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

2Measurement precision

If thin tissue section inputs are used for spatially-resolved omics, then spatial information is captured, but incomplete cells/nuclei are captured leading to low capture rates

Engineering Contradiction:

Improvespatial resolutionVSAvoidcapture rate

Core Design Contradiction:

Measurement precisionVSProductivity

Solution Approach 1:

The patent performs preliminary tissue permeabilization before barcode delivery, preparing the tissue sample in advance to facilitate complete nucleus capture. By pre-permeabilizing the tissue, the system ensures that subsequent barcode delivery efficiently tags all nuclei present in the section, maximizing capture rate while maintaining spatial resolution.

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The patent changes the physical state of the tissue from intact to permeabilized, allowing spatial barcodes to diffuse into nuclei. This parameter change (permeability) enables complete nucleus capture without requiring thick sections, thereby resolving the contradiction between spatial resolution and capture rate.

Inventive Principle:

Principle #35Parameter changes

3Quantity of substance

If voxel-based spatial profiling is used, then spatial information is obtained, but multiple cells per voxel require deconvolution limiting analysis resolution

Engineering Contradiction:

Improvespatial coverageVSAvoidsingle-cell resolution

Core Design Contradiction:

Quantity of substanceVSMeasurement precision

Solution Approach 1:

The patent segments the spatial profiling process by delivering unique spatial barcodes to individual nuclei within each voxel. Instead of capturing bulk RNA from multiple cells and requiring deconvolution, each nucleus receives a distinct barcode that uniquely identifies its spatial location. This segmentation eliminates the need for computational deconvolution and enables true single-cell resolution spatial mapping.

Inventive Principle:

Principle #1Segmentation

4Adaptability or versatility

If single-combinatorial-indexing based profiling is used, then spatial information is captured, but the capture rate and spatial resolution remain low

Engineering Contradiction:

Improveprofiling capabilityVSAvoidspatial resolution

Core Design Contradiction:

Adaptability or versatilityVSMeasurement precision

Solution Approach 1:

The patent creates a universal spatial barcode delivery system that can be applied to any nucleus in any tissue type. The spatial barcodes are designed to work with standard single-nuclei sequencing workflows, making the approach universally applicable across different tissue types and sequencing platforms. This universality enables high capture rates and spatial resolution without requiring tissue-specific optimizations.

Inventive Principle:

Principle #6Universality (Multi-functionality)

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

Enables high-resolution spatial genomics with improved capture rates and single-cell resolution, facilitating multiomic studies without the need for multiple experiments, and unifying spatial profiling with single-cell sequencing.

Implementation Method 1

the spatial barcodes are delivered to the nuclei by diffusion

Methodology Applied

Scientific EffectDiffusion: Diffusion

Data Source

PatentUS20250340864A1Single-nucleus high-resolution multi-modal spatial genomics

Publication Date: 2025.11.06 THE BROAD INST INC

AI summary

Embodiments disclosed herein provide for spatially tagged nuclei that are compatible with any genomic or multiomic single cell/nuclei assay to allow generation of a spatially resolved single cell sequencing library with single cell resolution.