Extended Branched Oligonucleotide Probes for Spatial Transcriptomics
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Solution Overview
Problem
Conventional spatial transcriptomics systems face challenges in capturing biological analytes located deep within tissue samples due to limited probe extension and probe density, leading to reduced resolution and inefficient analyte capture.
Innovation Solution
The development of extended and branched oligonucleotide capture probe assemblies that extend into the tissue sample and increase probe density, allowing for more efficient analyte capture by extending the reach of capture probes and increasing the density of capture domains within the tissue section.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Length of moving object
If conventional planar oligonucleotide arrays are used, then the system structure is simple and easy to manufacture, but the probe extension into tissue is limited and probe density is insufficient
Solution Approach 1:
The patent transitions from a conventional two-dimensional planar array to a three-dimensional extended probe assembly structure. The probe assembly includes a support with capture probes extending outward into the tissue sample, creating vertical depth dimension. This dimensional change allows probes to reach analytes located deeper within the tissue section, directly addressing the limitation of insufficient probe extension depth while accepting increased structural complexity.
Solution Approach 2:
The probe assembly employs a nested structure where multiple components are organized hierarchically: the support structure contains multiple probes, each probe contains a capture domain, and the entire assembly is positioned within the tissue sample context. This nested organization allows the system to maintain manageable complexity while achieving extended reach and increased probe density through systematic arrangement of nested elements.
2Productivity
If conventional planar arrays with limited probe density are used, then the manufacturing process is simpler, but the analyte capture efficiency is reduced
Solution Approach 1:
The probe assembly is segmented into multiple functional components: a support structure, multiple capture probes with distinct capture domains, and organizational frameworks. This segmentation allows for modular manufacturing where each component can be prepared separately and then assembled, improving analyte capture efficiency through higher probe density while managing fabrication complexity through standardized modular units.
Solution Approach 2:
The probe assembly utilizes composite construction combining the support material with multiple probe materials, each with specific functional properties. This composite approach enables the system to achieve high probe density and improved capture efficiency while maintaining manufacturability through the use of compatible materials that can be integrated using established fabrication techniques.
3Reliability
If the distance between analyte release site and capture probe is large, then the tissue sample can be thicker, but the migration distance increases and capture probability decreases
Solution Approach 1:
The probe assembly implements local quality by positioning capture probes at specific locations and orientations within the tissue sample. Each probe is strategically positioned to capture analytes in its local vicinity, creating zones of high capture probability throughout the tissue depth. This localized approach ensures that analytes released at any position within the tissue have a high probability of encountering a nearby capture probe, reducing the effective migration distance while accommodating thicker tissue samples.
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 enhances the resolution of spatial transcriptomics systems by decreasing the distance analytes need to migrate before capture and reducing the likelihood of missed analytes, thereby improving the accuracy of spatially aligned analyte expression data.
Implementation Method 1
The oligonucleotides also encode analyte-capture domains that can capture specific analytes released from the overlying cells (e.g., by hybridization of the oligonucleotide's analyte-capture domain to specific analyte mRNAs from the cells)
Data Source
AI summary
Disclosed are extended and/or branched oligonucleotide capture probe assemblies for use in spatial transcriptomics systems, and methods for making the capture probe assemblies.