Ellipsometry Monitoring for Oligonucleotide Synthesis Uniformity
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Solution Overview
Problem
Existing methods for solid-phase synthesis, particularly in photolithographic synthesis of oligonucleotides, face challenges in monitoring the quality and uniformity of each step, leading to issues like incomplete or truncated probe sequences and poor signal-to-noise ratios.
Innovation Solution
A method for real-time, in-situ, and/or in-line monitoring of solid-phase reactions using ellipsometry, which measures properties such as thickness at multiple positions on the substrate before and after each reaction step, allowing for the determination of reaction quality and uniformity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If photolithographic methods are used for oligonucleotide synthesis, then high density DNA sequences can be synthesized on the substrate, but truncated probe sequences are generated which deteriorate array performance
Solution Approach 1:
The patent applies preliminary action by performing quality monitoring of each synthesis step before proceeding to the next step. The system measures properties such as thickness at multiple positions on the substrate before and after each reaction step, determining reaction quality and uniformity in real-time. This allows incomplete reactions to be detected and corrected early, preventing the formation of truncated probe sequences that would otherwise compromise the entire synthesis batch.
2Manufacturing precision
If quality monitoring is performed at each step of solid-phase synthesis, then synthesis quality and uniformity improve, but measurement and detection complexity increases
Solution Approach 1:
The patent replaces complex chemical analysis methods with optical measurement techniques. By using ellipsometry to measure thickness changes on the substrate surface, the system can non-invasively and rapidly assess reaction progress and uniformity without requiring complex sample preparation or chemical analysis. This substitution of mechanical/optical measurement for chemical analysis simplifies the detection process while maintaining high measurement precision.
3Reliability
If real-time monitoring is implemented during solid-phase synthesis, then synthesis issues can be detected early saving labor and cost, but device complexity increases
Solution Approach 1:
The patent applies universality by designing a monitoring system that can assess multiple synthesis parameters simultaneously using a single measurement approach. The ellipsometry-based system measures thickness changes that reflect reaction completeness, uniformity, and quality all at once, eliminating the need for multiple separate monitoring devices or complex assay procedures. This multi-functional approach achieves comprehensive quality control while minimizing device complexity.
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 enables precise monitoring of each step in solid-phase synthesis, improving the yield and uniformity of synthesized molecules, and allowing for early detection of synthesis issues, thus reducing labor and costs.
Implementation Method 1
Taking a first measurement of a property of the surface at a plurality of positions on the surface before a first reaction on the surface; taking a second measurement of the property of the surface at the plurality of positions on the surface after the first reaction on the surface
Data Source
AI summary
The present disclosure relates to method of monitoring a solid-phase reaction on a surface of a substrate by taking measurements at a plurality of positions on the surface. Properties of the surface are determined based on the measurements taken. Based on the properties determined, the extent of the solid-phase reaction is determined. This method can be achieved by using an ellipsometer and measuring the changes in thickness of the surface before and after the solid-phase reaction.