Nucleic Acid Sequencer Optical Mask for Extended Depth of Field
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Solution Overview
Problem
Existing nucleic acid sequencers face challenges in maintaining focus accuracy due to the degradation of the point spread function (PSF) with defocus, which affects noise ratio and overall imaging quality, limiting throughput and increasing costs.
Innovation Solution
Implementing a nucleic acid sequencer with a detection system that includes an objective lens and a mask, such as a phase or amplitude mask, to extend the depth of field by optimizing the mask using iterative optimization steps based on discrepancies between actual and ideal PSFs, and updating the mask to improve focus across multiple surfaces and wavelengths.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If a high numerical aperture objective lens is used to improve signal to noise ratio, then imaging quality improves, but depth of field decreases
Solution Approach 1:
A mask is introduced as an intermediary element in the optical path between the objective lens and the detection pixels. This mask modifies the point spread function to extend depth of field while preserving the high numerical aperture benefits for signal to noise ratio. The mask acts as a mediator that reconciles the conflicting requirements of high imaging quality and extended depth of field.
Solution Approach 2:
The optical parameters of the system are modified by introducing a mask with specific transmission characteristics. The mask changes the effective point spread function parameters, allowing the system to achieve both high numerical aperture (for signal to noise ratio) and extended depth of field simultaneously. This parameter transformation resolves the contradiction between these two optical performance metrics.
2Measurement precision
If focus accuracy is improved by reducing defocus, then noise decreases, but throughput is limited due to restricted depth of field
Solution Approach 1:
The mask serves as an intermediary that allows the system to maintain focus accuracy across an extended depth range. By modifying the point spread function, the mask enables acceptable focus quality over a larger axial range, thereby increasing throughput without sacrificing base calling accuracy. The mask mediates between the conflicting demands of precision and productivity.
3Length of stationary object
If depth of field is extended to cover multiple surfaces, then throughput increases, but focus accuracy degrades
Solution Approach 1:
The mask is designed to create a modified point spread function that maintains acceptable focus quality across multiple surfaces and depths. Rather than achieving perfect focus at a single plane, the mask optimizes the local quality of focus across an extended axial range, allowing imaging of multiple surfaces with sufficient accuracy for base calling.
Solution Approach 2:
The system parameters are transformed by the mask to achieve an extended depth of field while maintaining adequate focus accuracy. The mask modifies the optical transfer function parameters to distribute focus quality acceptably across a larger depth range, resolving the contradiction between extended depth of field and maintained focus precision.
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
The solution enhances focus accuracy, reduces noise, and increases throughput by extending the depth of field to greater than +/−300 nm, improving sequencing accuracy and reducing errors in base calling.
Implementation Method 1
determining a first result, wherein the first result is a result of passing light emitted by a sample at a nucleic acid site through an objective lens and a mask
Implementation Method 2
passing light emitted by a sample at a nucleic acid site through an objective lens and a mask
Implementation Method 3
the mask is a phase mask
Implementation Method 4
the mask is an amplitude mask
Implementation Method 5
the mask is a deformable mirror or a spatial light modulator
Data Source
AI summary
A method for extending a depth of field of a nucleic acid sequencer may comprise optimization steps which are repeated one or more times, in which a result of passing light through an objective lens and a mask is compared with an ideal result, and any discrepancy is used to update the mask. Such a mask may be incorporated into a nucleic acid sequencer which adds fluorescent tags to nucleic acid sites and then detect light emitted from the fluorescent tags, thereby extending the sequencer's depth of field.