Integrated DFP Flow Cell Layout for Time-Resolved Sequencing
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Solution Overview
Problem
Current sequencing methods, particularly real-time single molecule sequencing, face challenges due to system complexity, sub-optimal setups, and slower processing rates, especially in reversible terminator-based sequencing systems, which are hindered by stochastic processes and inefficient fluidic manipulations.
Innovation Solution
An integrated detection, flow cell, and photonics (DFP) device is developed, featuring a CMOS substrate with photon time of arrival detector elements, waveguides, and a functionalization layer for precise detection of fluorescence signals, enabling improved photon collection and timing accuracy to enhance sequencing efficiency.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If real-time single molecule sequencing is implemented, then sequencing speed is improved, but system complexity increases
Solution Approach 1:
The patent combines multiple functions into a single integrated device structure. The flow cell substrate integrates sample positioning, fluorescence excitation, and photon detection capabilities into one unified platform, eliminating the need for separate complex systems for each function and thereby reducing overall system complexity while maintaining high sequencing speed
Solution Approach 2:
The flow cell substrate serves multiple purposes: it positions nucleic acid samples, provides the surface for fluorescence excitation, and integrates photon detection capabilities. This multi-functional design reduces the number of separate components needed, simplifying the system while enabling real-time single molecule sequencing
2Measurement precision
If reversible terminator-based sequencing is used, then sequencing accuracy is improved, but processing speed decreases
Solution Approach 1:
The patent replaces traditional mechanical fluidic manipulation systems with an integrated optical detection approach. By using fluorescence lifetime decay measurements and time-resolved detection, the system eliminates the need for complex mechanical operations while maintaining the accuracy benefits of reversible terminator chemistry, thereby improving processing speed
Solution Approach 2:
The patent utilizes fluorescence lifetime decay parameters to distinguish between different nucleotide incorporations. By measuring the temporal characteristics of fluorescence emission rather than relying solely on intensity measurements, the system maintains high sequencing accuracy while enabling faster data acquisition and processing rates
3Measurement precision
If integrated DFP device with photon time of arrival detectors is implemented, then timing accuracy is improved, but device complexity increases
Solution Approach 1:
The patent introduces waveguides as intermediary structures that channel and concentrate photons to the detection elements. This intermediary optical pathway enables precise timing measurements by ensuring that photons from specific locations are directed to corresponding pixel elements, achieving high timing accuracy without requiring complex direct detection geometries
Solution Approach 2:
The patent adds the temporal dimension to the detection process by measuring photon time of arrival with high precision. By incorporating time-resolved detection capabilities into the spatial array of pixel elements, the system achieves enhanced timing accuracy while utilizing the existing spatial detection architecture, thereby managing 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
The DFP device enhances sequencing efficiency by improving photon detection and timing accuracy, allowing for faster and more precise analysis of nucleic acid sequences, even in real-time single molecule sequencing, thereby overcoming the limitations of existing systems.
Implementation Method 1
at least one wave guide formed on the IC photo detection layer as a photonics layer
Implementation Method 2
The pixel elements include photon time of arrival (TOA) detector elements that continues one of an avalanche diode, a single photon avalanche diode, and a silicon photon multiplier
Implementation Method 3
The pixel elements include photon time of arrival (TOA) detector elements that continues one of an avalanche diode, a single photon avalanche diode, and a silicon photon multiplier
Implementation Method 4
Each sequencing cycle extends the sstDNA by a single nucleotide (e.g., A, T, G, C) having a unique fluorescent label
Data Source
AI summary
An integrated detection, flow cell and photonics (DFP) device is provided that comprises a substrate having an array of pixel elements that sense photons during active periods. The substrate and pixel elements form an IC photon detection layer. At least one wave guide is formed on the IC photo detection layer as a photonics layer. An optical isolation layer is formed over at least a portion of the wave guide. A collection of photo resist (PR) walls patterned to define at least one flow cell channel that is configured to direct fluid along a fluid flow path. The wave guides align to extend along the fluid flow path. The flow cell channel is configured to receive samples at sample sites that align with the array of pixel elements.