Semiconductor Biosensor Layout for Multi-Cluster Sequencing Detection
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Solution Overview
Problem
Conventional solid-state imaging systems for DNA sequencing are limited by pixel density, leading to low throughput and high costs due to the need for large optical systems and limited ability to detect multiple clusters per sensor, which restricts the analysis of nucleic acid arrays.
Innovation Solution
A device comprising a biosensor with a sample surface and an array of sensors that generate sequences of pixel signals, allowing for base calling of multiple clusters per sensor through advanced signal processing and illumination techniques, enabling the detection of nucleotide bases with improved throughput and accuracy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If conventional solid-state imaging systems are used for DNA sequencing, then the system structure is simple and costs are reduced, but the throughput is limited due to pixel density constraints and inability to detect multiple clusters per sensor
Solution Approach 1:
The patent divides the detection task by separating the illumination function from the detection function. Multiple independent light sources illuminate different subsets of clusters, while a single sensor array detects signals from all clusters. This segmentation allows the system to overcome pixel density limitations by enabling each sensor to effectively monitor multiple clusters through temporally or spatially separated illumination events.
Solution Approach 2:
The system performs preliminary illumination of clusters before detection, using multiple light sources to pre-illuminate different subsets of clusters in sequence. This preliminary action allows the sensor array to capture signals from multiple clusters over time, effectively increasing the number of detectable clusters beyond the instantaneous pixel density limit.
2Measurement precision
If optical systems with lenses and filters are used to detect fluorescent signals, then detection accuracy is improved, but the device complexity and benchtop footprint increase significantly
Solution Approach 1:
The patent extracts the illumination function from the detection path, using separate light sources positioned close to the clusters rather than requiring complex optical paths with lenses and filters. This extraction simplifies the optical system by eliminating the need for sophisticated imaging optics while maintaining detection accuracy through direct proximity illumination and detection.
Solution Approach 2:
The sensor array performs multiple functions: it detects fluorescent signals from clusters illuminated by different light sources at different times, effectively replacing the need for multiple dedicated detection paths. This multi-functionality reduces device complexity by using a single sensor array for all detection tasks rather than requiring separate optical systems for each wavelength or cluster subset.
3Productivity
If pixel pitch is decreased to increase pixel density, then the number of detectable clusters per sensor increases, but manufacturing precision requirements and costs increase significantly
Solution Approach 1:
The patent changes the operational parameters of the system by introducing temporal multiplexing of illumination. Instead of relying solely on spatial resolution (pixel pitch), the system uses time-separated illumination from multiple light sources to increase the effective number of detectable clusters. This parameter change allows the system to achieve higher throughput without requiring smaller pixel pitches, thereby avoiding increased manufacturing precision requirements.
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 sequencing throughput and reduces costs by enabling the simultaneous detection of multiple clusters per sensor, improving the analysis of nucleic acid arrays and increasing the efficiency of DNA sequencing processes.
Implementation Method 1
the controlled reactions occur immediately over a solid-state imager (e.g., charged-coupled device (CCD) or a complementary metal-oxide-semiconductor (CMOS) sensor) that does not require a large optical assembly to detect the fluorescent emissions
Implementation Method 2
an optical system is used to direct an excitation light onto fluorescently-labeled analytes and to also detect the fluorescent signals that may emit from the analytes
Data Source
AI summary
In one embodiment, a sample surface of a biosensor includes pixel areas and holds a plurality of clusters during a sequence of sampling events such that the clusters are distributed unevenly over the pixel areas. In another embodiment, a biosensor has a sample surface that includes pixel areas and an array of wells overlying the pixel areas, the biosensor including two wells and two clusters per pixel area. The two wells per pixel area include a dominant well and a subordinate well. The dominant well has a larger cross section over the pixel area than the subordinate well. In yet another embodiment, an illumination system is coupled to a biosensor that illuminates the pixel areas with different angles of illumination during a sequence of sampling events, including, for a sampling event, illuminating each of the wells with off-axis illumination to produce asymmetrically illuminated well regions in each of the wells.