Semiconductor Sequencing Biosensor for Multi-Cluster Base Calling
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Conventional solid-state imaging systems for nucleic acid sequencing are limited by their ability to perform only one base call per sensor pixel, leading to low throughput and high costs due to the constraints of pixel density, which necessitates the development of methods to increase the number of base calls per sensor pixel.
Innovation Solution
A biosensor system that uses a signal processor to classify results from multiple clusters by mapping pixel signals from two illumination stages into at least four bins, allowing for the identification of nucleotide bases A, C, T, or G, and applies algorithms like k-means clustering to process signals from multiple clusters sharing a pixel area, thereby increasing throughput.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If conventional solid-state imaging systems perform only one base call per sensor pixel, then the system structure remains simple, but the throughput is low and sequencing costs are high
Solution Approach 1:
The patent segments the base calling process by introducing multiple illumination stages (first illumination stage for A/T bases, second illumination stage for C/T bases) and dividing the signal processing into distinct classification steps. This allows multiple clusters to be analyzed sequentially through different illumination conditions, enabling multiple base calls per pixel while maintaining manageable processing complexity through structured segmentation of the detection workflow
Solution Approach 2:
The patent implements periodic action through sequential illumination stages where the sensor pixel is alternately exposed to different illumination conditions. The first illumination stage excites A/T fluorescent labels, followed by a second illumination stage that excites C/T fluorescent labels. This periodic switching of illumination conditions enables multiple base calling opportunities per pixel without requiring permanent system complexity increases
2Productivity
If the pixel density is increased to improve throughput, then more clusters can be detected, but the system cost increases and the benchtop footprint enlarges
Solution Approach 1:
The patent transitions from a two-dimensional pixel array limitation to a temporal dimension by implementing multiple illumination stages. Instead of increasing spatial resolution (pixel density), the system exploits the time dimension to perform sequential base calling. A single pixel can now generate multiple base calls through different illumination conditions, effectively increasing throughput without requiring higher pixel density or larger system footprint
3Productivity
If multiple clusters are assigned to share a pixel area, then the throughput increases, but the signal processing complexity and difficulty of accurate base calling increase
Solution Approach 1:
The patent introduces fluorescent labels as intermediaries that mediate between multiple clusters and the single sensor pixel. Different fluorescent labels (A/T labels and C/T labels) are attached to different nucleotide bases, and these labels emit distinct fluorescent signals when excited by specific illumination wavelengths. This intermediary labeling system enables the pixel to distinguish and accurately base call multiple clusters even when they share the same pixel area, as each cluster's fluorescent label provides a unique spectral signature for identification
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 system achieves higher throughput in nucleic acid sequencing by enabling multiple cluster base calling per sensor pixel, reducing sequencing time and costs while maintaining accurate base calling.
Implementation Method 1
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
Figure 1
Figure 2
Figure 3
AI summary
A biosensor (102, 300) for base calling is provided. The biosensor (102, 300) comprises a sampling device (304), which includes a sample surface (334) that has an array of pixel areas (306', 308', 310', 312', 314') and a solid-state imager that has an array of sensors (306, 308, 310, 312, 314). Each sensor (306, 308, 310, 312, 314) generates pixel signals in each base calling cycle. Each pixel signal represents light gathered from a corresponding pixel area (306', 308', 310', 312', 314') of the sample surface (334). The biosensor (102, 300) further comprises a signal processor (130) configured for connection to the sampling device (304). The signal processor (130) receives and processes the pixel signals from the sensors (306, 308, 310, 312, 314) for base calling in a base calling cycle, and uses the pixel signals from fewer sensors (306, 308, 310, 312, 314) than a number of clusters (306AB, 308AB, 310AB, 312AB, 314AB) base called in the base calling cycle.