Microfluidic Flow Cell With Flexible Lid for Automated Biomarker Analysis
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Solution Overview
Problem
Current methods for multiplexed in situ biomarker analysis of tissue samples are time-consuming and prone to errors due to manual staining and imaging processes, with limitations in reagent delivery and sample handling, leading to potential loss or movement of samples during processing.
Innovation Solution
A microfluidic subassembly with a stacked planar assembly comprising an adherent layer, an optically transparent substrate layer, and a gasket layer, allowing for fluidic connections outside the main substrate, enabling flexible imaging and controlled reagent delivery through fluidic ports, and a flexible lid for modulating the internal dimensions of the flow cell.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If manual staining and imaging processes are used, then flexibility in sample handling is maintained, but the process becomes time-consuming and error-prone
Solution Approach 1:
The system enables automated staining and imaging workflows where the microfluidic flow cell and robotic components perform operations autonomously without manual intervention. The flow cell design with integrated fluidic channels allows reagents to be delivered and processed automatically, while the imaging system captures data without manual coverslip handling, thus improving productivity while managing complexity through self-service automation.
Solution Approach 2:
The system divides the staining and imaging process into distinct automated modules: a microfluidic flow cell for reagent delivery, a robotic positioning system for sample handling, and an imaging system for data capture. This segmentation allows each component to be optimized independently while working together to automate the overall workflow, resolving the contradiction between automation benefits and system complexity.
2Reliability
If coverslip is placed over the sample to keep it wet during imaging, then sample hydration is maintained, but the sample may be lost or moved during cover slipping and de-cover slipping
Solution Approach 1:
The microfluidic flow cell acts as an intermediary structure between the sample and the external environment. It provides a sealed chamber that maintains sample hydration through controlled fluid delivery without requiring physical coverslips. The sample remains fixed on the substrate within the flow cell, eliminating the risk of sample loss or movement associated with manual coverslip handling, thus improving reliability while maintaining ease of operation.
Solution Approach 2:
The invention extracts the coverslip function from the traditional staining and imaging workflow. Instead of using separate coverslips that require manual placement and removal, the system integrates the sealing and hydration functions into the microfluidic flow cell structure itself. This extraction eliminates the problematic coverslip handling steps while maintaining sample stability and hydration.
3Quantity of substance
If reagent volume is reduced and confined to an area close to the sample using a fluidic channel, then reagent delivery control is improved, but the diffusion length is limited by the channel height
Solution Approach 1:
The system employs dynamic flow control within the microfluidic channels to overcome diffusion limitations. By actively pumping reagents through the channels at controlled rates, the system maintains fresh reagent supply to the sample area without requiring large volumes. The dynamic flow compensates for the limited diffusion length imposed by the small channel height, allowing effective reagent delivery with minimal reagent consumption.
Solution Approach 2:
The invention uses hydraulic principles to control reagent delivery through the microfluidic channels. Pressure-driven flow systems enable precise control of reagent volume and flow rate, delivering sufficient reagent concentration to the sample area despite the limited channel height and diffusion length. This hydraulic control allows efficient reagent usage while maintaining effective staining.
4Measurement precision
If traditional imaging devices are used to image the sample through the flow cell, then sample analysis is possible, but focusing and image quality modulation is limited
Solution Approach 1:
The system implements local quality optimization in the imaging path by positioning the flow cell at specific locations relative to the objective lens and using the flow cell's own structure (substrate, gasket, lid) as part of the optical path. The design allows for localized focusing adjustments and image quality modulation without requiring complex additional imaging components, thus improving measurement precision while 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
This solution automates the biomarker analysis workflow, ensuring uniform reagent delivery and high-quality imaging by maintaining the sample in a controlled environment, reducing sample loss and movement, and allowing for real-time or archived analysis with improved staining uniformity and image quality.
Implementation Method 1
the substrate layer forms a flexible optically transparent lid capable of bending in either direction to alter the internal dimensions of the subassembly
Data Source
AI summary
A microfluidic flow cell subassembly, which may be assembled into a flow cell having fluidic connections outside of the main substrate, is described for encapsulating a sample to allow for subsequent controlled delivery of reagents to the sample, such as multiplexed in situ biomarker staining and analysis. As configured, the subassembly comprises a substrate layer forms a flexible optically transparent lid which is capable of bending in either direction to alter the internal dimensions of the subassembly. Methods of use are also disclosed.