Microfluidic Shear Flow for T Cell Avidity Discrimination
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current methods for selecting T cells based on TCR-pMHC binding strength are inefficient, fail to account for co-receptors and cell-cell interactions, leading to inaccurate predictions of T cell functionality and potential autoimmune risks, and lack the ability to assess the overall strength of cellular interactions between T cells and tumor cells.
Innovation Solution
A microfluidic device with a channel configuration that applies a uniform shear stress to detach T cells from tumor cells, allowing for the collection and analysis of cells based on their binding strength, enabling the evaluation of cellular avidity by ensuring only cells subjected to uniform shear stress are collected for further analysis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If surface plasmon resonance (SPR) is used to detect molecular kinetics and affinity of TCR-pMHC binding, then affinity readouts are obtained, but the method is time-consuming, expensive and inefficient, and fails to account for co-receptor and cell-cell interactions
Solution Approach 1:
The patent replaces complex mechanical/electronic detection systems (SPR, flow cytometry) with a simple microfluidic shear flow system. The measurement principle shifts from optical/electronic detection to hydrodynamic separation based on shear stress-induced detachment, achieving high throughput while maintaining measurement precision through controlled fluid mechanics.
Solution Approach 2:
The patent uses hydraulic principles (shear flow through microfluidic channels) to separate cells based on binding strength. Fluid flow exerts controlled shear stress on TCR-pMHC complexes, causing detachment of weaker binders while stronger binders remain attached, enabling efficient separation and collection of high-avidity cells.
2Productivity
If multimer/tetramer staining is used to generate avidity readouts, then high-throughput analysis is achieved, but functional T cells are not detected resulting in false negative readouts
Solution Approach 1:
The patent employs a self-service approach where the cells themselves serve as the detection target. Instead of using external probes or stains that may fail to detect functional cells, the system directly measures the binding strength of T cells to pMHC complexes through shear flow detachment. The cells' own binding properties are exploited for separation and detection, eliminating false negatives.
3Strength
If T cells are engineered with supraphysiological affinity/avidity, then anti-tumour activity is enhanced, but cross-reactivity to self-antigens increases resulting in autoimmune diseases
Solution Approach 1:
The patent uses parameter changes in shear stress magnitude to selectively separate T cells based on their binding strength. By controlling the shear stress parameter, the system can isolate T cells with optimal avidity without selecting for supraphysiological affinity cells that pose autoimmunity risks. The shear stress parameter acts as a filter to achieve the optimal balance between anti-tumour activity and safety.
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 approach allows for accurate discrimination and collection of T cells with optimal avidity, reducing the risk of autoimmune responses and improving the selection of T cells for cancer immunotherapy by assessing the overall strength of cellular interactions, thereby enhancing the efficacy of TCR T cell therapy.
Implementation Method 1
a transverse cross-section of the channel is configured for application of a substantially uniform shear stress to the second cells that are adhered to the first cells in at least a central region of the channel as the fluid flows along the channel, to detach at least some of the second cells from the first cells
Data Source
AI summary
The present disclosure relates to a microfluidic device for discriminating between second cells, as a function of binding strength between first cells and the second cells, the device comprising: a microfluidic channel, a base of the channel comprising a substrate; wherein the channel is configured to receive first cells, for adhesion of the first cells to the substrate; receive second cells, for adhesion of the second cells to the first cells; and receive a fluid, for fluid flow over the second cells; and wherein a transverse cross-section of the channel is configured for application of a substantially uniform shear stress to the second cells that are adhered to the first cells in at least a central region of the channel as the fluid flows along the channel, to detach at least some of the second cells from the first cells, and to cause the detached second cells to flow towards a downstream end of the channel.