Microbubble Cell Selection Chamber for Magnet-Free Target Cell Isolation
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Solution Overview
Problem
Existing methods for isolating target cells from a heterogeneous cell population, such as T-cells for CAR T-cell therapy, are inefficient and require strong magnets or large amounts of contaminants, leading to complications in the separation process.
Innovation Solution
A cell selection chamber with streptavidin-coated microbubbles and a fluid flow circuit that uses membranes with pores smaller than the microbubbles to separate target cells from other cells, facilitated by a biotinylated antibody additive to bind target cells to the microbubbles.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If magnetic particles are used to bind target cells, then cell isolation can be achieved, but strong magnets are required which increases device complexity and operational difficulty
Solution Approach 1:
The patent introduces streptavidin-coated microbubbles as an intermediary substance that binds to biotinylated antibodies on target cells. This mediator enables cell separation without requiring strong magnetic fields, as the microbubbles are separated using standard centrifugation techniques instead of strong magnets.
Solution Approach 2:
The patent replaces the magnetic field-based mechanical separation system with a centrifugation-based separation system. Instead of using strong magnets to separate bound cells, the system uses centrifugal force to separate the microbubble-cell complexes from unbound cells, thereby reducing the need for complex magnetic field generation equipment.
2Reliability
If large amounts of contaminants are used for cell separation, then separation can be achieved, but centrifugation or spinning membrane separation is required which increases device complexity
Solution Approach 1:
The streptavidin-coated microbubbles serve as a specific intermediary that binds to biotinylated antibodies on target cells with high affinity. This specific binding mechanism eliminates the need for non-specific contaminants that would require centrifugation for removal, as the microbubbles themselves become the separable carrier of the target cells.
Solution Approach 2:
The patent changes the physical parameters of the separation medium by using microbubbles with specific size and density characteristics. These parameter changes allow the microbubble-cell complexes to be separated from plasma and unbound cells through simple centrifugation at lower forces compared to traditional contaminant-based methods.
3Productivity
If buoyant separation is used to separate blood components, then separation can be achieved, but the process is inefficient for isolating specific cell types
Solution Approach 1:
The patent introduces biotinylated antibodies as a specific intermediary that selectively binds to target cells (e.g., CD3+ T-cells). This specific binder enables the system to distinguish and isolate particular cell types from the heterogeneous blood population, overcoming the non-specific nature of buoyant separation methods.
Solution Approach 2:
The patent changes the separation parameter from physical density-based buoyant separation to biochemical affinity-based binding. By using biotin-streptavidin specific binding interactions, the system achieves high-specificity cell isolation rather than relying on general density differences that provide poor cell type discrimination.
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
Efficient isolation of target cells with reduced contamination and minimal equipment requirements, enabling precise separation and modification for therapeutic applications.
Implementation Method 1
mixed with a biotinylated antibody additive including regions configured to bind to the target cells and not to other cells of the heterogeneous population of cells
Implementation Method 2
conveyed into a cell selection chamber... into a reservoir of the cell selection chamber containing a plurality of microbubbles each at least partially coated with streptavidin so as to cause the target cells to become bound to the microbubbles
Implementation Method 3
An upstream membrane is positioned between the inlet and the reservoir, while a downstream membrane is positioned between the outlet and the reservoir, with the membranes including a plurality of pores each having a diameter less than a diameter of the microbubbles
Data Source
AI summary
A cell selection chamber includes an inlet and an outlet, with a reservoir positioned therebetween and configured to allow for fluid flow from the inlet to the outlet. The reservoir contains a plurality of microbubbles, which are each at least partially coated with streptavidin. An upstream membrane is positioned between the inlet and the reservoir, while a downstream membrane is positioned between the outlet and the reservoir. The membranes include a plurality of pores each having a diameter that is less than a diameter of the microbubbles. In use, a heterogeneous population of cells is mixed with a biotinylated antibody additive and then conveyed into the cell selection chamber so as to cause target cells of the heterogeneous population of cells to become bound to the microbubbles and to cause other cells of the heterogeneous population of cells to flow out of the cell selection chamber as unbound cells.