Hydrocyclone Cell Retention for Bioreactor Perfusion
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Solution Overview
Problem
Conventional continuous perfusion cell culture systems face limitations such as membrane fouling, overheating, low separation efficiencies, and complex, expensive cell retention devices that are prone to failure, especially at large scales, which hinder the efficient production of biologic molecules like antibodies.
Innovation Solution
A bioprocessing system utilizing a hydrocyclone as a cell retention device to link culture and production bioreactors, allowing for continuous production of biologic molecules by retaining viable cells and removing spent media, thereby improving separation efficiency and reducing media usage.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If membrane-based cell retention devices are used in continuous perfusion bioreactors, then cell retention and media removal can be achieved, but the membranes eventually plug with cell debris and require frequent changes
Solution Approach 1:
The patent removes the membrane component entirely from the cell retention device, replacing it with a hydrocyclone separator. This extraction of the problematic membrane element eliminates the plugging issue while maintaining cell retention functionality through a different physical mechanism (centrifugal separation).
Solution Approach 2:
The patent replaces the membrane filtration mechanism with a hydrocyclone-based centrifugal separation system. This substitution uses rotational motion and centrifugal force instead of passive membrane filtration, achieving cell retention without the fouling problems associated with membranes.
2Productivity
If membrane-based cell retention devices are used at high cell densities and high perfusion rates, then productivity is improved, but membrane fouling is accelerated
Solution Approach 1:
By removing the membrane component, the system eliminates the fouling mechanism that would otherwise be accelerated under high productivity conditions. The hydrocyclone design handles high cell densities and perfusion rates without the membrane fouling that limits membrane-based systems.
Solution Approach 2:
The centrifugal separation mechanism in the hydrocyclone is inherently more resistant to fouling under high-flow, high-density conditions compared to membrane filtration. The system maintains reliable operation at high productivity levels where membrane systems would suffer accelerated fouling.
3Reliability
If conventional cell retention devices are used, then cell retention can be achieved, but they are complex, expensive, and prone to failure at large scales
Solution Approach 1:
The patent simplifies the cell retention device by removing complex membrane assemblies, pumps, and associated control systems. The hydrocyclone is a single-component device with no moving parts, dramatically reducing complexity while maintaining cell retention functionality at large scales.
Solution Approach 2:
The patent replaces complex mechanical membrane filtration systems with a passive hydrocyclone separator that uses only gravitational and centrifugal forces. This substitution eliminates motors, pumps, and electronic controls, resulting in a simple, reliable device suitable for large-scale operation.
4Reliability
If membrane-based cell retention devices are used, then cell retention can be achieved, but they are damaging to cells through excessive shear forces
Solution Approach 1:
The patent replaces the high-shear membrane filtration system with a low-shear hydrocyclone separation system. The centrifugal forces in the hydrocyclone are distributed more gently across the cell population, reducing mechanical damage while maintaining effective cell retention.
Solution Approach 2:
The patent changes the physical parameters of the separation process from high-shear membrane filtration to lower-shear centrifugal separation. This parameter change in the separation mechanism reduces the harmful shear forces applied to cells while maintaining the necessary cell retention capability.
5Reliability
If membrane-based cell retention devices are used, then cell retention can be achieved, but cleaning and sterilization are challenging at large scales
Solution Approach 1:
The patent removes the membrane component that creates cleaning and sterilization challenges. The hydrocyclone design with its simple, smooth-walled construction allows for easy access, thorough cleaning, and effective sterilization even at large scales, unlike membrane systems with crevices and filtration elements.
Solution Approach 2:
The patent replaces the membrane filtration system with a hydrocyclone design that is inherently easier to clean and sterilize. The smooth, simple geometry of the hydrocyclone allows for complete drainage, thorough cleaning access, and effective sterilization, overcoming the challenges associated with membrane-based systems at large scales.
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 high and consistent production of biologic molecules with increased separation efficiency and reduced media usage, enabling operation for extended periods without the need for frequent membrane changes, and can handle large-scale bioprocessing effectively.
Implementation Method 1
at least one hydrocyclone; wherein the culture bioreactor and the production bioreactor are linked by the hydrocyclone that serves as a cell retention device for the culture bioreactor, wherein the hydrocyclone produces an underflow stream containing concentrated cell culture and a partially cell-free overflow stream
Data Source
AI summary
Systems and methods for continuous production of at least one biological molecule of interest are provided. More specifically, the systems include (i) at least one culture bioreactor; (ii) at least one hydrocyclone; and (iii) at least one production bioreactor; wherein the culture bioreactor and the production bioreactor are linked by the hydrocyclone. The methods include the steps of (i) culturing a plurality of host cells capable of producing a biologic molecule of interest in at least one culture bioreactor; (ii) inoculating at least one production bioreactor with cells obtained from step (i); and (iii) culturing the cells in the production bioreactor.