Dual Circulation Microphysiological System for Metabolite Analysis
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Solution Overview
Problem
Current microphysiological systems for drug metabolism studies face challenges in maintaining cell functionality over extended periods, especially when dealing with slowly metabolized compounds, due to high cell death rates and inefficient medium exchange, which complicates the measurement of rare metabolites.
Innovation Solution
A microphysiological cell culture system with dual circulation routes allows for a high volume of medium during pre-culture and a low volume during testing, enabling a switch from a low to a high cell-to-medium ratio, thereby maintaining cell functionality and allowing extended culture periods.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of stationary object
If a low cell number to medium volume ratio is used during pre-incubation to reduce frequent medium exchanges, then cell functionality is maintained, but accurate determination of metabolism of slowly metabolised compounds becomes challenging
Solution Approach 1:
The system divides the culture chamber into two distinct compartments: a first compartment for pre-incubation with low cell density and large medium volume, and a second compartment for metabolism testing with high cell density and small medium volume. This segmentation allows each compartment to optimize for its specific function without compromising the other.
Solution Approach 2:
The system dynamically switches between two circulation modes: a first circulation route during pre-incubation that supports low cell density conditions, and a second circulation route during testing that supports high cell density conditions. This dynamic reconfiguration allows the system to adapt to different functional requirements at different time points.
2Loss of time
If hepatocytes are cultured in suspension for extended periods to study slowly metabolised compounds, then sufficient contact time is achieved, but cells stop functioning and die after 6 hours
Solution Approach 1:
The culture system is segmented into two phases occurring in separate compartments: Phase 1 in the first compartment extends cell survival by providing optimal pre-incubation conditions with low cell density and frequent medium exchange, while Phase 2 in the second compartment enables extended metabolism studies with high cell density. This segmentation allows the system to overcome the 6-hour limitation by separating survival optimization from metabolism measurement.
Solution Approach 2:
The system performs preliminary action by pre-incubating hepatocytes in the first compartment under optimized conditions for extended periods (beyond 6 hours) before transferring them to the second compartment for metabolism testing. This preliminary cultivation phase prepares cells for long-term functionality and enables subsequent extended assay periods.
3Measurement precision
If a high cell number to medium volume ratio is used to accurately measure metabolism, then metabolite detection accuracy improves, but frequent medium exchanges are required that disrupt cell function
Solution Approach 1:
The system segments the culture process into two distinct operational phases in separate compartments: the first compartment operates with low cell density and large medium volume requiring infrequent exchanges, while the second compartment operates with high cell density and small medium volume enabling accurate metabolite measurement. This spatial segmentation resolves the contradiction between measurement accuracy and operational simplicity.
4Measurement precision
If compound is incubated with suspension cells using the relay method to determine low-clearance values, then measurement accuracy improves, but the process becomes time consuming and requires large numbers of cells
Solution Approach 1:
The system consolidates the multi-step relay method into a single continuous process by segmenting the culture chamber into two compartments that work sequentially. Cells are pre-incubated in the first compartment and then transferred to the second compartment for metabolism testing, eliminating the need for repeated cell transfers and medium exchanges required in traditional relay methods. This reduces both time consumption and cell requirements while maintaining measurement accuracy.
Data Source
AI summary
A microfluidic cell culture system is provided. The system includes a dual circulation arrangement for providing the cell culture with culture medium (and, optionally, selected compounds for study). The dual circulation arrangement permits culture conditions to be readily modified for different phases of cell culture. In particular, a first circulation route can be used to circulate a relatively high volume of medium, thereby allowing a low cell number to medium volume ratio, and a second circulation route can be used to circulate a relatively low volume of medium, thereby allowing a high cell number to medium volume ratio. The first circulation is optimised for a pre-culture period, before test compounds are added, and the second circulation is optimised for the test phase, providing a high cell number to medium ratio while preserving function during the test period.