Periodic Reporting for period 4 - SIRIUS (Simulations for Inertial Particle Microfluidics)
Reporting period: 2023-07-01 to 2024-09-30
Cancer and bacterial infections are estimated to kill 18 million people worldwide annually by 2050.
Fast and reliable diagnostics are essential for early and targeted treatments to increase life expectancy. Microfluidics is an emerging technology where tiny samples of liquids or biological fluids (for example blood) are processed and analysed in tiny fabricated channels with diameters comparable to that of a human hair. Microfluidics is already used for fast and early diagnostics, for example in lateral flow tests that have become popular during the COVID pandemic. Inertial particle microfluidics (IPMF) is a specific type of microfluidics where the fluid sample is moving with high speeds. IPMF is particularly useful for the separation of biological particles, for example the isolation of cancer cells or bacteria from blood. However, the underlying principles and physical rules of IPMF are not well understood, making technological progress slow and costly. The aim of the SIRIUS project was the development of computational methods for and the simulation of IPMF to analyse and better understand how it works.
The SIRIUS project had five key objectives:
1. Develop accurate computational models for IPMF.
2. Understand the role and importance of particle softness (such as blood cell flexibility) in IPMF.
3. Investigate the flow physics in IPMF when particles interact with each other.
4. Learn how small particles (for example bacteria) can be separated more effectively.
5. Work towards a computational toolkit to enable simulation-driven design of IPMF devices.
Conclusion:
SIRIUS developed new methods for the accurate simulation of IPMF. We now largely understand the role of particle softness in IPMF and how particles interact. Progress toward the separation of small particles and the development of a computational toolkit were more challenging than expected and could not be completed in the project.
Fast and reliable diagnostics are essential for early and targeted treatments to increase life expectancy. Microfluidics is an emerging technology where tiny samples of liquids or biological fluids (for example blood) are processed and analysed in tiny fabricated channels with diameters comparable to that of a human hair. Microfluidics is already used for fast and early diagnostics, for example in lateral flow tests that have become popular during the COVID pandemic. Inertial particle microfluidics (IPMF) is a specific type of microfluidics where the fluid sample is moving with high speeds. IPMF is particularly useful for the separation of biological particles, for example the isolation of cancer cells or bacteria from blood. However, the underlying principles and physical rules of IPMF are not well understood, making technological progress slow and costly. The aim of the SIRIUS project was the development of computational methods for and the simulation of IPMF to analyse and better understand how it works.
The SIRIUS project had five key objectives:
1. Develop accurate computational models for IPMF.
2. Understand the role and importance of particle softness (such as blood cell flexibility) in IPMF.
3. Investigate the flow physics in IPMF when particles interact with each other.
4. Learn how small particles (for example bacteria) can be separated more effectively.
5. Work towards a computational toolkit to enable simulation-driven design of IPMF devices.
Conclusion:
SIRIUS developed new methods for the accurate simulation of IPMF. We now largely understand the role of particle softness in IPMF and how particles interact. Progress toward the separation of small particles and the development of a computational toolkit were more challenging than expected and could not be completed in the project.
SIRIUS included activities in a) computational method development, b) analysis of inertial particle microfluidics (IPMF) through computer simulations, and c) knowledge transfer with stakeholders.
a) In terms of computational method development, we investigated the “immersed-boundary-lattice-Boltzmann method” which forms the basis for the simulation of the interaction of particles and flow. We found a way to predict the stability and accuracy of this method before running any simulations, making it easier for scientists to plan simulations.
Simulations of IPMF in curved channels (such as spiralling channels) are very challenging since there are hardly any available computational methods with all required features. We started developing a novel method that has the potential to overcome these shortcomings. We were not able to finish this part of the project due to the complexity of the algorithm and plan to continue this work in a different project.
We developed a new algorithm to calculate the forces that the fluid exerts on the particles flowing in channels. This algorithm gives scientists the ability to understand how exactly particles are influenced by the flow inside channels.
b) The SIRIUS team conducted several simulation-based projects to understand the interaction of multiple particles in IPMF and the characterisation of the properties of individual particles in bespoke channel geometries.
In microfluidics, particles influence the behaviour of other particles nearby through “hydrodynamic interactions” (such as we feel a car driving by). In IPMF, these interactions can lead to the spontaneous formation of pairs or trains of particles where particles flow in groups. Understanding under which circumstances these groups form is of high importance as this behaviour determines how easily different blood cell types can be separated. Through our simulations we found that size and softness of the particles play crucial roles. We were able to explain why an existing microfluidic device, designed for the separation of circulating tumour cells from blood cells, does not perform as well as expected. Our work opens up the possibility to design more reliable IPMF devices.
Another microfluidic application is “cytometry” where the properties of biological cells are measured by exposing individual cells to specific flow fields that stretch the cells. We investigated how particles of different properties behave in a so-called “cross-slot junction”, a geometry often used to stretch cells. For example, the company Cytovale Inc. (California) uses this technology for early sepsis detection. Through our simulations, we learned how the particle properties influence the way the particles travel through the junction. Our findings give experimental researchers the tools to design better geometries to probe biological cells for more accurate disease detection.
We also investigated the flow of “dense suspensions” in IPMF. Undiluted blood is an example of a dense suspension where 45% of the volume of the fluid consists of blood cells. While IPMF is usually applied to diluted blood samples (with cell concentrations of 1% or less), it is a major challenge to scale this method to undiluted blood. Our simulations show that there is a non-trivial interaction of IPMF and the high concentration of blood cells. We found that different types of blood cells tend to segregate under certain conditions, potentially enabling the separation of different cell types even at higher cell concentrations.
c) As the SIRIUS project was of computational nature, it is crucial to validate simulation results and transfer knowledge with experimental researchers and end users.
One of the SIRIUS researchers spent six months in the experimental lab of Prof. Ian Papautsky (Chicago). We validated parts of our simulation results and exchanged ideas between modellers and experimentalists. Importantly, the SIRIUS team learned about the practical needs of experimentalists. Likewise, the experimentalists learned from us which IPMF mechanisms are important under which circumstances and how the design of IPMF devices can be improved to achieve better separation of biological cells.
We worked closely with Cytovale Inc. These interactions taught us how to improve our computational IPMF models, while our simulations provided unprecedented insight into the particle dynamics in cross-slot junctions.
Finally, we distilled most of our knowledge in modelling and simulating IPMF in a tutorial review paper that serves as a single point of entry for researchers who want to get started in this area.
Concluding, the SIRIUS project enabled the development of new and improved numerical algorithms. We performed several simulation investigations and uncovered fundamental mechanisms of IPMF. Interacting with experimental researchers, we contributed to knowledge transfer between computational modelling and experimental communities, thus enabling improved real-world applications.
a) In terms of computational method development, we investigated the “immersed-boundary-lattice-Boltzmann method” which forms the basis for the simulation of the interaction of particles and flow. We found a way to predict the stability and accuracy of this method before running any simulations, making it easier for scientists to plan simulations.
Simulations of IPMF in curved channels (such as spiralling channels) are very challenging since there are hardly any available computational methods with all required features. We started developing a novel method that has the potential to overcome these shortcomings. We were not able to finish this part of the project due to the complexity of the algorithm and plan to continue this work in a different project.
We developed a new algorithm to calculate the forces that the fluid exerts on the particles flowing in channels. This algorithm gives scientists the ability to understand how exactly particles are influenced by the flow inside channels.
b) The SIRIUS team conducted several simulation-based projects to understand the interaction of multiple particles in IPMF and the characterisation of the properties of individual particles in bespoke channel geometries.
In microfluidics, particles influence the behaviour of other particles nearby through “hydrodynamic interactions” (such as we feel a car driving by). In IPMF, these interactions can lead to the spontaneous formation of pairs or trains of particles where particles flow in groups. Understanding under which circumstances these groups form is of high importance as this behaviour determines how easily different blood cell types can be separated. Through our simulations we found that size and softness of the particles play crucial roles. We were able to explain why an existing microfluidic device, designed for the separation of circulating tumour cells from blood cells, does not perform as well as expected. Our work opens up the possibility to design more reliable IPMF devices.
Another microfluidic application is “cytometry” where the properties of biological cells are measured by exposing individual cells to specific flow fields that stretch the cells. We investigated how particles of different properties behave in a so-called “cross-slot junction”, a geometry often used to stretch cells. For example, the company Cytovale Inc. (California) uses this technology for early sepsis detection. Through our simulations, we learned how the particle properties influence the way the particles travel through the junction. Our findings give experimental researchers the tools to design better geometries to probe biological cells for more accurate disease detection.
We also investigated the flow of “dense suspensions” in IPMF. Undiluted blood is an example of a dense suspension where 45% of the volume of the fluid consists of blood cells. While IPMF is usually applied to diluted blood samples (with cell concentrations of 1% or less), it is a major challenge to scale this method to undiluted blood. Our simulations show that there is a non-trivial interaction of IPMF and the high concentration of blood cells. We found that different types of blood cells tend to segregate under certain conditions, potentially enabling the separation of different cell types even at higher cell concentrations.
c) As the SIRIUS project was of computational nature, it is crucial to validate simulation results and transfer knowledge with experimental researchers and end users.
One of the SIRIUS researchers spent six months in the experimental lab of Prof. Ian Papautsky (Chicago). We validated parts of our simulation results and exchanged ideas between modellers and experimentalists. Importantly, the SIRIUS team learned about the practical needs of experimentalists. Likewise, the experimentalists learned from us which IPMF mechanisms are important under which circumstances and how the design of IPMF devices can be improved to achieve better separation of biological cells.
We worked closely with Cytovale Inc. These interactions taught us how to improve our computational IPMF models, while our simulations provided unprecedented insight into the particle dynamics in cross-slot junctions.
Finally, we distilled most of our knowledge in modelling and simulating IPMF in a tutorial review paper that serves as a single point of entry for researchers who want to get started in this area.
Concluding, the SIRIUS project enabled the development of new and improved numerical algorithms. We performed several simulation investigations and uncovered fundamental mechanisms of IPMF. Interacting with experimental researchers, we contributed to knowledge transfer between computational modelling and experimental communities, thus enabling improved real-world applications.
We improved the community’s understanding of the immersed-boundary-lattice-Boltzmann method by developing a model for stability and accuracy of the method.
SIRIUS generated fundamental understanding of the formation and stability of particle pairs in inertial particle microfluidics (IPMF), which helps designing improved devices for particle separation and manipulation.
The project advanced the community’s ability to model and simulate cross-slot cytometry, and uncovered how particle properties are linked to particle dynamics in cross-slot junctions.
SIRIUS generated fundamental understanding of the formation and stability of particle pairs in inertial particle microfluidics (IPMF), which helps designing improved devices for particle separation and manipulation.
The project advanced the community’s ability to model and simulate cross-slot cytometry, and uncovered how particle properties are linked to particle dynamics in cross-slot junctions.