Modeling and Control of Microscale Cell Culture Environments

Abstract

Culturing cells in vitro is one of the core techniques used in a wide range of biomedical engineering areas. Special care is required to successfully grow cells in an artificial environment. It is essential to ensure that the culture environment is cell-friendly and sterile, supplies important products such as nutrients and growth factors, and provides a proper physiological microenvironment. To optimize long-term cell culturing, parameters such as pH, oxygen concentration, and temperature, should be precisely maintained at the desired levels. Furthermore, it is sometimes desirable to change environmental parameter(s) in a controlled way to study the cell response.<br/><br/>Bioreactors are typically used for cell culture in vitro. However, precise control of each cell culture’s microenvironment is difficult, leading to uneven culture conditions that can affect cell behavior. Furthermore, studying how certain environmental parameter affect the cultures is challenging, as it is difficult, or even impossible, to vary certain parameters in a controlled manner between each culture.<br/><br/>Microscale cell culture systems, known as microbioreactors, have recently been extensively studied to enhance control and improve long-term cell culturing by better mimicking cells’ microenvironments. Microbioreactors provide better environment control, thereby enhancing long-term cell cultivation. Unfortunately, integrating microbioreactors with the required sensors, actuators, electronics and other required devices can be challenging. Implementing sensors near the cell culture can also disturb them or prevent other measurements, such as optical microscopy. Certain measurements, such as direct longterm pH measurement, can be impossible, as there are no suitable microscale sensors available.<br/><br/>For these reasons, there is a huge demand for methods that can be used to study and develop proper microbioreactors. This thesis includes several studies in which modeling was used as design tools to improve and control culture environments. First, an analytical model to study gravity-driven flows in microfluidic devices is developed. Next, developed finite element method (FEM) computer models are used to study fluid flow profiles, drug distributions, shear stress levels on cells, and sensitivity of a calorimetric flow measurement system. A FEM model of carbon dioxide transport and liquid pH is also created. Additionally, the thesis proposes a novel method to indirectly control the cell culture temperature. Using system identification techniques, a developed estimation model can precisely control temperature with a sensor that does not disturb cells or other measurements. Although this thesis only demonstrates temperature control in the cell culture, the method can potentially be used to control other environment parameters as well. Lastly, this thesis considers the limitations of the presented models and control methods, and provides recommendations for future studies.