High-Throughput Microfluidic Bioreactor Compatible with Standard 96 Well Plate
Open Access DepositedBioreactors as a technology enable the development of a controlled environment for a wide variety of applications including cell culture, tissue engineering, disease modeling, and drug development. These reactors may better model physiological conditions by providing relevant nutrient delivery, shear stresses, and growth surfaces. One area of study aided by the implantation of perfusion bioreactors is that of bacterial biofilms. Biofilm infections represent a major public health threat due to their high tolerance to antimicrobials and the lack of specific anti-biofilm drugs. In vitro biofilm bioreactors such as the CDC biofilm reactor have been developed to deliver conditions such as material growth substrate, shear stress, and oxygenation. However, these reactors often require bulky setups, suffer from low throughput, and may be incompatible with in situ evaluation techniques. Furthermore, the area of cardiac tissue engineering benefits from the use of perfusion bioreactors to enable chronic cell culture and physiologically relevant multicellular environment. Static cultures for such highly metabolically-active samples over longer periods of time may fail to provide proper oxygenation under increased workload. As a result, it is highly desirable for a high throughput (HT) platform that allows characterization and measurements of function in these cells in situ within their multicellular environment.This dissertation focuses on a platform that incorporates the high-throughput format and convenience of a standard 96 well-plate with the capability of a microfluidic perfusion flow cell system. The fabrication, characterization, and testing of system components is demonstrated both through numerical simulation and experimentally through the culture and evaluation of bacterial biofilm under varying shear stress conditions. The potential of the platform is further demonstrated through the addition of in situ optical pericellular oxygen sensor, and the method of characterizing, calibrating, and testing those sensors is discussed. Additionally, this work describes a theoretical framework to assess bioreactor oxygen transport and fluid shear stress for given design inputs. This framework is validated with numerical simulation and experiments to achieve reactor pericellular oxygen and fluid shear stress informed by channel geometry and volumetric flow rate. The significance of this research is to overcome existing limitations of bulk and in situ evaluation techniques for bioreactors by employing microfluidic technology, numerical simulation, and advanced fabrication techniques. By addressing these challenges, this dissertation presents a path for innovation in the areas of cell culture, tissue engineering, and disease modeling.
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