Thin film, wireless, flexible sensing system for real-time cell-culture monitoring

Abstract

As the demonstrated effectiveness of stem cell therapies in regenerative medicine increases, there is a growing demand for scale-up and standardization of cell proliferation processes. The design and functionality of in-vitro vessels used in these processes often have adverse impact on cell behavior, differentiation, and survival rate. In fact, mechanical force and stress from hard devices interfacing physically with cells affect cell differentiation, size, and shape. Commercial and industry-level sensitive cell proliferation processes can benefit from cell bag bioreactors that are deformable soft bag structured vessels. This thesis demonstrates that hard-soft material integration and flexible circuit fabrication techniques, that are used in implantable and wearable medical applications to achieve conformal contact with deformable surfaces, can potentially be used to design a flexible small form factor monitoring system for cell bag bioreactors. Since polymer encapsulated flexible electronics and thin film sensors achieve lower stiffness and higher flexibility, they can form a monitoring system that has the capacity to undergo deformation with the soft cell-bag reactor wall. Such a system could eliminate the need for cell bag bioreactors to be interfaced with hard and rigid sensing systems, introducing a bioreactor configuration that is more cell friendly. Additionally, the small form factor of the miniaturized sensors, fabricated using MEMs techniques on wafers, can be incorporated in a high-density sensor array to achieve localized multi-point spatial resolution monitoring in cell cultures of large volumes. Further on, it reports the results of development and tests of prototype sensors and a custom data acquisition system for such a cell bioreactor monitoring system. The data acquisition electronics are based on soft material employing reduced area and thinned ICs to obtain a lower overall stiffness. The system samples eight temperature and eight pH sensors using multiplexers and a high precision ADC being run by a low power on-board micro-controller. The sensors are characterized separately, once before connection to the DAQ system and once after connection with the DAQ system, for performance parameters. Data processing is used to compensate pH measurements for variations due to temperature. The system is verified in cell culture basal media solution, Dulbecco's Modified Eagle's medium (DMEM), and the current bottlenecks for long-term continuous measurements in culture immersion are discussed.