Lab-on-CMOS Sensors and Real-time Imaging for Biological Cell Monitoring

Monitoring biological cell growth and viability is essential for in vivo biomedical diagnosis and therapy, and in vitro studies of pharmaceutical efficacy and material toxicity. Conventional monitoring techniques involve the use of dyes and markers that can potentially introduce side effects into the cell culture and often function as end-point assays. This eliminates the opportunity to track fast changes and to determine temporal correlation between measurements. Particularly in drug screening applications, high-temporal resolution cell viability data could inform decisions on drug application protocols that could lead to better treatment outcomes. This work presents development of a lab-on-chip (LoC) sensor for real-time monitoring of biological cell viability and proliferation, to provide a comprehensive picture of the changes cells undergo during their lifecycle. The LoC sensor consists of a complementary metal-oxide-semiconductor (CMOS) chip that measures the cell-to-substrate coupling of adherent cells that are cultured directly on top. This technique is non-invasive, does not require biochemical labeling, and allows for automated and unsupervised cell monitoring. The CMOS capacitance sensor was designed to addresses the ubiquitous challenges of sensitivity, noise coupling, and dynamic range that affect existing sensors. The design includes on-chip digitization, serial data output, and programmable control logic in order to facilitate packaging requirements for biological experiments. Only a microcontroller is required for readout, making it suitable for applications outside the traditional laboratory setting. An imaging platform was developed to provide time-lapse images of the sensor surface, which allowed for concurrent visual and capacitance observation of the cells. Results showed the ability of the LoC sensor to detect single cell binding events and changes in cell morphology. The sensor was used in in vitro experiments to monitor chemotherapeutic agent potency on drug-resistant and drug-sensitive cancer cell lines. Concentrations higher than 5 μM elicited cytotoxic effects on both cell lines, while a dose of 1 μM allowed discrimination of the two cell types. The system demonstrates the use of real-time capacitance measurements as a proof-of-concept tool that has potential to hasten the drug development process