Abstract
There is an increasing interest in developing microfluidic bioreactors and organs-on-a-chip platforms combined with sensing capabilities for continual monitoring of cell-secreted biomarkers. Conventional approaches such as ELISA and mass spectroscopy cannot satisfy the needs of continual monitoring as they are labor-intensive and not easily integrable with low-volume bioreactors. This paper reports on the development of an automated microfluidic bead-based electrochemical immunosensor for in-line measurement of cell-secreted biomarkers. For the operation of the multi-use immunosensor, disposable magnetic microbeads were used to immobilize biomarker-recognition molecules. Microvalves were further integrated in the microfluidic immunosensor chip to achieve programmable operations of the immunoassay including bead loading and unloading, binding, washing, and electrochemical sensing. The platform allowed convenient integration of the immunosensor with liver-on-chips to carry out continual quantification of biomarkers secreted from hepatocytes. Transferrin and albumin productions were monitored during a 5-day hepatotoxicity assessment in which human primary hepatocytes cultured in the bioreactor were treated with acetaminophen. Taken together, our unique microfluidic immunosensor provides a new platform for in-line detection of biomarkers in low volumes and long-term in vitro assessments of cellular functions in microfluidic bioreactors and organs-on-chips.
Highlights
IntroductionA sensing platform should allow for convenient integration with a microfluidic bioreactor with the capability of automated interface and integrated control[7], which can improve the accuracy of measurements
The sensitivity of the EC immunoassay was optimized off-chip against the number of MBs, concentrations of secondary antibody and streptavidin horseradish peroxidase (SA-HRP), and the incubation time, after which, the biomarker measurements were performed within the biological concentration range (0–16,000 ng/ml)
The automated operation of the microfluidic system for biomarker detection was achieved through integrated microvalves for required liquid manipulations including bead loading, binding steps, washing processes, and sample loading
Summary
A sensing platform should allow for convenient integration with a microfluidic bioreactor with the capability of automated interface and integrated control[7], which can improve the accuracy of measurements Conventional approaches such as ELISA and mass spectroscopy cannot fulfill the requirements of continual monitoring because they are labor-intensive and not integrable with low-volume bioreactors. Among the available analytical methods integrated with microscale systems to measure biomolecules[10,11,12,13,14,15,16,17,18,19], electrochemical (EC) techniques[20,21,22,23] are highly suited for microfluidic systems This is mainly due to easy miniaturization of detection elements and high degree of integration ability with analytical functions for analysis of small-volume biochemical samples at low cost[22]. Such a surface immobilization strategy hinders the use of the sensor for continual analysis of biomolecules due to the saturation of the electrodes over repeated detection cycles[23]
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