Cellular metabolism biosensing: From extracellular microenvironment to intracellular physiology monitoring

Metabolism is crucial for the growth, development, and life activities of organisms. Microsensors designed to monitor cellular metabolism are essential for investigation in cell culture. Electrochemical and optical sensors are dominantly applied to analyze classic metabolites in extracellular microenvironments, such as protons, oxygen, glucose, pyruvate, lactate, and reactive oxygen/nitrogen species. These methodologies facilitate the label-free, noninvasive, and continuous recording of transient effects, providing insights beyond static images and endpoint assays. This comprehensive review aims to critically evaluate and discuss advances in cellular metabolic monitoring, particularly focusing on the utilization of integrated biosensors in cell culture and detection systems, which are commonly termed as microphysiological systems. Initially, metabolic pathways are analyzed to elucidate the roles of key metabolites related to acidification, respiration, energy metabolism, and transient reactive species. Subsequently, this review comprehensively discusses sensing analytes, mechanisms, systems, cultures, and applications in advanced multimodal biosensing systems, including commercial products, as documented in references. Finally, current challenges and future directions associated with the development of more advanced metabolic biosensing systems are delineated to enhance their sensing capabilities, and meet the emerging clinical and scientific demands.