Designing Recognition Molecules and Tailoring Functional Surfaces for In Vivo Monitoring of Small Molecules in the Brain.

The in vivo analysis of chemical signals in brain extracellular fluid (ECF) using implanted electrochemical biosensors is a vital way to study brain functions and brain activity mapping. This approach offers excellent spatial (10-200 μm) and temporal (approximately second) resolution and the major advantage of long-term stability. By implantation of a microelectrode in a specific brain region, changes in the concentration of a variety of ECF chemical species can be monitored through applying a suitable electrical signal and, typically, recording the resulting Faradaic current. However, the high performance requirements for in vivo biosensors greatly limit our understanding of the roles that biomolecules play in the brain. Since a large number of biological species, including reactive oxygen species (ROS), metal ions, amino acids, and proteins, coexist in the brain and interact with each other, developing in vivo biosensors with high selectivity is a great challenge. Meanwhile, it is difficult to quantitatively determine target molecules in the brain because of the variation in the distinct environments for monitoring biomolecules in vitro and in vivo. Thus, there are large errors in the quantification of concentrations in the brain using calibration curves obtained in artificial cerebrospinal fluid (aCSF). More importantly, to gain a full understanding of the physiological and pathological processes in the brain, the development of novel approaches for the simultaneous determination of multiple species in vivo is urgently needed. This Account provides insight into the basic design principles and criteria required to convert chemical/electrochemical reactions into electric signals, while satisfying the increasing requirements, including high selectivity, sensitivity, and accuracy, for the in vivo analysis of biomolecules in the brain. Recent developments in designing various functional surfaces, such as self-assembled monolayers, gold nanostructures, and nanostructured semiconductors for facilitating electron transfer from specific enzymes, including superoxide dismutase (SOD), and further application to an O2 •- biosensor are summarized. This Account also aims to highlight the design principles for the selective biosensing of Cu2+ and pH in the brain through the rational design and synthesis of specific recognition molecules. Additionally, electrochemical ratiometric biosensors with current signal output have been constructed to correct the effect of distinct environments in a timely manner, thus greatly improving the accuracy of the determination of Cu2+ in the live brain. This method of using a built-in element has been extended to biosensors with the potential signal output for in vivo pH analysis. More importantly, the new concept of both current and potential signal outputs provides an avenue to simultaneously determine dual species in the brain. The extension of the design principles and developed strategy demonstrated in this Account to other biomolecules, which may be closely correlated to the biological processes of brain events, is promising. The final section of this Account outlines potential future directions in tailoring functional surfaces and designing recognition molecules based on recent advances in molecular science, nanoscience and nanotechnology, and biological chemistry for the design of advanced devices with multiple target species to map the molecular imaging of the brain. There are still opportunities to engineer surfaces that improve on this approach by constructing implantable, multifunctional nanodevices that promise to combine the benefits of multiple sensing and therapeutic modules.