Challenges and strategies faced in the electrochemical biosensing analysis of neurochemicals in vivo: A review

Our brain is an intricate neuromodulatory network, and various neurochemicals, including neurotransmitters, neuromodulators, gases, ions, and energy metabolites, play important roles in regulating normal brain function. Abnormal release or imbalance of these substances will lead to various diseases such as Parkinson's and Alzheimer's diseases, therefore, in situ and real-time analysis of neurochemical interactions in pathophysiological conditions is beneficial to facilitate our understanding of brain function. Implantable electrochemical biosensors are capable of monitoring neurochemical signals in real time in extracellular fluid of specific brain regions because they can provide excellent temporal and spatial resolution. However, in vivo electrochemical biosensing analysis mainly faces the following challenges: First, foreign body reactions induced by microelectrode implantation, non-specific adsorption of proteins and redox products, and aggregation of glial cells, which will cause irreversible degradation of performance such as stability and sensitivity of the microsensor and eventually lead to signal loss; Second, various neurochemicals coexist in the complex brain environment, and electroactive substances with similar formal potentials interfere with each other. Therefore, it is a great challenge to design recognition molecules and tailor functional surfaces to develop in vivo electrochemical biosensors with high selectivity. Here, we take the above challenges as a starting point and detail the basic design principles for improving in vivo stability, selectivity and sensitivity of microsensors through some specific functionalized surface strategies as case studies. At the same time, we summarize surface modification strategies for in vivo electrochemical biosensing analysis of some important neurochemicals for researchers' reference. In addition, we also focus on the electrochemical detection of low basal concentrations of neurochemicals in vivo via amperometric waveform techniques, as well as the stability and biocompatibility of reference electrodes during longterm sensing, and provide an outlook on the future direction of in vivo electrochemical neurosensing.