Electrochemical Aptamer-Based Neurotransmitter Sensors for Application in Precision Psychiatry

Neurotransmitters, such as dopamine and serotonin, are endogenous chemicals that enable neurons to communicate with one another throughout the body. Alterations in the levels of specific neurotransmitters are associated with various neuropsychiatric disorders. Dopamine (DA) - often known as the feel-good hormone – is primarily responsible for reward and motivation and is a key biomarker of Parkinson’s disease. Medications such as Levodopa alter its level in biological fluids, monitoring of which is important to ensure the proper therapeutic range for sufficient medication to cross the blood-brain barrier. Serotonin (5-HT) regulates mood, stress response, sleep, and autonomic function, and its dysregulation is implicated in depression, anxiety, and other neuropsychiatric disorders. Continuous or longitudinal monitoring of serotonin—especially in accessible biological matrices—can provide critical insights into serotonergic modulation, drug response (e.g., depression medication: SSRI-selective serotonin reuptake inhibitors), and mental-health–related physiological states beyond invasive blood measurements. This work utilizes electrochemical aptamer-based (EAB) sensors with an optimized hydrogel layer to achieve high sensitivity to neurotransmitters (DA and 5-HT). Aptamers are short nucleic acid sequences that selectively bind to target molecules, undergoing conformational changes that generate electrochemical or optical signals, and have been shown to achieve femtomolar sensitivity for neurotransmitter detection. By attaching a redox reporter, such as methylene blue (MB), to one end of the aptamer, target binding can induce specific electrochemical activity. This work leverages the electrochemical activity generated through MB-modified aptamer binding with target neurotransmitters, interrogated using square-wave voltammetry. Flexible three-electrode sensors fabricated on a polyimide substrate via gold evaporation using the shadow mask technique enable the interfacing of the sensors with a wide range of biological organs (Figure 1a). A carefully optimized working electrode activation scheme for flexible substrates, along with aptamer and backfilling layer modification parameters (Figure 1b and 1c), enable high sensitivity in the nanomolar to micromolar range (Figures 1f and 1g). A key challenge in EAB sensor interfacing with biological media is the potential damage to functionalized aptamers and self-assembled monolayers, which causes alterations in molecular conformation and binding affinity in complex physiological matrices, thereby reducing sensitivity and stability. A hydrogel layer is crucial for addressing this issue in bio-interfacing, as aptamer recognition relies on a stable, hydrated microenvironment. To address this need, a composite hydrogel system is utilized as a protective layer, combining the mechanical robustness and tunable crosslinking density of polyethylene glycol-based polymer hydrogels with the high water retention, biocompatibility, and biomimetic properties of hyaluronic acid-based polymers. By systematically tuning the constituent composition, crosslinking density, and hydration properties, the hydrogel layer was engineered to provide a stable, highly hydrated microenvironment that minimizes aptamer loss while avoiding excessive diffusion barriers. This optimized hydrogel layer enables the interfacing of EAB sensors with a wide range of biological media, including sweat, interstitial fluid, and gastrointestinal fluids. Moreover, through the use of an analog front end capable of performing square-wave voltammetry up to 400Hz, this sensor platform can be utilized for real-time wireless monitoring of dopamine and serotonin. This work leverages advances in materials, fabrication, electrochemistry, and electronics to realize flexible EAB sensors with enhanced sensitivity and seamless data acquisition for neurotransmitter monitoring. The sensor platform has the potential to advance research on neurotransmitter dysregulation-related psychiatric diseases and guide future therapeutic interventions. Figure 1