The development of Point-of-Care (POC) biosensors strives to facilitate rapid, sensitive, and reliable detection of disease biomarkers in a cost-effective and convenient manner.1 Continuous POC testing over extended periods is particularly vital for medication management, including adaptive cancer therapy and recurrence diagnosis.
My focus on transistor biosensing began during the COVID-19 pandemic. At that time, the state of SARS-CoV-2 biomarker testing highlighted the difficulty in creating highly sensitive yet affordable biosensor devices for serial biomarker detection. We recognized that making high-sensitivity POC sensors reusable by end-users could significantly reduce diagnostic costs and enhance disease control efforts.
Both previous reports and our preliminary experiments have demonstrated that organic electrochemical transistors (OECTs) are a stable and sensitive class of biosensors. Consequently, our primary challenge is to identify sensing probes that not only fulfill the sensitivity requirements for OECT functionalization but are also capable of multiple regenerations. We unleashed our boundless imagination to envision this type of probe. Firstly, these probes should have a designable targeting ability for the specific recognition of various biomarkers. Secondly, to achieve simple and gentle regeneration, the interactions between transducer surface-sensing probe or sensing probe–target analyte should ideally be weak, while the probe’s active structure remains stable. Lastly, it would be advantageous if the probe itself could directly modulate the transistor’s electrical performance.
We analyzed various existing probes and found it challenging to identify suitable types. The commercial glucose meter serves as a good example of a reusable biosensor; however, enzyme probes in such devices are primarily effective for detecting small molecules. Antibodies and nucleic acids, widely adopted as probes in biosensing, have been successfully applied in transistor biosensors in recent years. However, their affinities are highly sensitive to molecular assembly and sensing conditions, often necessitating professional operations for reactivation. This complexity renders them unsuitable for reusable POC applications.
Zhang’s previous research2 inspired us to consider using drug molecules as sensing probes on OECTs. Her studies revealed that conjugated drug molecules can not only be used for targeted therapy in disease treatment but also play a significant role in carrier transport modulation of transistors. We pondered: what if these two functionalities could be effectively integrated into an OECT biosensor? The stable and diverse molecular structure of drug probes could provide greater flexibility for refreshing the transducer surface, enhancing both performance and usability.
Under the guidance of Prof. Di and Prof. Zhang, we selected several drug probe-target analyte pairs and designed various strategies for probe grafting and target sensing. Fortunately, the gefitinib-functionalized OECT devices demonstrated excellent detection sensitivity to the EGFR protein. Notably, when gefitinib was non-covalently grafted onto the transducer surface (PEDOT:PSS), its specific signals significantly decreased upon EGFR rinsing, as characterized by XPS. This observation led us to hypothesize that the sensing process might inherently refresh the transducer surface without the need for additional cleaning steps—a phenomenon rarely reported before. This refreshing in sensing (RIS) process turned out to be much simpler than anticipated. We conducted further characterizations and confirmed this concept. Additionally, the device’s sensing performance could be recovered by simply soaking it in a gefitinib solution. Impressively, this approach enabled an unprecedented regeneration cycle exceeding 200 uses.
While thrilled by these findings, we also pondered the mechanism and potential applications of this reusable device. Why does it exhibit such remarkable sensitivity and regenerability? Could this phenomenon be universal to other drug probe-target analyte pairs? Can this device be used in clinical applications? Driven by these questions, we decided to uncover the mechanism first. After numerous discussions and experimental analyses, we deduced that the high sensitivity is induced by the reversible surface gating effect of ionic drug probes. Additionally, the competitive interaction between gefitinib-PEDOT:PSS and gefitinib-EGFR leads to the RIS process on our OECT device.
With a deeper understanding of the mechanism, we explored the universality of the RIS concept in various types of drug-functionalized OECT biosensors. The excellent sensing performance of refreshed devices was also demonstrated on clinical samples from non-small cell lung cancer patients. We are pleased to see the expansion of our device into diagnostic arrays and its application on a POC biosensing platform. We hope that RIS concept-derived reusable biosensor devices can help achieve better disease diagnosis and control in the future.
For more details, please refer to our paper “A drug-mediated organic electrochemical transistor for robustly reusable biosensors” in Nature Materials (2024). https://doi.org/10.1038/s41563-024-01970-5
1 Land, K.J., Boeras, D.I., Chen, XS. et al. REASSURED diagnostics to inform disease control strategies, strengthen health systems and improve patient outcomes. Nat. Microbiol. 2019, 4, 46–54.
2 Zhang, F., Lemaur, V., Choi, W. et al. Repurposing DNA-binding agents as H-bonded organic semiconductors. Nat. Commun. 2019, 10, 4217.
Reusable OECT biosensor | Research Communities by Springer Nature
