~A Comprehensive Pipeline from Biomolecular Design to Autonomous Clinical Intervention~ 

 

Our research program establishes a multi-scale pipeline transitioning from the rational design of biomolecules to advanced biosensing platforms, culminating in long-term, continuous monitoring systems. Our ultimate goal is to transform chronic disease management through autonomous, closed-loop therapeutic devices. The core scientific pillar of this work is Direct Electron Transfer (DET), facilitating a seamless, mediator-less exchange of electrons between biological recognition elements and electronic transducers.  

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1.  Biomolecular Engineering: Creating Innovative Biological Recognition Elements 

The foundation of our work lies in the structural engineering of "ideal" biological recognition elements (BREs) to expand continuous monitoring beyond glucose.  

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1.1.  Biocatalytic Recognition Elements (BioCat-BREs) 

• Advantages of DET: Third-generation sensors utilize DET-type enzymes to bypass ambient oxygen or toxic chemical mediators, operating at low overpotentials to minimize chemical interference during in vivo use.  

• Engineering Novel DET Functionality: By genetically fusing electron transfer domains (e.g., hemes) or employing "2.5th generation" quasi-DET techniques with built-in redox probes, we have created novel continuous monitoring engines for glucose, lactate, glutamate, polyamine, GABA, levodopa, and ketone bodies (beta-hydroxybutyrate).  

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1.2.  Bioaffinity Recognition Elements (BioAff-BREs) 

• Anti-Idiotype Strategy: To monitor therapeutic monoclonal antibodies (mAbs) amidst a high background of endogenous IgGs, we develop anti-idiotype aptamers and antibodies that specifically recognize the drug’s unique complementarity-determining regions (CDRs).  

• In Situ Regeneration: To overcome the challenge of target entrapment caused by high binding affinity, we design environmentally responsive antibodies and aptamers that allow for controlled dissociation in response to localized electrochemical signals.  

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2.  A Multi-Scale Pipeline for Biosensor Development 

 

We translate engineered biomolecules into next-generation biosensing platforms designed to achieve long-term, continuous monitoring for precision medicine.  

 

2.1.  DET and Quasi-DET Enzymatic Platforms:  

 

We apply protein engineering to build 3rd-generation sensors (demonstrated for glucose, lactate, levodopa, and spermine/spermidine). For non-DET enzymes, a site-specific wiring strategy using amine-reactive phenazine ethosulfate (arPES) enables quasi-DET sensing of glucose, glycated proteins, lactate, D-serine, glutamate, GABA, and ketone bodies.  

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2.2.  Size-Independent Sensing Modalities:  

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To replace conventional amperometry and enable extreme miniaturization, we utilize Open Circuit Potential (OCP) & Transient Potentiometry, which maintain high sensitivity at the 10 µm scale with sub-second temporal resolution. Additionally, DET-Integrated EGFETs provide label-free signal amplification and robust readout in complex media.  

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2.3.  High-Sensitivity Sensing for Proteins and Nucleic Acids:  

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We utilize Electrochemical Impedance Spectroscopy (EIS) for the label-free detection of proteins like insulin and UCH-L1 with pathways toward in vivo monitoring, alongside aptamer systems for therapeutic mAb tracking.  

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2.4.  Continuous Monitoring & Stability:  

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Our DET-OCP glucose sensors have demonstrated stable physiological operation for up to 3 months. We have achieved cross-talk-free simultaneous dual-biomarker monitoring (glucose/lactate). Furthermore, through de novo engineering of copper ligand residues, we developed Copper Dehydrogenase (CoDH) for continuous levodopa monitoring.  

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3. Future Outlook: Precision Medicine and Closed-Loop Systems 

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These engineered recognition elements form the foundation for next-generation medical devices providing Total Physiological Awareness.  

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• AI-Driven Design: Utilizing AI-based protein structure prediction to accelerate the design of recognition elements with optimized electron transfer and refined binding properties. 

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• Multimodal Monitoring: Integrating sensors for glucose, lactate, and ketones for comprehensive metabolic assessment.  

 

Through molecular-level biomolecular engineering, our laboratory bridges the gap between laboratory testing and autonomous clinical intervention to realize personalized, closed-loop therapeutic systems.  

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