A prototype of the microsensing system for i<i>n vivo</i> drug monitoring in the skin with diamond electrode
At a Glance
Section titled âAt a Glanceâ| Metadata | Details |
|---|---|
| Publication Date | 2022-01-01 |
| Journal | Proceedings for Annual Meeting of The Japanese Pharmacological Society |
| Authors | Norzahirah Ahmad, Seishiro Sawamura, Genki Ogata, Yasuaki Einaga, Hiroshi Hibino |
| Institutions | Keio University, The University of Osaka |
| Analysis | Full AI Review Included |
Executive Summary
Section titled âExecutive SummaryâThis research details the development and validation of a novel, needle-type Boron-Doped Diamond (BDD) microsensing system designed for real-time, minimally invasive drug monitoring in the dermal interstitial fluid (ISF).
- Core Technology: A needle-type BDD electrode utilized for highly stable electrochemical detection of drug molecules via redox reaction.
- Value Proposition: Enables real-time Pharmacokinetic (PK) tracking in the skin, overcoming the delays and invasiveness associated with conventional plasma sampling methods.
- Target Analyte: The anticancer drug Doxorubicin was selected as the test compound due to its redox activity.
- Performance Range: The BDD microsensor demonstrated a calibration curve covering the critical therapeutic window of 10 to 100 nM in vitro.
- In Vivo Achievement: Successful insertion and tracking of local Doxorubicin PK in the dermis layer of anesthetized rats for >1 hour post-injection.
- Key PK Results: Measured local maximum concentration (Cmax) was 3.1 ± 1.4 nM, occurring at a time (Tmax) of 33.6 ± 20.6 minutes.
- System Integration: The local dermal measurements are intended to be linked via a derived formula to provide real-time monitoring of systemic (plasma) PK.
Technical Specifications
Section titled âTechnical Specificationsâ| Parameter | Value | Unit | Context |
|---|---|---|---|
| Electrode Material | Boron-Doped Diamond (BDD) | N/A | Sensing element |
| Electrode Geometry | Needle-type | N/A | Designed for dermal insertion |
| Detection Principle | Redox Reaction | N/A | Electrochemical sensing mechanism |
| Analyte Tested | Doxorubicin | N/A | Anticancer drug |
| Applied Potential | Negative | Potential | Required for Doxorubicin current response |
| Calibration Range (In Vitro) | 10 - 100 | nM | Covers the therapeutic window |
| In Vivo Tracking Duration | >1 | hour | Post-intravenous injection monitoring |
| Local Cmax (Dermis) | 3.1 ± 1.4 | nM | Maximum concentration observed (n=7) |
| Local Tmax (Dermis) | 33.6 ± 20.6 | mins | Time to maximum concentration observed (n=7) |
| Sample Size (In Vivo) | 7 | N/A | Number of anesthetized live rats tested |
Key Methodologies
Section titled âKey MethodologiesâThe microsensing system was validated through a multi-stage experimental process, leveraging the unique electrochemical properties of BDD electrodes:
- Sensor Fabrication: A needle-type Boron-Doped Diamond (BDD) electrode was manufactured to allow for minimally invasive insertion into biological tissue.
- In Vitro Characterization: The BDD microsensor was tested using the analyte Doxorubicin, confirming that the drug elicited a measurable current response when a negative potential was applied.
- Calibration Curve Development: An in vitro calibration curve was established, demonstrating linearity and sensitivity across the critical therapeutic concentration range (10-100 nM).
- Ex Vivo Validation: The sensorâs performance was further tested in collected interstitial fluids to confirm functionality in a complex biological matrix.
- In Vivo Insertion: The BDD sensor was carefully inserted into the dermis layer of anesthetized live rats.
- Drug Administration: Doxorubicin was administered to the rats via intravenous (IV) injection.
- Local PK Tracking: The sensor tracked the local drug concentration in the dermal interstitial fluid for a duration exceeding one hour, yielding Cmax and Tmax values.
- Systemic Correlation: A mathematical formula was employed to link the measured local dermal PK data (Cmax, Tmax) to predicted systemic (plasma) PK data, enabling real-time systemic monitoring.
Commercial Applications
Section titled âCommercial ApplicationsâThis BDD-based microsensing technology is highly relevant to industries requiring stable, sensitive, and real-time electrochemical monitoring in complex environments.
- Pharmaceutical Development & Clinical Trials:
- Continuous Therapeutic Drug Monitoring (TDM) for drugs with narrow therapeutic indices (like Doxorubicin).
- Real-time Pharmacokinetic (PK) and Pharmacodynamic (PD) studies, reducing the need for frequent blood draws.
- Medical Devices and Diagnostics:
- Development of minimally invasive or implantable biosensors (analogous to Continuous Glucose Monitors) for tracking drug levels or biomarkers.
- Wearable electrochemical patches utilizing BDD for stable, long-term monitoring.
- Diamond Electrochemistry:
- Applications requiring electrodes with an exceptionally wide potential window and high resistance to fouling, corrosion, and biofouling, which are key advantages of BDD.
- Detection of complex, redox-active organic molecules and neurotransmitters in vivo.
- Material Science:
- Advancement in the fabrication and integration of needle-type BDD microelectrodes for biomedical applications.
View Original Abstract
Monitoring of plasma drug concentrations is required for effective pharmacotherapy. Repetitive collection of whole blood followed by analysis of plasma samples with conventional methods delays representation of crucial results. Skin is an easily accessible organ; a portion of systemically circulating drug molecules is diffused to the dermal interstitial fluid. Thus, the compoundâs pharmacokinetics (PK) in the fluid mirrors the plasma PK. To approach such local dermal space, here we describe a microsensing system with a needle-type boron-doped diamond (BDD) electrode, which detects chemical compounds by redox reaction. As a test analyte we chose an anticancer drug, doxorubicin. In an in vitro experiment with a BDD microsensor, doxorubicin elicited a current in response to applied negative potential. Calibration curve covered the therapeutic window (10â100 nM). The sensorâs performance was also tested in the collected interstitial fluids. Finally, the sensor was inserted into the dermis layer in anesthetized live rats; after doxorubicin was intravenously injected, the local PK was tracked for >1 hour with the Cmax and Tmax 3.1 ± 1.4 nM and 33.6 ± 20.6 mins, respectively (n = 7). By combining a formula linking the local measurements to plasma data, this microsensing system may be applicable to real-time monitoring of systemic PK.