Electrochemical Microneedles for Real-Time Monitoring in Interstitial Fluid: Emerging Technologies and Future Directions

Abstract

Conventional blood-based detection methods for biomarkers and analytes face significant limitations, including complex processing, variability in blood components, and the inability to provide continuous monitoring. These challenges hinder the early diagnosis and effective management of various health conditions. Electrochemical microneedles (MNs) have emerged as a minimally invasive and highly efficient platform to overcome these barriers, enabling continuous molecular monitoring by directly accessing the interstitial fluid. Electrochemical MNs offer several advantages, including reduced patient discomfort, real-time data acquisition, enhanced specificity, and potential applications in wearable, long-term monitoring. In this review, we first analyze material selection and fabrication techniques to optimize sensor performance, stability, and biocompatibility. We then examine diverse detection strategies utilized in electrochemical MNs, including enzyme-based, aptamer-based, and antibody-based sensing mechanisms, each offering unique benefits in sensitivity and selectivity. Finally, we highlight the integration of electrochemical MN technology with multi-target detection, AI-driven analytics, and theragnostic capabilities. This convergence offers strong potential for smart healthcare and precision medicine. Through these technological innovations, electrochemical MNs are expected to play an important role in advancing continuous, noninvasive health monitoring and personalized medical care.

Keywords: electrochemical detection; electrochemical microneedle (MN); interstitial fluid (ISF); real-time monitoring; wearable sensor.

Figure 1

Materials integration in electrochemical-based MNs. (a) Schematic illustration of a PL-pMNA-based biosensing platform. Reprinted with permission from [37]. Copyright 2024, Wiley-VCH. (b) Schematic diagram of HMN-CKM device application on the back of a rat. Reprinted with permission from [65]. Copyright 2024, Wiley-VCH. (c) Graphical illustration of “hospital-on-a-chip” inspired by the MXene MN system. Reprinted with permission from [76]. Copyright 2021, American Chemical Society.

Figure 8

Recent advances in electrochemical MN wearable sensors for personal healthcare. (a) Schematic diagram of a wearable MN-based multiplexed sensor system in ISF with Bluetooth signal transmission capabilities. Reprinted with permission from [176]. Copyright 2024, Elsevier. (b) Schematic illustration of a wearable MN-integrated electrochemical sensor for lidocaine detection featuring wireless signal transmission and machine learning-enabled data analysis. Reprinted with permission from [179]. Copyright 2024, Elsevier. (c) Graphical scheme of a wearable MN-based platform for MTX monitoring and on-demand iontophoretic drug delivery demonstrating sensing and controlled release capabilities in in vitro models. Reprinted with permission from [182]. Copyright 2023, American Chemical Society.

Figure 2

Fabrication methods for electrochemical-based MNs. (a) Schematic illustration of MN fabrication using subsequent photolithography and DRIE processes. Reprinted with permission from [91]. Copyright 2021, Springer Nature. (b) Schematic diagram of SU-8/SWCNT MN fabrication using casting and molding methods. Reprinted with permission from [93]. Copyright 2023, Elsevier. (c) Schematic of MN design using 3D printing and MN electrode fabrication using inkjet printing. Reprinted with permission from [95]. Copyright 2025, Royal Society of Chemistry. (d) Schematic diagram of LIG-MN patches using laser cutting technology. Reprinted with permission from [97]. Copyright 2024, Elsevier.

Figure 3

Direct detection in ISF using electrochemical MNs. (a) Schematic graphic of the HMN-CGM system for glucose monitoring using an NP-integrated HMN electrode. Reprinted with permission from [50]. Copyright 2022, Wiley-VCH. (b) Schematic illustration of uMEP for UA sensing in ISF via GO/MWCNT MNs. Reprinted with permission from [126]. Copyright 2024, American Chemical Society. (c) Schematic diagram of the fabrication and application of PMNA-based MN electrode patch enabling direct electrochemical sensing. Reprinted with permission from [142]. Copyright 2024, Elsevier.

Figure 4

Enzyme-based detection in ISF using electrochemical MNs. (a) Schematic graphic of cholesterol detection using a ChOx/Nafion-functionalized Pt electrode integrated into a hollow MN array. Reprinted with permission from [128]. Copyright 2024, Royal Society of Chemistry. (b) Schematic illustration of BHB monitoring in ISF using an MN sensor with selective NADH oxidation and wireless readout. The black line in the chronoamperometric response graph represents sensor data, while red dots indicate finger-prick validation. Reprinted with permission from [153]. Copyright 2024, American Chemical Society. (c) Illustration of monitoring of β-lactam antibiotics using an MN sensor via β-lactamase-induced pH change. Graph shows the in vivo response of three β-lactamase microneedle biosensors (red, green, and dark blue) applied to a human subject, along with serum (pink) and dialysate (light blue) penicillin V concentrations over time. Reprinted with permission from [129]. Copyright 2019, American Chemical Society.

Figure 5

Aptamer-based detection of electrochemical MNs in ISF detection. (a) Schematic of the fabrication of the Wearable Aptalyzer and in vivo sensing process with target-specific recognition. Reprinted with permission from [130]. Copyright 2024, Wiley-VCH. (b) Schematic illustration of the fabrication of MNs deposited with dendritic AuNPs and their aptamer modification. Reprinted with permission from [131]. Copyright 2024, Elsevier. (c) Schematic diagram of the μNEAB sensor and the aptamer-target binding process. Reprinted with permission from [8]. Copyright 2022, AAAS.

Figure 6

Antibody-based detection in ISF using electrochemical MNs. (a) Schematic diagram of Au–Si MN array immunosensor for selective HER2 detection in ISF. Reprinted with permission from [132]. Copyright 2021, Elsevier. (b) Pictorial scheme of MN patch for cytokine detection in ISF using CNT-enhanced electrochemical sensing. Reprinted with permission from [133]. Copyright 2023, Wiley-VCH. (c) Schematic illustration of a needle-shaped, antibody-functionalized microelectrode array for electrochemical antigen detection. Reprinted with permission from [134]. Copyright 2019, Elsevier.

Figure 7

Alternative detection strategies in ISF using electrochemical MNs. (a) Scheme of an MIP-functionalized MN sensor enabling selective and label-free IL-6 detection. Reprinted with permission from [135]. Copyright 2021, American Chemical Society. (b) Schematic diagram of an electrode-integrated MN patch (MNP-EA) for real-time, label-free detection of Na⁺, K⁺, Ca²⁺, and pH using ion-selective membranes. Reprinted with permission from [170]. Copyright 2023, American Chemical Society. (c) Schematic illustration of a tyrosinase-responsive MN sensor patch for melanoma detection via epidermal application and smart probe-based electrochemical sensing. Reprinted with permission from [136]. Copyright 2024, Wiley-VCH.