Can a Wearable Microneedle Biosensor Be Developed to Enable Early, Noninvasive Detection of Pro-inflammatory Cytokines in Dengue Infections Within Resource-Limited Settings?

Abstract:

Dengue virus (DENV) infections cause more than 390 million cases annually, (Bhatt et al., 2013) with the majority occurring in low- and middle-income countries across Latin America and Southeast Asia (WHO, 2024). Severe cases are frequently driven by a dysregulated immune response, leading to a cytokine storm characterized by elevated levels of pro-inflammatory markers such as IL-6 and TNF-α (Green et al., 2014). Early detection of these biomarkers is critical for effective triage and treatment, yet conventional diagnostic approaches, typically reliant on blood sampling and lab-based analysis, are invasive, costly, and often inaccessible in under-resourced settings, prolonged processes that strain already fragile healthcare infrastructures (Peeling et al., 2010). This paper explores the feasibility of a wearable microneedle biosensor designed to detect inflammatory cytokines noninvasively via interstitial fluid (ISF), that could enable continuous, point-of-care monitoring of patients at risk for severe disease, improving outcomes while reducing healthcare burden.

 

Introduction:

subtropical areas where vector control remains inconsistent and healthcare infrastructure is limited. Clinical management is complicated by the disease’s unpredictable progression: while most infections are asymptomatic or mild, a subset of patients rapidly deteriorate into severe dengue, marked by hemorrhage, plasma leakage, and organ dysfunction. (WHO, 2024). Importantly, this deterioration is not directly caused by the virus itself, but rather by the host's excessive immune response. (Martina et al., 2009). Research has identified several cytokines involved in this process, particularly interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ) as key drivers of dengue pathogenesis, that spike early during disease progression, even before clinical symptoms worsen (Martina et al., 2009). However, traditional diagnostic tools are typically focused on detecting viral antigens or antibodies, which do not offer insights into host immune activation and also require venous blood draws and centralized labs, making them poorly suited for rural or resource-scarce areas where dengue is most prevalent. Recent studies demonstrate that microneedle wearables, tiny patches that painlessly penetrate the outer skin to access ISF, can quantify levels of cytokines such as IL-6 in real time with precision, providing a dynamic window into systemic inflammation and immune dysregulation (Huang et al., 2023). ISF, which bathes skin cells and mirrors many components of blood plasma, is increasingly recognized as a viable medium for biomarker detection. A wearable microneedle biosensor could thus enable timely interventions before clinical deterioration occurs, representing a promising solution.

 

Literature Review:

Recent technological advances have brought microneedle biosensors closer to clinical reality. For instance, Takeuchi et al. (2021) demonstrated an array capable of detecting IL-6 in murine models using a sandwich immunoassay format integrated into a polymeric microneedle patch. Similarly, Zhao et al. (2022) created a functional wearable patch that could detect TNF-α in vitro with electrochemical transduction, achieving nanomolar sensitivity. These studies validate the underlying principles of cytokine monitoring through ISF, but none have yet been translated into tools for infectious disease triage. Dengue and other arboviruses represent ideal use cases for this emerging technology. In dengue-endemic regions, especially those affected by recurring epidemics, early identification of patients at risk for severe outcomes could dramatically reduce hospitalization rates and mortality. Studies by Soundravally et al. (2015) show that IL-6, IFN-γ, and IL-10 levels are significantly elevated during the febrile phase in patients who later develop severe dengue. If these cytokines could be monitored in real time, health workers could prioritize high-risk individuals even in the absence of laboratory support.

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Nonetheless, there are technical and systemic gaps. Most biosensor platforms focus on cancer or metabolic conditions, not infectious diseases. Current standard methods, such ELISA or multiplex bead-based assays, though highly sensitive, are impractical for rapid triage in outbreak settings due to need for venous blood samples and cold-chain storage (Chen et al., 2020; Lee et al., 2019). Lateral flow assays offer faster results but suffer from poor sensitivity and are not suitable for tracking changes over time. Even recent portable diagnostic devices require calibration, complex reagents, or external readers that limit scalability (Kim et al., 2021). These limitations underscore the need for an alternative approach.

 

Methodology:​ 

This research proposes a modular, low-cost microneedle biosensor capable of detecting IL-6 and TNF-α in ISF, optimized for early dengue diagnostics. The device will consist of three main components:

1. Microneedle Array: Fabricated from biodegradable polymers like poly(lactic-co-glycolic acid) (PLGA) or silicon, an array of 100–200 microneedles, (each ~800 μm in length), sufficient to breach the stratum corneum and access ISF without penetrating deeper vascularized layers (Kim et al., 2019). The needles will be coated with conductive nanomaterials (e.g., gold nanoparticles or carbon nanotubes) to enhance signal transduction (Yang et al., 2019).

2. Biorecognition Layer: Each microneedle tip will be functionalized with cytokine-specific monoclonal antibodies (e.g., anti-IL-6, anti-TNF-α) bound via linker chemistry to maintain bioactivity. When the target cytokine binds to the antibody, it will trigger a measurable signal (electrochemical or colorimetric) based on redox reactions (Liu et al., 2021).

3. Signal Processing and Transmission: A flexible circuit layer will convert the biochemical interaction into a quantifiable signal using differential pulse voltammetry. Power-efficient Bluetooth or NFC modules will transmit data to a smartphone or tablet app for visualization. Threshold alerts will be incorporated based on clinical cytokine cutoffs (Soundravally et al., 2015).

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Simulation and Optimization: COMSOL Multiphysics (a finite element analysis tool) will be used to model diffusion kinetics of cytokines in the dermal layer and optimize microneedle spacing, size, and material properties for maximal ISF extraction and signal resolution.

 

Accessibility Considerations: To enhance real-world feasibility, the device will be designed for low-cost mass production using screen printing and polymer molding. Reagents will be stored in lyophilized form to improve shelf life without cold chain dependency (Zhao et al., 2022).

 

Conclusion:

This project envisions a wearable microneedle biosensor platform capable of detecting early immunological changes in dengue infections, offering a noninvasive, real-time, and low-cost diagnostic alternative in resource-limited settings. By targeting IL-6 and TNF-α, cytokines implicated in the transition from mild to severe disease, the device could empower clinicians and health workers to triage patients more effectively and deploy limited medical resources where they are most needed. There is an urgent need for effective diagnostic tools to enable early detection and intervention for severe dengue, and exploring the use of wearable microneedle biosensors, as proposed in this study, is crucial, as it could significantly improve patient triage, reducing healthcare burden and potentially saving lives during outbreaks.

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References :

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