Wearable chemical sensors for biomarker discovery in the omics era

Abstract

Biomarkers are crucial biological indicators in medical diagnostics and therapy. However, the process of biomarker discovery and validation is hindered by a lack of standardized protocols for analytical studies, storage and sample collection. Wearable chemical sensors provide a real-time, non-invasive alternative to typical laboratory blood analysis, and are an effective tool for exploring novel biomarkers in alternative body fluids, such as sweat, saliva, tears and interstitial fluid. These devices may enable remote at-home personalized health monitoring and substantially reduce the healthcare costs. This Review introduces criteria, strategies and technologies involved in biomarker discovery using wearable chemical sensors. Electrochemical and optical detection techniques are discussed, along with the materials and system-level considerations for wearable chemical sensors. Lastly, this Review describes how the large sets of temporal data collected by wearable sensors, coupled with modern data analysis approaches, would open the door for discovering new biomarkers towards precision medicine.

Fig. 1. Wearable chemical sensor-enabled biomarker discovery.

a, Biomarker discovery in precision medicine via classic tissue or blood biopsy procedures and via emerging wearable chemical sensors. b, General workflow for wearable chemical sensor-enabled biomarker discovery. c, Workflow procedures for the development of wearable chemical sensors towards biomarker discovery. ISF, interstitial fluid.

Fig. 2. The primary biorecognition and signal transduction strategies in wearable chemical sensors.

a–c, Recognition and signal transduction for wearable electrochemical biosensors. a, Amperometric enzymatic electrodes: for glucose sensing, the working electrode is modified with glucose oxidase (GOx) and the glucose molecule is oxidized to gluconic acid. Glucose is detected by applying a fixed potential to measure the hydrogen peroxide (H₂O₂) by-product or to monitor the reaction of a mediator with low redox potential. The generated current signal increases with the increase of glucose concentration. b, Potentiometric ion-selective sensors: the working electrode is modified with an ion-selective membrane containing the ionophore (for example, valinomycin for potassium ion sensing) molecules with cavities allowing only ions with specific charge and size to interact. The measured potential has a log-linear relationship with the target ion concentration. c, Voltammetric sensors: an electroactive molecule (for example, uric acid) can directly lose or donate electrons on the electrode surface when a redox potential is applied to the sensing electrode. The measured oxidation or reduction peak current height is directly proportional to the concentration of the target analyte. d,e, Recognition and transduction for wearable optical biosensors. d, Colorimetric sensors: the colour indicator molecule is immobilized on a substrate and upon contact with the analyte it changes colour. For hydrogen sensing based on horseradish peroxidase (HRP), the colour change is promoted by changes in the redox state of the chromophore molecule 3,3′,5,5′-tetramethylbenzidine (TMB) during the enzymatic degradation of H₂O₂; the measured light absorbance or colour intensity directly correlates with the concentration of target analyte. e, Fluorescence sensors: fluorometric sensing relies on a high-energy light source (for example, ultraviolet light or blue light) to excite the fluorophore molecule so it emits light with a longer wavelength through radiative electron transitions. For example, lucigenin can be used as a fluorescent indicator for chloride ion sensing; the chloride ion (Cl^–) reacts with lucigenin by replacing NO₃⁻, resulting in the quench of lucigenin fluorescence intensity through a collisional mechanism. The change of fluorescence intensity is directly proportional to the change in analyte concentration. red, reduced analyte; ox, oxidized analyte; [C], analyte concentration.

Fig. 3. Emerging wearable sensing strategies for biosensing.

a, Target recognition based on bioaffinity receptors and molecular switches for wearable biosensing. Protein receptors include antibodies for target recognition through direct binding (panel 1) or displacement of a signalling probe (panel 2) and enzyme switches that change molecular configuration upon target binding (panel 3). Nucleic acid receptors include single-stranded DNA (ssDNA) used for target recognition through direct DNA hybridization (panel 1) or displacement of another DNA strand with a signal probe (panel 2), aptamer switch with shape change upon binding of the target molecule (panel 3) or a DNA-based molecular pendulum (coupled with a redox probe and a protein receptor) that changes the probe–electrode distance upon target binding (panel 4). Synthetic receptors such as molecularly imprinted polymers (MIPs) can perform target recognition through direct target binding (panel 1) or displacement of molecules with a signal probe (panel 2). b, Optical and electrochemical signalling tags used in bioaffinity sensors for in situ signal transduction. Optical tags such as fluorophores, quantum dots and nanoparticles can be used to transduce the target recognition to measurable optical signals. The resulting optical signal could offer qualitative analysis (yes/no response), semi-quantitative sensors based on colour change and quantitative analysis via absorbance or luminescence intensities. Electrochemical tags such as redox probe molecules, enzymes and nanoparticles are used to transduce the target recognition to measurable electrical signals; for example, the recognition of targets with aptamers decreases the distance of the tagged redox probe from the electrode, leading to increased redox signal; binding of target molecules with MIP sensors reduces the exposure of the redox probe to the biofluid, leading to a decreased redox signal. c, In situ sensor regeneration strategies based on intermolecular force modulations. Biosensors can be regenerated chemically, by introducing a competitor molecule that has a stronger binding affinity to the receptor than the target molecule; with heat and light, as external energy to cleave the bond between the receptor and target molecule; by electrical fields, which remove the target molecule by electrostatic repulsion; or by solvent effects, varying solution properties (for example, pH and ionic strength). λ, wavelength; E, potential; I, current; [C], analyte concentration.

Fig. 4. Materials for enhanced wearable chemical sensing.

A sensor immobilized with functional materials could result in enhanced wearable sensing performance (left). a, Conducting and functional electrode materials for wearable chemical sensing. Gold transducer surfaces are suited for modification with self-assembled monolayers (for example, alkanethiol) for anchoring the biorecognition elements to introduce selectivity. Due to the excellent electrochemical and optical properties, functional nanomaterials (for example, carbon nanotubes, graphene, MXenes, metal–organic framework) are also used for highly sensitive transducer surfaces. b, Porous materials with high electrochemically active areas and high bioreceptor loading abilities towards enhanced in situ chemical sensing. c, Surface coatings (for example, hydrogel or polymeric coating) towards enhanced in situ chemical sensing. The properties of these coatings (for example, surface charge, hydrophilicity or porosity) can be tailored to increase receptor loading capabilities and resist the adhesion of fouling/interferent molecules. d, Soft flexible and biocompatible materials for enhanced wearable sensing. Flexible and stretchable materials can be used to realize enhanced skin conformability. The flexibility and stretchability of the sensors can be realized by using intrinsically stretchable materials (for example, elastomers) or through structure designs (for example, mesh or serpentine configuration designs).

Fig. 5. System development for in situ wearable chemical sensing.

a, Minimally invasive microneedle-based interstitial fluid (ISF) extraction and chemical sensing. b, Non-invasive reverse iontophoresis-based ISF extraction and chemical sensing via a wearable device. c, Non-invasive iontophoresis-based sweat extraction, microfluidic sweat sampling and chemical sensing via iontophoresis using a wearable device. The sweat-stimulating electrodes are interfaced with the skin via a thin layer of the hydrogel loaded with agonists (for example, pilocarpine or carbachol). A small current is applied to transdermally deliver agonist molecules that stimulate the sweat gland to trigger local sweating. The microfluidics-based sample handling modules can be used for in situ intermittent storage and controlled handling of the secreted sweat. d, General wearable platforms. e, Wireless wearable system integration for mobile data collection. f, Wearable energy harvesting systems. These systems convert chemical energy in body fluids, mechanical energy from human motion and light into electricity to continuously power wearable sensors. Red, reduced analyte; Ox, oxidized analyte.

Fig. 6. Wearable biosensor-enabled data-driven biomarker discovery.

a, Multiplexed and multimodal wearable sensors continuously collect chemical and physical signatures from people’s daily activities. b, Simultaneous collection and coupling of sensing data from multiplexed and multimodal sensors is imperative for robust post-processing. c, With coupled sensor information, real-time calibrated values of chemical analytes can be generated. d, After obtaining calibrated sensor data, multiplexed associations between other physical traits (age, gender, body mass index and so on) and markers (vital signs) can be used for improved diagnostics. e, From multiplexed biomarker associations, molecular signatures corresponding to a biomarker’s significance for determination of various diseases can be discovered. f, General classification of machine learning algorithms and models that can be implemented for biomarker discovery using wearable chemical sensors.