Microfluidic wearable electrochemical sweat sensors for health monitoring

Abstract

Research on remote health monitoring through wearable sensors has attained popularity in recent decades mainly due to aging population and expensive health care services. Microfluidic wearable sweat sensors provide economical, non-invasive mode of sample collection, important physiological information, and continuous tracking of human health. Recent advances in wearable sensors focus on electrochemical monitoring of biomarkers in sweat and can be applicable in various fields like fitness monitoring, nutrition, and medical diagnosis. This review focuses on the evolution of wearable devices from benchtop electrochemical systems to microfluidic-based wearable sensors. Major classification of wearable sensors like skin contact-based and biofluidic-based sensors are discussed. Furthermore, sweat chemistry and related biomarkers are explained in addition to integration of microfluidic systems in wearable sweat sensors. At last, recent advances in wearable electrochemical sweat sensors are discussed, which includes tattoo-based, paper microfluidics, patches, wrist band, and belt-based wearable sensors.

I. INTRODUCTION

Recently, due to high demand for user friendly and portable health monitoring devices, researcher find the solution in wearable sensors to facilitate a non-invasive and continuous real-time health monitoring for humans.^1,2 Wearable devices are expected to govern the future of health monitoring and sports medical diagnostics due to its easy wearability, operation, and delivery of spontaneous sensing information about the analytes.^3,4 Body fluids-based analyte like saliva, tears, urine, and sweat provides precise diagnostic information upon investigation.^5–7 Traditional analytical methods often use bulky and expensive instruments with complex sample loading. To overcome these constraints, compact wearable health monitoring devices are preferred for a rapid analysis.⁸ As of late, we experience an extraordinary growth in the field of wearable devices (Scheme 1), which integrates diverse research areas like nanoscience and technology, flexible electronics, microfluidics, and wireless technology.⁹

Scheme 1.

Various microfluidic wearable devices for the sweat analysis

Sweat is one of the many important body fluids that secretes for regulating the core body temperature.¹⁰ Sweat contains the following metabolites like proteins, ions, and a large number of small molecules that includes lactate, glucose, and amino acids.^11,12 The components of sweat possess a rich information regarding human health. Some important diagnostics are made possible through sweat biomarkers like metabolic activities, dehydration status, and cystic fibrosis.^13,14 Also, sweat has become a vital body fluid for drug-related investigations as well.¹⁵ Sweat is collected through various activities like heating, iontophoresis, reverse iontophoresis, and physical activities.¹⁶ Collected sweat is directly processed for analysis unlike blood where it is an invasive process. Sweat-based sensor causes less irritation than blood-dependent sensors for humans. Sweat is easy to process, store, and transport than other body fluids. The fast, real-time, and continuous sweat analysis can be performed through a wearable sensor.^17,18

Numerous wearable sensors for the sweat analysis are recently reported in patch formats, tattoos, eyeglasses, papers, wrist bands, and textile integrated devices.^19–21 The challenging part of these wearable sweat sensors is the fabrication of a sensing element that should be designed to be in an intimate contact with skin constantly. Continuous and precise investigation becomes quite difficult because of sweat aggregation, reabsorption of electrolyte by sweat glands, and dehydration.¹⁹ Additionally, the mechanical activity causes friction among the sensing element and the surface of skin. The friction in some cases induces damages to delicate sensor components and chemicals used in sensor may lead to skin exasperation.²²

Despite many advantages, the wearable sensor also presents numerous issues like sweat evaporation, contamination of sweat, interference of chemicals, mixing of new and old sweat, and biodegradation.^23,24 In order to minimize these issues, establishing an efficient sweat processing technology is of great importance. One such technique is integration of microfluidics in the sensor system.^25–27 The objective of using microfluidics is channelled collection of sweat and structured mobility of sweat samples to the detection site.²⁸ The microfluidic system offers continuous sweat sampling though its micro-sized channels and delivering it in the detection area. Microfluidic channels are often connected to electrodes that prevent re-absorption back to the surface of skin and also sweat evaporation.^29–31 Some ideal requirements for microfluidics to be used in wearable sensors are conforming capability, light weight, and user friendliness. These are achieved through flexible polymer materials.³² Microfluidic channels only allow desired amount of sweat sample for the analysis. This behavior improves accuracy and reliability of wearable sensors.³³ Additionally, microfluidics has little chambers in the system, which stores the sweat for future analysis. The most traditional way of microfluidic fabrication methods is chemical etching using glass or silica and also photolithography.^34–36 The resultant microfluidic product from these techniques is not uniform and requires usage of chemicals. So, 3D printing technology is an efficient alternative option where it can create economical and flexible microfluidic channels. Integrating these 3D printed microfluidics into a wearable sweat sensor is the futuristic way of health monitoring systems.^37,38 This review concentrates on wearable sensing technology for health monitoring applications. Further discussions will cover the evolution, and types of wearable devices, sweat chemistry, and the influence of microfluidics in wearable sensor systems. We have also discussed the current advances in microfluidic-based wearable health monitoring, which are reported in recent years.

II. EVOLUTION OF WEARABLE DEVICES

In 1960s and 1970s, electrochemical analytical procedures predominantly relied on big devices and electrodes.³⁹ Later in 1980s, huge interest and demand started arising for biosensors, and as a result, researchers started developing chemically modified electrodes for boosting the performance of electrochemical-based sensors.⁴⁰ This strategy ultimately led to the establishment of enzyme-based glucose biosensors.⁴¹ In 1990s, we observed the research studies shifted in the direction of miniaturization of sensors. This paved the way for evolution in electrochemical studies like emergence of screen-printed electrodes and portable analytical devices.⁴² Early part of 2000s experienced a tremendous advancement in microfluidic-based biosensors,⁴³ potentiometric sensors,⁴⁴ flexible materials for electrode fabrication,⁴⁵ and portable electrochemical instruments.⁴⁶ In addition to this, many catalytic nanomaterials also developed like metallic nanomaterials,⁴⁷ carbon nanomaterials,⁴⁸ etc., for electrochemical sensing. Specially, carbon nanotubes (CNTs) and graphene revolutionized the flexible electrochemical sensors.^49,50 The first ever commercial continuous non-invasive glucose monitoring device is developed (GlucoWatch).⁵¹ Glucose monitoring devices effectively transitioned into a clinical tool for diagnostics and inspired millions of researchers to work toward the development of similar biosensing wearable platform for other harmful diseases concerning humans. All the growth of biosensors from 1980s to technological advancements (flexible printed electronics and wireless technology) until date assisted in the fabrication of high-performance point-of-care (POC) electrochemical biosensors for health monitoring applications.⁵² Lately, body-conformal wearable biosensors equipped with mobile tracking facilities of human vitals are an important field of research since 2010.⁵³ The brief history and evolution of wearable devices are shown in Fig. 1.

FIG. 1.

Evolution of electrochemical wearable devices. Traditional electrochemical instruments commonly used in 1990s (a) electrochemical system with the rotating disk electrode setup and (b) the dropping mercury electrochemical system. Electrochemical handheld systems used in 2000s. (c) Portable electrochemical analyzers and (d) screen printed carbon electrodes. Reproduced with permission from Ainla et al., Anal. Chem. 90, 10 (2018). Copyright 2018 American Chemical Society. (e) Flexible printed electrodes. Reproduced with permission from Varodi et al., Sensors 20, 12 (2020). Copyright 2020 Author(s), licensed under a Creative Commons Attribution (CC BY) License. Emergence of wearable electrochemical devices and (f) tattoo-based wearable sensor for sweat analysis. Reproduced with permission from Jia et al., Anal. Chem. 85, 14 (2013). Copyright 2013 American Chemical Society. (g) Microfluidic based wearable sensor and (h) flexible wearable smart sensors. Reproduced with permission from Manjakkal et al., Biosensors 9, 1 (2019). Copyright 2019 Author(s), licensed under a Creative Commons Attribution (CC BY) License.

III. CLASSIFICATIONS OF HEALTHCARE WEARABLE SENSORS

Wearable POC healthcare devices took over the domestic healthcare sector by drastically reducing the load of visiting the hospital for diagnosis.⁵⁴ Different types of wearable devices are textile-based wearable sensor,⁵⁵ skin-based wearable sensor,⁵⁶ and flexible wearable systems.⁵⁷ Sensors are mounted on different sections of body parts like wrist band-type wearables,⁵⁸ contact lens-based systems, and head band attached wearable sensor. These sensors have capability to monitor important physiological markers that are significant to track many diseases. Wearable healthcare sensor devices are classified into two major categories. They are skin-based wearables and biofluidic-based wearable sensors.⁵⁹ They are shown in Fig. 2.

FIG. 2.

Classification of healthcare wearable sensors. (a) Smart headband biosensor for electrochemical detection of glucose and sodium ions in sweat. Reproduced with permission from Zhao et al., Biosens. Bioelectron. 188, 113270 (2021). Copyright 2021 Elsevier. (b) Silicon micropillar-based wearable sweat sensor skin patch for continuous monitoring of glucose. Reproduced with permission from Dervisevic et al., ACS Appl. Mater. Interfaces. 14, 1 (2021). Copyright 2021 American Chemical Society. (c) Laser inscribed contact lens sensors for detection of glucose, proteins, pH, and nitrite sensing in tears. Reproduced with permission from Moreddu et al., Sens. Actuators, B 317, 12813 (2020). Copyright 2020 Elsevier.

In human body, skin occupies majority of area, which is an ideal operating area for many non-invasive wearable healthcare devices. Skin-based wearable healthcare devices can efficiently monitor biomarkers in body fluid.^60,61 The diagnosis of different health issues can be investigated through vital skin secretion sweat.^56,62 Depending upon contact with the skin, wearable sensors are divided into two. They are textile and epidermal-based wearable sensor devices. Textile-based wearable sensor system is directly integrated into textile, and in the case of epidermal based, the sensor device comes in contact with skin similar to the patch, tattoo, etc.^63–65 Wearable healthcare sensor devices are directly used for the analysis, but in some cases, they are integrated with microfluidic chambers. These chambers are often constructed to properly channel and transport the biofluid-like sweat or tear to the active are of the analysis.⁶⁶ Some of the microfluidics that can be integrated into wearables devices are micro-sized needles, paper microfluidic systems, and polymer-based microfluidic channels.^67–69

IV. SWEAT CHEMISTRY

The in-depth knowledge about the composition of sweat and information on biomarkers present are important in fabricating a wearable healthcare device.⁷⁰ Sweat comprises many biomarkers that aid in monitoring the human health and including the fitness. Sweat is a response for thermoregulation of body. In this process, components like metabolites, ions, amino acids, biomolecules, and hormones are injected into sweat.^71,72 Table I provides complete information about biomarkers in sweat and its concentration levels in human systems. Sweat has high levels of glucose, lactate, cortisol, uric acid, and many ions like K⁺, Cl⁻, Na⁺, Ca²⁺, Zn²⁺, Cd²⁺, etc.⁷³ Sweat originates from an eccrine sweat gland, which is a kind of exocrine gland that excretes sweat and sends it to the epithelial surface through a dermal duct.⁷⁴ Na–K pump helps in transportation of Na and Cl ions from blood serum to the secretory coil and vice versa. This activity helps to produce the osmotic pressure gradient that drags the fluids to the eccrine gland. As a result, Na⁺ and Cl⁻ ions are reabsorbed when sweat is travelling through skin channels.^75,76 Na⁺ secretion rate increases than the reabsorption rate when the sweat rate increases. This ultimately results in higher levels of Na⁺ ions during intense physical exercises. Detecting electrolytes in sweat helps us to monitor chemical and physical states of humans. In such a way, Na occurs in large concentrations in sweat and monitoring it would provide information on electrolyte loss especially during high endurance workouts.⁷⁷ The higher concentrations of Na quantity in sweat indicate the lower concentration of plasma sodium, which is referred as hyponatremia and minimal water content. These conditions can cause health hazards to human body like restriction in physical movements. Additionally, the disproportional level of sodium in sweat is significant in cystic fibrosis diagnostics, which is a genetic disorder affecting lungs.⁷⁸ The sweat-based sensing technology is globally used for monitoring cystic fibrosis.⁷⁹

TABLE I.

Compilation of sweat composition, concentration, and detection techniques.

Composition of sweat	Concentration in sweat	Potential hazards	Recognition element	Analysis technique	Reference
Ascorbic acid	10–50 μM	Immunity issues	Ascorbate oxidase	Cyclic voltammetry	80
Uric acid	2–10 mM	Renal dysfunction	Uricase	Cyclic voltammetry	81
Cortisol	10–140 ng mL−1	Pressure	Nanomaterial	Amperometry	82
Tyrosine	5–240 μM	Muscle issues	Nanomaterial	Cyclic voltammetry/Amperometry	83
Lactate	5–20 mM	Anerobic metabolism	Lactate oxidase	Amperometry	84
Glucose	10–200 μM	Diabetes	Glucose oxidase	Amperometry	85
K+	1–19 mM	Muscle discomfort	Potassium ion selective membrane	Potentiometric analysis	86
Na+	10–100 mM	Cystic fibrosis/dehydration	Sodium ion selective membrane	Potentiometric analysis	87
Cl−	10–100 mM	Cystic fibrosis/dehydration	Ag/AgCl	Potentiometric analysis	88
NH4+	0.1–1 mM	Anerobic metabolism	Nonactin ionophore	Potentiometric analysis	89
Ca2+	0.41–12.5 mM	Homeostasis	Calcium ion selective membrane	Potentiometric analysis	90
Zn2+	100–1560 μg l−1	Liver damage	Bismuth	Square wave anodic stripping voltammetry	91
Pb2+	<100 μg l−1	Toxic effect	Bismuth	Square wave anodic stripping voltammetry	92
Cd2+	<100 μg l−1	Toxic effect	Bismuth	Square wave anodic stripping voltammetry	93
pH	3–8	Skin disease	Conductive polymers	Potentiometric analysis	94

Hypo-osmotic sodium transfer to membranes of cell and for reabsorption at duct wall requires energy. The main source of energy for efficient functioning of sweat glands is predominantly from oxidative phosphorylation of plasma glucose.⁹⁵ Therefore, glucose acts like a fuel for secretion of sweat. Normal glucose level in sweat is <200 mM, which is much lower than that in blood serum (6–6.6 mmol l⁻¹).⁹⁶ Glucose in sweat is in higher levels for people with diabetes, which were in the range of 0.28–1.11 mM. Lactate belongs to the functions of eccrine metabolism when a minimal level of oxygen is available.⁹⁷ Anaerobic glycolysis takes place primarily when request for energy is needed in a short span of time.⁹⁸ When human body endures prolonged intense physical exercises, traditional aerobic metabolism is inadequate to fulfil energy demands.⁹⁹ So, anaerobic metabolism efficiently converts the stored glycogen into lactate and energy. This leads to larger levels of lactate concentration in the blood often referred to as lactate acidosis. Therefore, higher concentration of lactate in sweat is a clear indication of the oxygenation level in tissues.¹⁰⁰ Lower oxygen levels are a signal for cramps in muscle or fatigue. It is important to monitor the levels of lactate and a development of non-invasive technique that is vital for endurance athletes.¹⁰¹

Potassium plays a significant role in the functioning of muscles, nerves, and important components in biochemical reactions.¹⁰² The surplus loss of potassium through sweat results in potassium deficiency in blood, which is termed as hypokalemia.¹⁰³ Potassium levels in body are usually regulated with the help of kidneys and excessive potassium is sent out through sweat and urine.¹⁰⁴ Hypokalemia causes chronic kidney disorders, nerve-related issues, and also possess a potential risk for paralysis. Higher concentrations of potassium in blood plasma are referred to as hyperkalemia that minimizes urine production, holds risk for cardiac arrest, and nausea. So, periodic monitoring of potassium levels through sweat is an ideal way to diagnose any physiological problems in human body.^105,106 Ammonia is a resultant of disintegration of protein. When ammonia levels are irregular in blood plasma, it specifies liver issues and metabolic disorders.¹⁰⁷ Liver is a vital organ that converts ammonia into urea and excretes out of body though urine.¹⁰⁸ Ammonia present in sweat gets ionized and traps in secretory cell wall. This process elevates the concentration of ammonia in sweat in mM range. Therefore, sweat ammonia can be a potential biomarker for identifying concerns like hepatitis and cirrhosis.¹⁰⁹ Some of the important trigger points for sweat production are heat, physical exercises, emotional or physical stress, and chemicals.¹¹⁰ The metabolic activities, fitness levels, and psychological information of human body can be monitored through biomarkers in sweat.¹¹¹ All dynamic biomarkers generated in sweat depends on the type of sweat trigger. The wealth of information in sweat biomarkers can be studied though a wearable sweat sensor equipped with highly defined microfluidic channels, which regulates the flow of sweat.¹¹²

V. INTEGRATING MICROFLUIDICS IN WEARABLE SWEAT SENSORS

Microfluidics are highly significant toward the development of miniaturized components with ability to carry out multiple functions like cell sorting, formation of droplet, trapping of cells, and channelled delivery of analytes.¹¹³ Lab on a chip has become a reality in recent years thanks to integration of microfluidics. Some of lab on chip applications are biofluid analysis, drug delivery, disease diagnostics, etc., have successfully incorporated microfluidics for processing.^114,115 Wearable sensor technology has gathered interest from multidisciplinary research fields because it has the ability to effectively transmit sensing information wirelessly.⁴ Approximately, 110 × 10⁶ units of wearable technology has made global consumer market with nearly 20.6 billion USD worth by 2018.¹¹⁶ Although wearable sensor technology has seen a huge market growth yet, sensing ability and performance is limited. The future goal of healthcare wearable technology is to include capabilities like prognosis and diagnosis through body fluids as an analyte.¹¹⁷ Having said this, it is difficult to accomplish mainly due to its complexity in collecting the sensor signals from the human body. Additionally, some of the user expectations for fabrication of healthcare wearable sensor are resistant toward water/dust, portability, conformal attachment to the body, and also flexibility, which is also a great challenge.¹¹⁸ With utilization of microfluidics in wearable technology, some of the challenges can be solved. Figure 3 shows the challenges in attaining wearability, characteristics of skin, and requirements for sensors. Microfluidic-based wearable technologies possess some key functionalities. Microfluidic has become a vital part for sensor as it uses microstructures for storage of analytes. The microfluidic channels allow an accurate amount of desired analyte to be processed, and this improves reliability of the sensor.¹¹⁹ Body fluids like sweat are secreted in limited quantities, so the microfluidics play an important role in storage and transport of sweat for the analysis.²⁶

FIG. 3.

Challenges in attaining wearability, characteristics of skin, and requirements for wearable sensors.

Wearability of the sensor device depends on the choice of material that should be adaptable to biological, physical, and chemical properties of skin. Human body typically is made up of curvilinear and irregular surfaces, and they are difficult to mimic. Also, skin is viscoelastic and deformable in nature. Therefore, wearable sensor should efficiently match the properties of skin and coupled with ability to digitally process the signals.¹²⁰ Tremendous time has been put by researchers to design and construct a material that adapts well with our skin surface. Materials like polymers, fabrics, and elastomers are often preferred to act like an interfacial substrate to our skin.¹²¹ These materials possess properties that are adaptable to our skin and acts as an ideal platform for fabricating wearable sensor devices. Polymer-based materials have important properties like chemical resistance, flexibility, and robustness. Similarly, elastomers are highly stretchable and conformal.¹²² Due to its absorbing and soft nature, fabrics are used in wearable technology. Combining the substrate material with microfluidic channel is important for accurate biofluid handling and further electrochemical reactions. Furthermore, when electrical components are connected with sensor, it allows a rapid data analysis and transmission. In such a way, there are several reports exhibiting microfluidics-incorporated wearable technology. Wang et al. research group constructed a flexible polydimethylsiloxane (PDMS) microfluidic chamber using the laser engraving process.⁶⁷ The prepared polymer-based microfluidic chambers are coupled with wearable sensor that is fabricated using conducting poly(3,4-ethylenedioxythiophene) (PEDOT): poly(styrene sulfonate) (PSS) often referred to as PEDOT:PSS. Wearable sensor is developed to mainly monitor the uric acid levels in human sweat [Fig. 4(i)]. Liu and his team fabricated a wearable perspiration sensor mainly focusing the sodium ion monitoring in sweat.¹²³ Biocompatible threads are to collect sweat through the capillary action. Then, polyethylene terephthalate (PET) is used to create microfluidic channels and integrated it to electrodes for investigation. The schematic of the overall device is shown in Fig. 4(ii).

FIG. 4.

(I) (a) Schematic representation of wearable microfluidic sensor device reinforced with PEDOT:PSS hydrogel. (b) Fabrication of PEDOT:PSS hydrogel modified electrodes. Reproduced with permission from Xu et al., Sens. Actuators, B 348, 130674 (2021). Copyright 2021 Elsevier. (II) (a) Image showing various components of wearable microfluidic sweat sensor. (b)–(d) Photo showing the device collecting the sweat from different body positions. Reproduced with permission from Ma et al., Talanta 212, 120786 (2020). Copyright 2021 Elsevier.

A smart watch sensor based on paper substrate as a microfluidic layer to analyze sweat is efficiently developed by Professor Ye research team.¹²⁴ The main purpose of the smart watch is to monitor the levels of electrolytes (Na⁺ and K⁺) in sweat. An overview of the fabricated smart watch is shown in Fig. 5. Whatman filter paper is manipulated to act like a microfluidic channels for the analysis. Corresponding ion selective layers for Na⁺ and K⁺ are printed on PET substrates. Through stationary cycling, on-body real-time investigation is performed using a smartwatch sensor. Integration of microfluidics in the wearable sensor system proves to be efficient in managing the storage, transport, and analysis of sweat.

FIG. 5.

Overview of integrated smart watch designed for Na⁺ and K⁺ ions in sweat. (I) (a) Structure of paper-based microfluidic sensor and smart watch sensor being investigated on forearm. (b) Detailed description of electrodes and (c) block diagram of smart watch. (II) On body perspiration investigating though fabricated smart watch. Reproduced with permission from Cao et al., Electroanaylsis 33, 3 (2021). Copyright 2021 Wiley.

VI. RECENT ADVANCEMENTS IN ELECTROCHEMICAL WEARABLE SWEAT SENSORS

Electrochemical sensors are analytical devices that efficiently process the information present in the analyte through the sensing material in combination with the transducer.¹²⁵ Electrochemical transduction needs an ideal modification of the working electrode in order to make it sensitive and selective for the biomarker in sweat.^126–128 To effectively detect biomarkers in sweat like glucose, lactose, potassium, sodium, etc., enzyme-reinforced electrodes and ion-sensitive electrodes are widely adopted.¹²⁹ Current advances in rapidly growing sweat-based wearable devices that predominantly rely on an electrochemical approach provide an excellent path for various biomedical and healthcare applications. Many research groups are actively working on fabricating a high-performance sweat sensor to monitor the physiological state and fitness of human subjects. These wearable sensors have the capability to detect biomarkers in sweat at lower concentrations, providing a continuous assessment. Some of the developed wearable sensors are microfluidic channel-integrated sweat patch,¹³⁰ flexible skin conformal fabrics,¹³¹ stretchable polymer-based sensors,¹³² sensing tattoo,¹³³ microfluidic paper-based sweat sensor,¹³⁴ iontophoresis epidermal system,¹³⁵ etc. Sections VI A and VI B showcases two modes of approaches in fabricating a wearable sweat sensor. Important approaches are the direct skin contact-based wearable sensor and the microfluidic integrated wearable sensor (Fig. 6). In the direct skin contact-based wearable sensor, the sensing array of electrodes are in direct contact with the surface of skin where the electrochemical reaction occurs to monitor the sweat metabolites. On the other hand, in microfluidic-integrated wearable sensors, initially sweat is efficiently collected and manipulated through the microfluidic channels. Then, finally, sweat is delivered to the sensing region of electrodes for investigation.

FIG. 6.

(a) Direct skin contact approach for fabricating wearable sensor and (b) microfluidic layer integrated approach for fabricating wearable sensor.

A. Direct skin contact electrochemical sweat sensors

Professor Joseph Wang's research group is a major contributor in developing the majority of wearable sensors for the sweat analysis.^136–138 Their innovation includes plastic-based, textile fabric-based, microfluidic-based, temporary tattoos, and nano-/micro-needles-based devices for ultrasensitive sweat analysis.^139–141 They engineered an electrochemical tattoo sensor for non-invasive human perspiration analysis [Fig. 7(a)]. This skin worn sensing platform had capability to detect any dynamic changes in lactose levels in sweat during intense physical activity.¹⁴² Apart from electrolytes and ions, it is also important to monitor the levels of metals present in sweat. In such a way, Wang group developed a bismuth@nafion film flexible electrode to monitor the levels of zinc in sweat.¹⁴³ The device utilized square wave stripping voltammetry to characterize film electrodes for zinc detection [Fig. 7(b)]. In order to monitor the concentration of sodium in sweat, Schazmann and his group established a wearable sensor based on a belt. The belt is fabricated using 3D prototyping with the help of an acrylonitrile butadiene styrene (ABS) polymer that is light and highly porous plastic.¹⁴⁴ Then, the belt is equipped with a sodium selective electrode for real-time analysis. Morallon and his team fabricated a glucose sensor based on stretchable serpentine-like Pt–graphite electrodes.¹⁴⁵ Polyurethane (PU) is used as a stretchable substrate to draw the electrodes. The glucose is efficiently estimated using these printed electrodes via an electrochemical route for real-time sweat samples [Fig. 7(c)].

FIG. 7.

(a) Electrochemical tattoo-based sweat sensors for lactate monitoring. Reproduced with permission from Jia et al., Anal. Chem. 85, 14 (2013). Copyright 2013 American Chemical Society. (b) Real world sensing of Zinc while workout though a temporary tattoo on a human subject. Reproduced with permission from Kim et al., Electrochem. Commun. 51, 41 (2015). Copyright 2015 Elsevier. (c) Design and fabrication of stretchable and wearable biosensor for glucose monitoring. Reproduced with permission from Abellan-llobregat et al., Biosens. Bioelectron. 91, 885 (2017). Copyright 2015 Elsevier. (d) Textile silk carbon reinforced electrochemical sensor patch for simultaneous monitoring of sweat analytes. Reproduced with permission from He et al., Sci. Adv. 5, 11 (2019). Copyright 2019 Author(s), licensed under a Creative Commons Attribution (CC BY) License.

Although sensing a single targeted biomarker using sweat through wearable devices is appreciable, but moving forward, simultaneous detection of multiple sweat biomarkers is necessary to effectively monitor the overall fitness information of humans. Researchers from Gao group reported a fully integrated wearable biosensor covering a large spectra of biomarkers in sweat.¹⁴⁶ The fabricated sensor can detect glucose, lactose, sodium ions, and potassium ions in addition to temperature. Single-walled carbon nanotubes-modified electrodes are used for glucose and lactose sensing, and ion-sensitive electrodes are fabricated for the detection of ions. A fully integrated sensor array is fabricated using photolithography technique, and it is connected to the electronic circuit possessing ability to transmit data wirelessly. Similarly, Yang and Zhang group constructed an integrated textile patch sensor using nitrogen-doped highly porous textile carbon for multiplexed sweat analysis.¹⁴⁷ This sensor has the ability to simultaneously detect multiple components of sweat like uric acid, ascorbic acid, glucose, lactate, Na⁺, and K⁺. In the flexible PET substrate, a conductive nickel tape is used to make path for electrodes and nitrogen-doped carbon is used as a working electrode for sweat metabolites. The fabricated electrodes are integrated with the circuit for the real-time analysis of sweat [Fig. 7(d)]. Heavy metals like Hg, Zn, Cd, Pb, and Cu can cause adverse effect on humans if they are present in higher concentration. Therefore, monitoring heavy metals through sweat is an efficient non-invasive analytical process. Javey et al. developed a flexible microarrays-based sensor device that can simultaneously detect numerous heavy metals though a square-wave voltammetry technique.¹⁴⁸ The multiple array of Au and Bi is used to pattern the working electrodes. The sensor arrays are patterned on the flexible PET substrate. This skin interfaced wearable device serves as an ideal platform for real-time heavy metal detection though sweat.

B. Microfluidic integrated wearable electrochemical sensor

Many technological innovations are made in fabricating a high-performance wearable sweat sensor, but still there is some important challenge to address. Some challenges include manipulation of sweat, miniaturization, dilution of sweat, contamination of sweat, transport of sweat at defined intervals, and evaporation.¹⁴⁹ With the help of integrating microfluidics into the sensor system, these issues can be effectively countered. Microfluidic channels can be constructed using materials like polymers, papers, textiles, etc., and some techniques used to construct them are 3D printing, roll-to-roll printing, laser engraving, and photolithography.¹⁵⁰

Recently, Martin et al. developed an epidermal microfluidic electrochemical system for superior sapling of sweat and analysis.¹¹² They constructed a flexible PDMS microfluidic channel through photolithography process and they are connected to the electrodes for electrochemical sweat analysis. Simultaneous detection of glucose and lactose is performed successfully on human subjects using a microfluidic-based wearable sensor [Fig. 8(a)]. Ye's research team fabricated a paper-based microfluidic electrochemical sensor device.¹⁵¹ Paper pattering is done using the screen-printing process. The sensor device consists of five layers of sweat-collecting chambers, vertical channels, electrode layers, and sweat evaporating layer. The screen-printed electrodes are connected to the electrode layer and the design of the folded paper helps in the 3D flow of collected sweat via working electrodes. Sweat travels from the collector to the vertical chamber with the assistance of capillary force. This fabricated paper-based microfluidic device periodically analyze the sweat during intense physical workouts [Fig. 8(b)].

FIG. 8.

(a) Schematic representation of multi-layered configuration of microfluidic wearable device and picture of sensor device integrated with a wireless electronic system. Reproduced with permission from Martin et al., ACS Sens. 2, 12 (2017). Copyright 2017 American Chemical Society. (b) 3D paper-based microfluidic electrochemical sensor and real time monitoring of glucose using a fabricated sensor. Reproduced with permission from Cao et al., RSC Adv. 9, 10 (2019). Copyright 2019 Author(s), licensed under a Creative Commons Attribution (CC BY) License. (c) Roll to roll screen printing of wearable sweat sensor patches. Reproduced with permission from Nyein et al., Sci. Adv. 5, 8 (2019). Copyright 2019 Author(s), licensed under a Creative Commons Attribution (CC BY) License.

Most of research works on microfluidic-based wearable sensors mainly utilize complex and expensive microfabrication techniques. As a cheap alternative, Gao's group used the CO₂ laser engraving procedure to fabricate most of the important parts of the sensor device. The sensor contains important layers which include the polyimide substrate layer, the microfluidic channel layer patterned on a double sided medical tape, the PET layer, and medical adhesive layers. The fabricated flexible microfluidic electrochemical sensor is probed for detection of uric acid and tyrosine. Uric acid is an important biomarker for the diagnosis of diabetes, and tyrosine is a vital compound needed for brain signaling and also for dopamine and stress hormone secretion. Therefore, it is important to monitor them. Laser-engraved graphene sensing electrodes are coupled with wireless circuits for real-time analysis. Dynamic sweat sampling is made possible mainly due to laser-engraved microfluidic channels. Sensor also has temperature-monitoring capabilities. This microfluidic-based wearable is important for the development of large-scale wearable devices.¹⁵² Upon combining laser engraving and roll to toll screen printing fabrication techniques, cost-effective and mass production of microfluidic-based wearable devices can be employed for reliable sweat analysis. In such a way, Javey's research group established an ultrasensitive microfluidic wearable electrochemical sensor [Fig. 8(c)]. The sensor consists of many precisely patterned arrays of electrode for detection of biomarkers in sweat. The microfluidic channel helps in monitoring the sweat rate through a sweat reservoir. The important biomarkers in sweat like glucose, sodium, and potassium ions are simultaneously detected using the sensors. The design and fabrication of high-performance microfluidic sweat sensors help us in closing the gap between the hospital and personalized health monitoring.¹⁵³

VII. CONCLUSIONS

Hospital-based diagnosis often requires an invasive technique to extract blood for the analysis. But in recent years, non-invasive personalized biomedical analysis has become popular.¹⁵⁴ The development of POC and remote diagnostic device has become a real objective. As a result, the emergence of wearable sensor devices has become prominent and an important part of analytical biochemistry. Recent growth in wearable electrochemical sensors helps us to slowly avoid laboratory-based analytical platforms. Thanks to all researchers in last 20 years who made advancements in printed electronics, chemically modified electrodes, flexible substrates, and lab on a chip systems. This is very crucial for successful design and fabrication of wearable electrochemical sensors. Ultimately, all these advancements in electrochemical systems created a way for evolution from the benchtop electrochemical analysis to rapid on skin analysis. Scientists integrated the wearable sensors to wireless systems in order to get data on handheld devices like smartphone. In order to achieve this, the sensor device must be very reliable and simultaneously detect all the biomarkers in sweat.

Current wearable electrochemical sensors mainly focus on important metabolites and electrolytes on sweat or tears, and it is predicted that in future, these devices will have capabilities to monitor the biomarkers like proteins related to disease and hormone. In upcoming years, wearable sensors will be directly mounted or stitched on our attires and successfully integrated with a wireless electronic system. Sensing array of electrodes for devices will be researched in detail to obtain multiplexed signals of biomarkers in sweat. Highly advanced machine learning and artificial intelligence techniques will provide a reliable and continuous monitoring of human health. Wearable sensors are anticipated to be a vital platform for fitness and general health monitoring. Call for the development of such devices is of prime importance in current COVID 19 pandemic. Considering the future energy demands, research focus will be toward the fabrication of self-powered wearable electrochemical sensors. Many researchers are already focusing their research interest in this direction and establishing an ultrasensitive biosensor with energy-harvesting abilities like biofuel cell-powered sweat analyzers. There is no significant wearable sensor device on commercial market with exception of glucose-monitoring devices for on-body analysis. This proves that there is a huge gap to cover and achieve the full potential in monitoring the sweat-related biomarkers. Multidisciplinary approach from many researchers in the field of material science, electronic and electrical engineers, and computer science engineers will enable us to address the gap and minimize challenges. This will ultimately help us to successfully realize the lab on skin concept to efficiently analyze important biomarkers in sweat.

AUTHOR DECLARATIONS

Conflict of Interest

The authors have no conflicts to disclose.

Author Contributions

Balaji Ramachandran: Conceptualization (equal); Methodology (equal); Software (equal); Visualization (equal); Writing – original draft (equal); Writing – review & editing (equal). Ying-Chih Liao: Conceptualization (equal); Funding acquisition (equal); Project administration (equal); Resources (equal); Supervision (equal); Writing – review & editing (equal).

DATA AVAILABILITY

The data that support the findings of this study are available from the corresponding author upon reasonable request.