Biochips on the Move: Emerging Trends in Wearable and Implantable Lab-on-Chip Health Monitors

Abstract

Wearable and implantable Lab-on-Chip (LoC) biosensors are revolutionizing healthcare by enabling continuous, real-time monitoring of physiological and biochemical parameters in non-clinical settings. These miniaturized platforms integrate sample handling, signal transduction, and data processing on a single chip, facilitating early disease detection, personalized treatment, and preventive care. This review comprehensively explores recent advancements in LoC biosensing technologies, emphasizing their application in skin-mounted patches, smart textiles, and implantable devices. Key innovations in biocompatible materials, nanostructured transducers, and flexible substrates have enabled seamless integration with the human body, while fabrication techniques such as soft lithography, 3D printing, and MEMS have accelerated development. The incorporation of nanomaterials significantly enhances sensitivity and specificity, supporting multiplexed and multi-modal sensing. We examine critical application domains, including glucose monitoring, cardiovascular diagnostics, and neurophysiological assessment. Design considerations related to biocompatibility, power management, data connectivity, and long-term stability are also discussed. Despite promising outcomes, challenges such as biofouling, signal drift, regulatory hurdles, and public acceptance remain. Future directions focus on autonomous systems powered by AI, hybrid wearable–implantable platforms, and wireless energy harvesting. This review highlights the transformative potential of LoC biosensors in shaping the future of smart, patient-centered healthcare through continuous, minimally invasive monitoring.

1. Introduction

In recent years, the healthcare industry has experienced a significant shift from traditional, episodic care toward proactive, continuous, and personalized health monitoring [1,2,3]. This transformation is largely driven by the development of advanced biosensing technologies capable of tracking physiological parameters in real time [4,5,6]. Among these, Lab-on-Chip (LoC) biosensors have gained considerable attention for their potential to miniaturize laboratory functions and enable real-time diagnostics in compact, portable formats [7,8]. Lab-on-Chip technology integrates various laboratory processes such as sample handling, chemical reactions, and signal detection onto a single micro-scale platform [9,10]. These systems can analyze small volumes of biological fluids with high precision and speed [11]. When implemented as wearable or implantable devices, LoC biosensors offer continuous monitoring capabilities that extend beyond clinical environments, making healthcare more accessible and responsive [12,13,14].

Wearable LoC biosensors are designed to be worn externally and can monitor biomarkers found in sweat, saliva, interstitial fluid, or other readily accessible body fluids [15,16]. These devices are commonly found in forms such as skin patches, smart textiles, or wrist-mounted systems [16]. They are particularly useful in monitoring fitness, chronic diseases, hydration levels, and stress. On the other hand, implantable LoC biosensors are placed inside the body and offer access to more stable and concentrated sources of biomarkers. These devices are critical in managing conditions that require continuous and precise tracking, such as diabetes, neurological disorders, and cardiovascular diseases [17].

The functionality of these sensors has been greatly enhanced by recent advancements in microfluidics, nanomaterials, wireless communication, and artificial intelligence [18,19,20]. Modern LoC biosensors can detect multiple biomarkers simultaneously, transmit data to mobile devices or cloud platforms, and even process information locally using embedded computing systems [21]. This level of sophistication supports real-time decision-making, early diagnosis, and tailored treatment strategies for individual patients [22]. Despite these promising capabilities, several challenges must be addressed before wearable and implantable LoC biosensors can be widely adopted [23]. Issues such as biocompatibility, long-term operational stability, power management, data privacy, and regulatory approval are critical for both clinical and commercial deployment. Moreover, balancing performance with user comfort and cost-effectiveness remains a key consideration in the design and manufacturing process [24].

This review provides a detailed and critical synthesis of the rapidly evolving field of wearable and implantable LoC biosensors for continuous health monitoring. It begins by outlining the core technological framework of LoC systems (Section 2), including microfluidics, transduction mechanisms, and the integration of electronics and wireless communication. Emphasis is placed on how these elements collectively enable real-time, in situ biochemical analysis with high precision and minimal invasiveness. Section 3 explores the diverse modalities of wearable LoC biosensors ranging from skin-mounted patches and smart textiles to commercial wrist-worn devices and highlights their applications in glucose tracking, sweat biomarker detection, cardiovascular monitoring, and respiratory assessment. Section 4 turns to implantable LoC platforms, detailing their subtypes, physiological targets, and key use cases such as continuous glucose monitoring, neural interfacing, cardiac sensing, and closed-loop drug delivery. The review also addresses the essential materials and fabrication strategies (Section 5), including the use of biocompatible polymers, nanomaterials for signal enhancement, and micro/nanofabrication techniques like soft lithography, additive manufacturing, and MEMS integration. In Section 6, the authors critically examine persistent challenges such as biofouling, sensor drift, data reliability, power limitations, regulatory barriers, and public acceptance. Section 7 discusses the emerging directions in the field, including the development of autonomous, AI-integrated systems, multi-analyte platforms, and next-generation biosensors capable of adaptive therapeutic response. By offering a holistic view across technical, clinical, and translational dimensions, this review underscores the transformative potential of LoC biosensors in enabling continuous, personalized, and connected healthcare shaping the foundation for next-generation patient monitoring technologies.

2. Overview of Lab-on-Chip (LoC) Technology

LoC technology has emerged as a powerful platform that enables the integration of multiple laboratory functions onto a single micro- or nano-scale chip [25]. This miniaturization allows for rapid, cost-effective, and sensitive biochemical analyses, significantly advancing the development of wearable and implantable biosensors [15,26]. LoC devices are designed to handle small volumes of fluids and operate autonomously or semi-autonomously, making them particularly suitable for point-of-care diagnostics and continuous physiological monitoring [7]. By consolidating key laboratory processes such as sample preparation, reaction, separation, and detection onto a compact platform, LoC technology significantly reduces reagent use and analysis time while enhancing portability and throughput [27,28].

At the core of every LoC system are several essential components that support its functionality [14]. These include microchannels and reservoirs for fluid transport and storage, micropumps and microvalves for regulating fluid flow, and various types of sensors for detecting specific biochemical events. These components are typically fabricated using materials like glass, silicon, or polymers (e.g., polydimethylsiloxane or PMMA), chosen for their biocompatibility, optical clarity, and ease of microfabrication [14,18,29,30,31]. LoC systems also integrate electronics such as microcontrollers, actuators, and data processors to enable real-time control and analysis. The seamless integration of these elements ensures that LoC platforms can operate as fully functional analytical systems on a chip, ideal for in situ and in vivo applications.

Microfluidics plays a fundamental role in LoC technology by enabling the precise manipulation of fluids at the microscale [11]. The design of microfluidic networks allows for the controlled movement and mixing of tiny volumes of biological samples, enhancing reaction kinetics due to the high surface-area-to-volume ratio. This control also allows for the creation of spatial and temporal gradients of temperature, concentration, and other reaction parameters, which is particularly useful in biological assays. Miniaturization not only makes the devices more compact and suitable for wearable and implantable formats but also reduces power consumption and enhances response times [32]. Furthermore, advances in flexible and stretchable microfluidic materials have facilitated the development of conformal LoC devices that can be seamlessly integrated with soft tissues and dynamic biological surfaces [33].

Biosensing in LoC systems relies on a variety of transduction mechanisms, with electrochemical [29], optical [34], piezoelectric [35], and thermal sensing [36] being the most prominent. Electrochemical sensors detect changes in current, voltage, or impedance resulting from biochemical reactions and are widely used due to their high sensitivity, low power requirements, and ease of miniaturization. These sensors are prevalent in applications such as glucose monitoring and nucleic acid detection. Optical sensors, including fluorescence, absorbance, and surface plasmon resonance-based devices, offer high specificity and are well-suited for multiplexed assays, although they often require more complex integration of optical components [37]. Piezoelectric sensors detect changes in mass or pressure on a sensing surface, enabling label-free detection of biomolecules [35]. Thermal and magnetic sensors, though less commonly used, provide unique advantages in specific applications, especially when combined with nanoparticles or external fields to enhance signal detection [36].

A crucial advancement in LoC technology is its integration with electronics and wireless systems, which is especially important for wearable and implantable biosensors. The incorporation of microcontrollers, analog-to-digital converters, and custom ASICs (Application-Specific Integrated Circuits) allows for signal conditioning, processing, and storage directly on the chip [38]. Powering these systems can be achieved through miniaturized batteries, energy harvesting devices such as triboelectric or biofuel cells, or wireless power transfer. Wireless communication modules like Bluetooth Low Energy (BLE), Near Field Communication (NFC), and Radio Frequency Identification (RFID) enable real-time data transmission to smartphones or remote servers for further analysis [39,40]. This integration supports continuous health monitoring and data-driven decision-making. Furthermore, the convergence of LoC platforms with Internet of Things (IoT) technologies and artificial intelligence (AI) algorithms is paving the way for smart biosensing systems that can not only monitor but also interpret and respond to physiological changes dynamically [41].

Table 1. Comparative Characteristics of Wearable and Implantable Biosensors.

Characteristic	Wearable Biosensors	Implantable Biosensors
Anatomical Placement	Non-invasive placement on external body sites such as wrist, chest, or skin surface; designed for continuous or intermittent monitoring [2]	Surgically implanted within the body’s internal environment (e.g., subcutaneous tissue, organs, vascular system) for direct physiological measurement [42]
Invasiveness and Biocompatibility	Non-invasive or minimally invasive; typically skin-contact-based with biocompatible adhesive or straps to minimize irritation [3]	Highly invasive; requires biocompatible materials to prevent immune rejection, fibrotic encapsulation, and long-term tissue damage [43]
Power Supply and Energy Harvesting	Primarily battery-powered (lithium-ion or polymer), often with recharge capability; emerging technologies include energy harvesting from body heat or motion [37]	Limited by size constraints; use of micro-batteries, wireless inductive power transfer, or biofuel cells; long-term energy sustainability remains a challenge [44]
Data Acquisition and Transmission	Employs optical, electrical, or mechanical transduction mechanisms; data transmitted wirelessly via Bluetooth, NFC, or Wi-Fi to external devices for processing and storage [37]	High fidelity signal acquisition close to target tissue; data transmission via wireless telemetry systems or implantable transceivers; latency and security considerations critical [44]
Measurement Parameters	Monitors vital signs (heart rate, respiratory rate, temperature), biochemical markers (sweat glucose, lactate), and physical activity metrics [45,46]	Measures biochemical analytes (glucose, ions, neurotransmitters), electrophysiological signals (ECG, EEG), and therapeutic feedback signals (e.g., pacemaker rhythms) [26]
Operational Lifetime	Limited by battery capacity, environmental exposure, and adhesive degradation; operational lifespan ranges from days to several weeks depending on use case [47]	Designed for long-term operation (months to years); reliability affected by biofouling, sensor degradation, and immune responses [42]
User Compliance and Comfort	High user compliance due to non-invasiveness, lightweight materials, and ergonomic design; potential for skin irritation or discomfort over prolonged use [48]	Lower user compliance due to surgical implantation, risk of pain or discomfort, and potential for complications requiring clinical intervention [49]
Safety and Risk Profile	Minimal safety risks primarily related to skin irritation or allergic reactions; data privacy and cybersecurity considerations are pertinent [50,51]	Significant risks include surgical complications, infection, inflammatory response, device migration, and long-term biocompatibility challenges [43]
Data Accuracy and Signal Quality	Susceptible to motion artifacts, environmental noise, and inconsistent skin contact leading to signal degradation; advanced signal processing required [52]	High signal-to-noise ratio due to direct tissue contact; reduced artifacts but potential signal drift over time due to biological encapsulation [53]
Maintenance and Calibration	User-friendly maintenance; routine calibration often performed via software updates or standardized protocols; sensors generally replaceable [54]	Requires invasive procedures for maintenance or replacement; in situ calibration challenging; efforts focus on self-calibrating and stable sensor design [55]
Typical Applications	Fitness and health monitoring, early disease detection, outpatient telemedicine, stress and sleep analysis [56,57]	Chronic disease management (diabetes, cardiac arrhythmias), neuroprosthetics, drug delivery control, and real-time therapeutic feedback [58,59]

summarizes the critical technical, functional, and operational characteristics of wearable and implantable biosensors. The comparison encompasses anatomical placement, invasiveness, power supply methods, data acquisition and transmission modalities, measurement parameters, operational lifespan, user compliance, safety considerations, data accuracy, and maintenance requirements. Understanding these distinctions is essential for optimizing biosensor design tailored to specific biomedical applications and patient needs.

3. Wearable LoC Biosensors

Wearable LoC biosensors represent a transformative convergence of miniaturized analytical platforms with wearable technologies. These systems enable continuous, real-time, non-invasive monitoring of physiological biomarkers, offering unprecedented opportunities in personalized healthcare, chronic disease management, and preventive medicine [15]. Their integration with wireless networks and mobile devices further enhances their functionality, allowing seamless data acquisition, transmission, and analysis. Table 2 presents the characteristics of wearable LoC biosensors.

3.1. Types of Wearable Biosensors

Wearable LoC biosensors can be classified into several main types based on their form factor, method of integration with the body, and target application. Each type leverages different materials and sensor configurations to address specific monitoring needs while maintaining comfort and usability. The following subsections outline the most prominent categories of wearable biosensors, highlighting their design principles, sensing capabilities, and typical use cases.

3.1.1. Skin-Based Patches

Skin-mounted LoC biosensors are typically flexible, adhesive patches embedded with microfluidic and sensing components [60]. These devices are designed to conform to the skin’s topology, facilitating the detection of sweat, interstitial fluid, or even epidermally extracted blood biomarkers [61]. Advanced materials such as stretchable polymers (e.g., PDMS, Ecoflex) and conductive inks are used to ensure comfort, durability, and skin compatibility. Some patches incorporate microneedles for minimally invasive access to interstitial fluid, expanding the scope of detectable analytes [16,62,63]. Simultaneous monitoring of multiple biofluids holds significant promise for enhancing diagnostic precision through comprehensive multi-analyte analysis. By correlating biomarkers from distinct sources such as sweat and interstitial fluid (ISF) with established blood markers, it becomes possible to develop algorithmic models that enable non-invasive health assessments using minimal input parameters. Despite its potential, the clinical adoption of this approach is hindered by the lack of integrated systems capable of concurrently extracting, sampling, and analyzing multiple biofluids in a wearable format. To overcome this limitation, an innovative epidermal biofluidic patch was developed, designed to enable on-demand collection and analysis of both sweat and ISF [61]. The device was fabricated using a cleanroom-free process that combines laser-patterned three-dimensional microfluidic structures, a low-cost screen-printed electrostimulation module for ISF extraction, and potentiometric ion-selective sensors for detecting chloride ions in sweat and calcium ions in ISF. These sensors exhibited high repeatability, selectivity, and stability, ensuring reliable performance during continuous monitoring. A proof-of-concept study conducted on a healthy individual demonstrated the patch’s ability to simultaneously sample, store, and monitor both biofluids at different times of the day, highlighting its utility for real-time, personalized health tracking. Additionally, the integration of wireless data transmission capabilities supported its use as a non-invasive, lab-on-skin diagnostic platform suitable for point-of-care applications [61].

The monitoring of vital signs and physiological responses during routine activities was recognized as essential for the early detection and prevention of cardiovascular diseases. In response, a wireless and flexible biosensor patch was developed to enable continuous and long-term measurement of various physiological parameters, including body temperature, blood pressure (BP), and electrocardiography (ECG) signals [64]. Additionally, functionalities for motion detection and GPS-based location tracking were incorporated to support emergency response efforts. The design of the biosensor patch was optimized for mechanical stretchability and skin conformity, allowing stable and prolonged attachment to curved skin surfaces. For integration into smart healthcare ecosystems, an Internet of Things (IoT)-enabled platform was constructed, consisting of a mobile application, web-based services, a database server, and a mobile gateway (Figure 1). This IoT infrastructure was intended to alleviate the burden on healthcare systems and was aimed at improving service quality. To support continuous and non-invasive BP monitoring, a deep learning model was implemented using single-channel ECG input. The performance of the model was validated using an independent dataset, achieving compliance with the standards established by the Association for the Advancement of Medical Instrumentation and the British Hypertension Society. The experimental outcomes demonstrated the practical feasibility of the biosensor patch as a component of Internet of Medical Things (IoMT)-based healthcare solutions for real-time physiological monitoring [64].

3.1.2. Smart Textiles

Smart textiles, or e-textiles, integrate LoC biosensing components directly into fabrics, allowing for distributed sensing over large body areas [18,65]. Conductive fibers and yarns serve as the foundation for embedding sensors that can monitor biomechanical movements, hydration levels, and even electrophysiological signals like ECG and EMG [66]. Textile-based LoC systems prioritize washability, breathability, and mechanical robustness, making them ideal for long-term wear in daily or athletic settings [67].

ECG, a key diagnostic tool for heart rhythm analysis, traditionally uses Ag/AgCl gel-based wet electrodes, which can be uncomfortable for prolonged use and are not reusable. To overcome these limitations, textile-based ECG electrodes were developed using two conductive yarns: silver nanoparticle-coated nylon and stainless steel-coated two-ply nylon [66]. These yarns were stitched into cotton fabric using a lock-stitch method to form wearable electrodes. A simplified three-electrode ECG setup was used, and signals were recorded by placing both textile and commercial electrodes on the right arm, left arm, and right leg. SEM and XRD analyses were performed to examine surface morphology and crystallinity, while antimicrobial testing assessed biocompatibility. The silver-coated yarn showed a voltage range of −0.4 V to 1.2 V, compared to −0.4 V to 0.7 V for the stainless-steel version, indicating higher sensitivity and better performance for ECG signal detection [66].

Recently, a novel acoustic-based smart textile system, termed SonoTextiles, was developed [68]. This system incorporated flexible glass microfibres embedded within the textile structure. Piezoelectric transducers were mounted at both ends of each fiber, allowing them to function as both acoustic wave transmitters and receivers. The microfibres acted as waveguides, and physical stimuli such as touch and bending were detected by measuring changes in wave propagation and energy loss along the fibers. To enhance computational efficiency, frequency-selective acoustic signals and frequency-domain signal processing algorithms were employed. Smart acoustic textiles integrate glass microfibre waveguides into everyday garments to enable a range of sensing and interactive functions such as touch detection, smart glove applications, and respiratory monitoring (Figure 2a).

To demonstrate the working principle, a single-input single-output (SISO) system setup was designed (Figure 2b). This configuration included a transmitting PZT, a receiving PZT, a glass microfibre, and the textile base. The transmitter converts electrical signals into sound waves, while the receiver converts the acoustic signals back into electrical form. The glass microfibre, woven into the fabric, acts as an acoustic channel, linking the transmitter and receiver. When the textile was touched or pressed, these physical interactions lead to signal loss along the waveguide, which was detected as a drop in the received acoustic wave’s amplitude illustrated by the decay shown in Figure 2b. This loss was mainly caused by increased contact between the fiber and the fabric or skin, which absorbs acoustic energy. Expanding on this principle, advanced configurations for specific uses were created. One example was a fiber array tactile sensing system shown in Figure 2c, where thin, flexible glass microfibres were arranged in both warp and weft directions. Their intersections form individual sensing points that can detect touch location. The pattern and design of these waveguides can be tailored for various smart textile functions. Figure 2d presents a photo of the SISO system, showing both PZTs and the woven glass microfibre within the dark textile. Figure 2e displays a tactile sensing array composed of 16 touchpoints arranged in a 4  ×  4 grid. The resulting textile demonstrated breathability, durability, and stability under thermal fluctuations. Its functionality was validated in various applications, including distributed tactile sensing, hand gesture recognition, and respiratory rate monitoring [68].

3.1.3. Wearable Wristbands and Watches

Commercially available wristbands and smartwatches increasingly incorporate LoC biosensor capabilities [69]. These devices integrate photoplethysmography (PPG), electrochemical sensors, and optical sensors to monitor heart rate, oxygen saturation, glucose levels, and other parameters [70]. Their compact form factor and widespread user adoption make them a practical platform for deploying LoC technologies at scale. Advanced versions are now exploring modular microfluidic cartridges for dynamic biofluid analysis [71]. Wearable devices like the Apple Watch Series 8 (ASWs8) have been adopted in healthcare for vital sign monitoring. However, limited studies have validated their accuracy. Alzahrani et al. conducted a study to assess the reliability of the ASWs8 in measuring heart rate and oxygen saturation, compared to conventional monitoring devices (CMD) [72]. A cross-sectional study was performed on 52 patients at King Abdulaziz University Dental Hospital, Jeddah. Heart rate and oxygen saturation were measured using both ASWs8 and CMD. The mean values were compared to identify significant differences. The ASWs8 recorded a heart rate of 83.04  ±  13.4 BPM, while CMD showed 82.81  ±  13.5 BPM. A mean difference of −0.23  ±  0.7 BPM was observed, with limits of agreement from −25% to 25%. No significant difference was found (Cronbach’s α  =  0.999, p  =  0.311). For oxygen saturation, ASWs8 showed 97.10  ±  1.6% and CMD recorded 98.23  ±  1.0%, with a mean difference of 0.74% (limits: −3% to 1%). Again, no significant variation was detected (Cronbach’s α  =  0.735, p  =  0.094). The ASWs8 was found to be reliable and consistent with CMD, supporting its use for monitoring heart rate and oxygen saturation. Its application may aid in early detection of abnormalities and reduce unnecessary hospital admissions [72].

The post-pandemic shift toward digital health has intensified interest in wearable technologies bridging wellness and clinical care. Skin hydration, a vital marker for overall health, fitness, and dermatological integrity, requires continuous and non-invasive monitoring something traditional methods fail to provide. In response, a novel optical sensing approach was developed using smartwatch-integrated, multi-wavelength PPG [73]. This system combined infrared light sources at 970 nm and 1450 nm with machine learning algorithms to track hydration-related changes in skin water content. Sensor performance was assessed through Monte Carlo simulations and validated through experimental and clinical studies. This proposed pipeline offered a promising platform for next-generation wearables in real-time skin hydration and optical health monitoring [73].

3.2. Applications

The versatility of wearable LoC biosensors has enabled their adoption across a wide range of health monitoring applications. These devices offer real-time insights into physiological and biochemical parameters, supporting early diagnosis, disease management, and personalized care. This section highlights key application areas where wearable LoC technologies are making a meaningful impact, including glucose tracking, sweat analysis, cardiovascular monitoring, and respiratory assessment.

3.2.1. Glucose Monitoring

Non-invasive or minimally invasive glucose monitoring is a key application area for wearable LoC biosensors, particularly for diabetes management [70]. Techniques include reverse iontophoresis for glucose extraction through the skin and microneedle arrays that sample interstitial fluid [74]. Electrochemical and optical transduction methods are commonly employed for quantification, and real-time data transmission allows for integration with insulin pumps or mobile applications [74,75,76].

Real-time monitoring of biological markers in sweat has emerged as an effective method for health assessment. Zhang et al. reported the development of an innovative wearable biosensor designed for the precise detection of glucose in sweat during physical activity [77]. The sensor utilized a single-atom platinum (Pt) catalyst uniformly dispersed on tricobalt tetroxide (Co₃O₄) nanorods combined with reduced graphene oxide (rGO), creating a unique three-dimensional nanostructure with excellent electrocatalytic properties. It demonstrated a wide detection range for glucose concentrations, spanning from 1 to 800 μM. Density functional theory calculations reveal the synergistic role of Pt active sites within the Co₃O₄/rGO/Pt composite, which enhanced glucose adsorption and facilitates electron transfer, thereby improving sensor performance. To facilitate practical application, an S-shaped microfluidic chip and a point-of-care testing (POCT) device were designed and validated through trials involving human volunteers. This provides valuable insights and introduces novel approaches for sweat glucose analysis, contributing to the advancement of wearable technologies in personalized healthcare [77].

3.2.2. Sweat Analysis

Sweat, a biofluid rich in electrolytes, metabolites, and hormones, offers a non-invasive medium for monitoring physiological status [78]. Wearable LoC devices can analyze sweat rate, pH, sodium, potassium, cortisol, and lactate levels [79,80]. Sweat-based LoCs leverage microfluidic channels to collect, and guide sweat to embedded sensors, often using colorimetric or electrochemical detection [81]. Applications span from hydration monitoring in athletes to stress detection and fatigue assessment in occupational settings [78,82]. Colorimetric sensors, while simple and energy-efficient, often face limitations related to subjective interpretation and ambient lighting variability. These challenges illustrate a broader issue in LoC systems: the difficulty of achieving accurate, standardized, and user-independent signal readout. Whether the transduction method is optical, electrochemical, or electrical, ensuring consistent signal interpretation across varying conditions remains a critical hurdle to reliable point-of-care deployment.

Wearable biosensors demonstrate significant potential for personalized health monitoring by delivering continuous, real-time physiological data. Among these, localized surface plasmon resonance (LSPR)-based sensors offer versatility and high sensitivity in detecting specific analytes. Monitoring endocrine responses to stress remains crucial for evaluating human performance, diagnosing stress-related disorders, and supporting mental health, as stress substantially impacts physiological and psychological well-being. Cortisol serves as a primary biomarker for stress, reflecting its levels through concentration in the body. Nan et al. developed a flexible LSPR biosensor to detect cortisol by depositing gold nanoparticles (AuNPs) on a poly(dimethylsiloxane) (PDMS) substrate functionalized with 3-aminopropyltriethoxysilane (APTES) [83]. An aptamer specific to cortisol is immobilized on the sensor surface, enabling selective and sensitive hormone capture. The biosensor exhibited effective detection across cortisol concentrations ranging from 0.1 to 1000 nM, with a detection limit of 0.1 nM. It maintained stability under various mechanical deformations, demonstrating flexibility. The sensor underwent testing on human skin to measure cortisol levels before and after exercise, as well as at different times of the day. The combination of straightforward fabrication and high cortisol sensitivity establishes this flexible LSPR biosensor as a promising tool for wearable stress monitoring applications [83].

The limited availability of sweat in sedentary individuals typically less than 10 µL—restricts on-demand, in situ analysis and hampers the full utilization of this valuable, noninvasive biofluid. To overcome this limitation, a wearable and miniaturized iontophoresis interface was developed as an effective solution [84]. The iontophoresis process employed electrical currents to deliver stimulating agents to sweat glands, inducing sweat secretion. Nevertheless, challenges persist in designing an iontophoresis interface capable of extracting sufficient sweat volume for reliable sensing while preventing electrode corrosion and minimizing discomfort or skin irritation. This challenge was addressed by creating an electrochemically enhanced iontophoresis interface integrated into a wearable sweat analysis platform. The interface can be programmed to induce varying sweat secretion profiles, facilitating real-time analysis and advancing the understanding of sweat gland physiology and secretion mechanisms. Figure 3 shows a flexible platform with electrodes for sweat induction and sensing, integrated on a wireless printed circuit board (FPCB).

The system electrically separates the iontophoresis and sensing modes (Figure 3c). Electrodes on a flexible PET substrate ensure stable skin contact (Figure 3b). Sweat induction electrodes interface through a hydrogel containing cholinergic agents like pilocarpine, connected via corrosion-resistant stainless-steel contacts. Different sweat secretion patterns can be programmed by adjusting the hydrogel composition. Sensing electrodes use a rayon pad to absorb sweat. The sensors detect sodium and chloride ions potentiometrically and glucose amperometrically, targeting markers relevant to cystic fibrosis and diabetes. The FPCB integrated iontophoresis control, signal processing, and wireless communication (Figure 3d), with safety circuits limiting current to protect the skin.

To demonstrate the clinical relevance of the platform, human studies were conducted focusing on cystic fibrosis diagnosis and preliminary investigations into the correlation between blood and sweat glucose levels. Results show that cystic fibrosis patients exhibit elevated sweat electrolyte concentrations compared to healthy control subjects. Furthermore, glucose ingestion in fasting individuals results in increased glucose levels detectable in both sweat and blood. This platform paves the way for a wide range of noninvasive diagnostic applications and continuous health monitoring for the general population [84].

3.2.3. Cardiovascular Health (ECG, Blood Pressure)

Wearable LoC biosensors play a crucial role in cardiovascular monitoring. Skin-integrated electrodes and flexible electronics allow for high-fidelity ECG monitoring [85,86]. Additionally, optical and piezoresistive sensors integrated into wearables can provide continuous blood pressure estimation using pulse transit time or tonometry [87]. These technologies enable early detection of arrhythmias, hypertension, and other cardiovascular anomalies in outpatient or home settings [88,89,90]. Kaisti et al. presented the integration of high-performance MEMS pressure sensors into a flexible wristband designed to measure the radial artery pulse [88]. The low-cost sensor elements were arranged in an array and embedded onto the wristband to capture detailed pulse waveforms. Testing was conducted on 13 healthy volunteers, successfully extracting average arterial waveforms, identifying key features such as systolic and diastolic peaks, the dicrotic notch, and calculating heart rate. These findings suggest that MEMS pressure sensors could serve as effective tools for mobile and remote cardiovascular health monitoring in future healthcare applications [88].

Contemporary cardiac and heart rate monitoring devices utilize optical and electrode-based sensors to capture physiological signals; however, they often lack the mechanical flexibility and compact design required for comfortable use in ambulatory and home environments. Lee et al. presented an ultrathin (~1 mm thickness), highly flexible wearable cardiac sensor (WiSP) characterized by its lightweight construction (1.2 g), cost-effectiveness through disposability, water resistance, and capability for wireless energy harvesting [91]. System-level analyses of bending mechanics demonstrated that the flexible electronics, soft encapsulation layers, and bioadhesives employed in WiSP enabled intimate and secure skin coupling. Clinical feasibility testing on patients with atrial fibrillation confirmed that WiSP accurately measures cardiac signals comparable to those obtained from Holter monitors while providing enhanced user comfort. The device’s physical properties and performance underscore its suitability for continuous cardiac monitoring during daily activities, physical exertion, and sleep, suggesting strong potential for application in home-based healthcare [91].

3.2.4. Respiratory and Metabolic Monitoring

Respiratory rate and metabolic parameters such as oxygen consumption and CO₂ exhalation are vital indicators of pulmonary function and overall metabolic health [92]. Wearable LoC devices can detect respiratory patterns through strain sensors, temperature sensors, or chemical detection of breath constituents [93,94]. Integrated gas sensors and microfluidic breath collectors are being developed to analyze volatile organic compounds (VOCs) for disease diagnostics and performance optimization.

Physiological signals such as electroencephalograms (EEGs) and galvanic skin response (GSR) are commonly used for stress assessment. However, existing commercial EEG-based stress detection systems often require multiple channels and controlled environments, limiting their use in daily life. To overcome these challenges, a wearable system combining EEG and GSR signals through a single-channel setup was developed as shown in Figure 4 [93]. This sensor fusion technique improves accuracy, reduces costs, and enhances ease of use. The system was tested on twenty subjects, analyzing the EEG power spectrum and employing five machine learning classifiers to distinguish between two levels of mental stress. The study also identified the optimal electrode placement on the scalp for single-channel recording. Results showed classification accuracies reaching 70.3% with EEG alone and 84.6% when combining EEG and GSR data. These findings demonstrate the potential for effective stress monitoring using a single-channel device positioned over the prefrontal and ventrolateral prefrontal cortex [93].

Lee et al. examined how 3D-printed electrode designs affect EEG signals and identifies key design factors for improved skin adhesion in smart wearables [95]. Ten electrode types with varying shapes (plain, checkered, striped, circular, radial cut-out) and thicknesses (0.5 mm, 1.0 mm) were tested on 20 healthy adults (10 men, 10 women). EEG data were collected using the BIOS-S8 system (BioBrain Inc., Daejeon, Republic of Korea) and analyzed with SPSS 26.0. Gender-based differences were observed: males showed higher RA, RST, RMT, and RSMT values, while females had elevated RA, RFA, and RSA activity. No significant gender differences were found across electrode types. However, in females, RA values at the T4 site varied significantly with shape but not thickness. Subjective evaluations also indicated that participants perceived differences in electrode shape and thickness [95].

Conductive polymer composites (CPCs) exhibiting the positive temperature coefficient (PTC) effect are highly valued for their material versatility and enhanced sensitivity. However, traditional CPCs usually have high PTC switching temperatures, often above 100 °C, limiting their suitability for wearable healthcare applications. Guo et al. introduced an innovative composite that integrated lauric acid (LA), an eco-friendly fatty acid, with a flexible styrene-ethylene-butylene-styrene (SEBS) thermoplastic elastomer (TPE) matrix and graphene nanoplatelets (GNPs) as conductive fillers [94]. The composite film demonstrated exceptional temperature responsiveness within the human body temperature range of 35–40 °C, achieving a PTC intensity increase by four orders of magnitude and a maximum temperature coefficient of resistance (TCR) of 471.4% °C⁻¹. These enhancements result from a deliberately engineered morphology, where LA distribution significantly influences the reformation of the conductive network, as revealed through in situ optical microscopy. Due to its flexibility and sensitivity, this composite shows strong potential for applications such as body temperature sensing, self-regulating heating, and passive cooling, paving the way for the development of eco-friendly, flexible sensors in wearable health monitoring and thermotherapy [94].

3.3. Design Considerations

Ensuring that materials in contact with the skin or bodily fluids are biocompatible is critical for long-term usability [33,85]. Materials must be non-toxic, hypoallergenic, and compliant with biomedical standards. Common materials include silicone elastomers, hydrogels, and bioinert metals (e.g., gold, platinum) for electrodes [96,97]. Antimicrobial coatings and breathable designs are also employed to prevent skin irritation and microbial growth [98]. Wearable LoC devices face stringent power constraints due to their compact form factor and continuous operation requirements [37,44]. Efficient power management strategies include ultra-low-power circuitry, duty cycling, and power-aware data acquisition. Energy harvesting techniques such as thermoelectric generators (TEGs), piezoelectric elements, and flexible solar cells are being integrated to extend device lifespan and minimize reliance on batteries [47]. Reliable and secure data transmission is essential for real-time biosensing applications. Most wearable LoC biosensors utilize wireless communication protocols like Bluetooth Low Energy (BLE), Zigbee, or NFC for short-range data transfer to smartphones or cloud platforms [39]. Data integrity, latency, and encryption are critical parameters, especially in medical-grade applications. Emerging approaches involve edge computing [99] and AI-based local data processing to reduce bandwidth and enhance privacy [100].

Table 2. Characteristics of wearable LoC biosensors.

Category	Sub-Category	Description
Types of Wearable Biosensors	Skin-based patches [101]	Conformal, adhesive devices applied to the epidermis enabling continuous, real-time biochemical and physiological monitoring through non-invasive or minimally invasive means.
	Smart textiles [65]	Biosensors integrated into textile fibers or fabrics, allowing seamless, unobtrusive data acquisition of vital signs during everyday activities or physical exertion.
	Wearable wristbands and watches [69]	Commercially viable platforms incorporating multi-modal sensors (e.g., photoplethysmography, ECG) for cardiovascular and metabolic monitoring with integrated data processing.
Applications	Glucose monitoring [102]	Continuous and non-invasive glucose tracking through interstitial fluid or sweat analysis; crucial for diabetes management and glycemic control.
	Sweat analysis [78]	Quantitative analysis of sweat constituents such as electrolytes, lactate, and cortisol; indicative of hydration status, physical exertion, or stress levels.
	Cardiovascular health [103]	Real-time monitoring of electrocardiography (ECG), heart rate, and blood pressure; instrumental in diagnosing arrhythmias and managing hypertension.
	Respiratory and metabolic monitoring [104]	Assessment of respiratory rate, oxygen saturation, and metabolic markers; applicable in chronic disease management and fitness optimization.
Design Considerations	Biocompatibility [105]	Use of materials and interfaces that are non-toxic, non-irritating, and compatible with prolonged dermal contact to prevent adverse biological responses.
	Power management and energy harvesting [106]	Implementation of low-power electronics, energy-efficient protocols, and self-sustaining power sources (e.g., thermoelectric, triboelectric) for extended operational lifespan.
	Data transmission and connectivity [107]	Integration of wireless communication protocols (e.g., Bluetooth, NFC, Wi-Fi) enabling real-time data transfer to external devices for storage, analysis, and feedback.

Table 2. Characteristics of wearable LoC biosensors.

Category	Sub-Category	Description
Types of Wearable Biosensors	Skin-based patches [101]	Conformal, adhesive devices applied to the epidermis enabling continuous, real-time biochemical and physiological monitoring through non-invasive or minimally invasive means.
	Smart textiles [65]	Biosensors integrated into textile fibers or fabrics, allowing seamless, unobtrusive data acquisition of vital signs during everyday activities or physical exertion.
	Wearable wristbands and watches [69]	Commercially viable platforms incorporating multi-modal sensors (e.g., photoplethysmography, ECG) for cardiovascular and metabolic monitoring with integrated data processing.
Applications	Glucose monitoring [102]	Continuous and non-invasive glucose tracking through interstitial fluid or sweat analysis; crucial for diabetes management and glycemic control.
	Sweat analysis [78]	Quantitative analysis of sweat constituents such as electrolytes, lactate, and cortisol; indicative of hydration status, physical exertion, or stress levels.
	Cardiovascular health [103]	Real-time monitoring of electrocardiography (ECG), heart rate, and blood pressure; instrumental in diagnosing arrhythmias and managing hypertension.
	Respiratory and metabolic monitoring [104]	Assessment of respiratory rate, oxygen saturation, and metabolic markers; applicable in chronic disease management and fitness optimization.
Design Considerations	Biocompatibility [105]	Use of materials and interfaces that are non-toxic, non-irritating, and compatible with prolonged dermal contact to prevent adverse biological responses.
	Power management and energy harvesting [106]	Implementation of low-power electronics, energy-efficient protocols, and self-sustaining power sources (e.g., thermoelectric, triboelectric) for extended operational lifespan.
	Data transmission and connectivity [107]	Integration of wireless communication protocols (e.g., Bluetooth, NFC, Wi-Fi) enabling real-time data transfer to external devices for storage, analysis, and feedback.

While Table 2 outlines the types and application domains of wearable biosensors, Table 3 provides a quantitative comparison of performance metrics including sensitivity, specificity, limit of detection, response time, and operational lifetime across key biosensor modalities. This comparison is intended to help readers assess the relative strengths and limitations of each technology.

Table 3. Comparative Performance Metrics of Wearable and Implantable LoC Biosensors.

Sensing Modality/Sensor Type	Target Analyte	Sensitivity	Specificity	LOD	Response Time	Operational Lifetime	Ref.
Electrochemical Glucose Sensor (Wearable)	Glucose	~10 µA/mM·cm2	High (enzyme-based)	~1 µM	~5–10 s	~7–14 days (enzyme-limited)	[29,79,80,108]
Optical Sweat Sensor (Colorimetric)	Lactate, pH, Na+	Qualitative	Moderate (cross-talk)	~0.1 mM (lactate)	~2–5 min	~1 day (disposable patches)	[78,80,109]
ISF Patch-Based Sensor (Microneedle)	Glucose, Ketone	~0.1 µA/mM·cm2	High	~10 µM	~15–30 s	~7 days	[108,110]
FET-Based DNA Sensor (Implantable)	DNA/RNA (biomarkers)	fM–pM range	Very high (probe-specific)	~10 fM	~60–120 s	Weeks–months (depends on stability)	[111,112,113]
Capacitive Sweat Sensor	Electrolytes (Na+, K+)	~0.1 pF/mM	Moderate	~1 mM	~30–60 s	~3–5 days	[78,114,115]
Piezoelectric Sensor (Implantable)	Cardiac Troponin	High (~ng/mL)	High	~0.05 ng/mL	~1–2 min	Weeks	[116,117]
Wearable Immunosensor (Lateral Flow)	CRP, IL-6, SARS-CoV-2	Qualitative/Quantitative	High (antibody-based)	~1 ng/mL	~5–15 min	Single-use (disposable)	[118,119,120]

Table 3. Comparative Performance Metrics of Wearable and Implantable LoC Biosensors.

Sensing Modality/Sensor Type	Target Analyte	Sensitivity	Specificity	LOD	Response Time	Operational Lifetime	Ref.
Electrochemical Glucose Sensor (Wearable)	Glucose	~10 µA/mM·cm2	High (enzyme-based)	~1 µM	~5–10 s	~7–14 days (enzyme-limited)	[29,79,80,108]
Optical Sweat Sensor (Colorimetric)	Lactate, pH, Na+	Qualitative	Moderate (cross-talk)	~0.1 mM (lactate)	~2–5 min	~1 day (disposable patches)	[78,80,109]
ISF Patch-Based Sensor (Microneedle)	Glucose, Ketone	~0.1 µA/mM·cm2	High	~10 µM	~15–30 s	~7 days	[108,110]
FET-Based DNA Sensor (Implantable)	DNA/RNA (biomarkers)	fM–pM range	Very high (probe-specific)	~10 fM	~60–120 s	Weeks–months (depends on stability)	[111,112,113]
Capacitive Sweat Sensor	Electrolytes (Na+, K+)	~0.1 pF/mM	Moderate	~1 mM	~30–60 s	~3–5 days	[78,114,115]
Piezoelectric Sensor (Implantable)	Cardiac Troponin	High (~ng/mL)	High	~0.05 ng/mL	~1–2 min	Weeks	[116,117]
Wearable Immunosensor (Lateral Flow)	CRP, IL-6, SARS-CoV-2	Qualitative/Quantitative	High (antibody-based)	~1 ng/mL	~5–15 min	Single-use (disposable)	[118,119,120]

4. Implantable LoC Biosensors

Implantable LoC biosensors represent a transformative technology that integrates miniaturized analytical devices directly within the body to enable continuous and real-time physiological monitoring [59]. These systems provide a critical interface between biological tissues and electronic data acquisition platforms, offering unprecedented insights into patient health and enabling precision medicine applications. These devices enable high-resolution monitoring of critical parameters such as glucose levels, neural activity, and cardiac function, often supporting closed-loop therapeutic feedback. Due to their invasive nature, implantable biosensors demand rigorous attention to biocompatibility, power efficiency, and long-term stability. Table 4 outlines the key types, applications, and design considerations of implantable LoC biosensors, highlighting their distinct features and technical requirements.

4.1. Types and Insertion Sites

4.1.1. Subcutaneous Sensors

Subcutaneous implantable LoC biosensors are designed for insertion just beneath the skin, providing minimally invasive access to interstitial fluid for biomarker detection [121,122]. These sensors are widely used due to their ease of implantation and reduced risk of complications [123]. They typically monitor metabolites such as glucose or lactate and rely on microfluidic channels to draw interstitial fluid into sensing chambers [124]. Wu et al. presented a wireless implantable sensor prototype that harnesses solar energy through a subcutaneous flexible solar panel [122]. To evaluate its feasibility, ex vivo experiments were performed under both natural sunlight and artificial lighting conditions. Results demonstrated that when covered by a 3 mm thick porcine tissue flap, the solar panel could generate power ranging from several tens of microwatts up to a few milliwatts, depending on the intensity of the light source. Further testing across various body regions identified the area between the neck and shoulder as the most optimal site for implantation of the energy harvester.

The complete implantable system powered by this subcutaneous solar module includes a power management circuit, a temperature sensor, and a BLE communication unit. For data monitoring, a dedicated mobile application was developed, enabling real-time visualization and paving the way for future Internet of Things (IoT)-based healthcare applications. The entire assembly is housed within a transparent silicone enclosure measuring 38 mm × 32 mm × 4 mm and incorporates a 7 mAh rechargeable battery for energy storage. The device maintains an average power consumption of approximately 30 μW during 10 min operational cycles [122]. Long-term tests confirmed that the sensor prototype can sustain self-powered operation using the harvested solar energy beneath the skin. Additionally, robustness was evaluated through ex vivo simulations of two critical scenarios: complete absence of light exposure and battery depletion, demonstrating the system’s reliability under challenging conditions [122].

4.1.2. Intravascular and Intracranial Sensors

Intravascular sensors are implanted within blood vessels, enabling direct blood analysis with high temporal resolution [125,126]. These are particularly valuable for monitoring blood gases, electrolytes, or circulating biomarkers in critical care. Intracranial implants, often used in neurological monitoring and neural interface systems, are inserted within brain tissue or cerebral ventricles [127]. They allow for electrophysiological recordings or detection of neurochemical markers to manage neurological disorders such as epilepsy or Parkinson’s disease.

Monitoring vital physiological parameters such as heart rate, respiratory rate, and intracranial pressure (ICP) with high accuracy is crucial, particularly for patients with severe cranial injuries. Despite notable advancements in implantable ICP sensing technology over recent decades, existing devices often face drawbacks including wired connections, limited sensitivity, poor resolution, and an inability to monitor multiple signals simultaneously. To overcome these challenges, Li et al. presented an ultrasensitive multimodal biotelemetric system that combined an iontronic pressure transducer with exceptional point (EP) operation specifically designed for ICP monitoring (Figure 5a).

Recently, the concept of parity–time (PT) symmetry, originally rooted in quantum mechanics, has been adapted to electronic systems. This concept implies that a non-Hermitian electronic circuit can maintain purely real eigenvalues beyond a critical threshold known as the exceptional point (EP). When a system operates near this EP, its eigenfrequencies undergo significant shifts (as illustrated in Figure 5b), resulting in performance that far exceeds that of traditional “LC” wireless sensing systems (see Figure 5c) [127].

This system achieved outstanding performance in detecting even the smallest ICP fluctuations, with a sensitivity of 115.95 kHz/mmHg and a resolution reaching 0.003 mmHg. Moreover, it not only provides precise ICP measurements but also differentiates respiratory and cardiac signals within the ICP data, enabling simultaneous real-time monitoring of intracranial pressure, respiration, and heart rate from a single device. This innovative solution offers a practical approach for continuous wireless ICP monitoring and holds significant promise for expansion to other critical physiological measurements [127].

4.1.3. Gastrointestinal and Organ-Targeted Implants

LoC biosensors can also be engineered for implantation within specific organs or the gastrointestinal tract [128]. These sensors are designed to withstand harsh internal environments and can provide localized biochemical monitoring or therapeutic feedback, such as pH, enzyme levels, or drug concentrations. Organ-targeted implants may be placed during surgical procedures and customized for specific diagnostic or therapeutic needs [129].

The use of implantable functional electrical stimulation (IFES) has been established as a viable alternative for managing certain conditions that cannot be treated through pharmaceutical means, such as cochlear implants, retinal prostheses, and spinal cord stimulators for pain relief. However, its application in gastrointestinal (GI) modulation has remained underdeveloped. This limitation has been primarily attributed to the limited understanding of the gut–brain axis and the inherent differences in stimulating and monitoring smooth muscle, skeletal muscle, and neural tissues. As a result, unique design challenges have been introduced for GI-specific implants. To address these challenges, specific design requirements for GI implants aimed at treating dysmotility were identified (Figure 6a) [128].

A miniaturized wireless implant was developed to both stimulate and monitor GI motility. The implant was constructed using a custom system-on-a-chip (SoC) combined with a heterogeneous system-in-a-package (SiP), enabling functional integration within a compact form factor (Figure 6b). The device’s performance was validated through in vivo studies conducted on both rodent and porcine models. Results confirmed the implant’s ability to modulate and record gastrointestinal activity effectively, demonstrating its potential as a therapeutic tool for GI disorders [128].

4.2. Applications

Implantable LoC biosensors have transitioned from conceptual research to real-world clinical applications, addressing the need for continuous and precise physiological monitoring. Their integration into the human body enables real-time tracking of critical biomarkers and physiological signals without reliance on external sampling or intermittent diagnostics. These capabilities are especially valuable in managing chronic diseases, monitoring neurological activity, and delivering targeted therapies. In the following subsections, we explore the key application domains where implantable LoC biosensors have shown significant impact, including continuous glucose monitoring, neural interfacing, cardiac health assessment, and smart drug delivery systems. These examples highlight how implantable biosensors are redefining personalized medicine through minimally invasive, autonomous, and responsive healthcare solutions.

4.2.1. Continuous Glucose Monitoring (CGM)

One of the most widespread applications of implantable LoC biosensors is in CGM for diabetes management [121]. These devices measure glucose levels in interstitial fluid or blood continuously, providing dynamic glycemic profiles that improve insulin dosing and patient outcomes [121,130,131]. Implantable CGMs benefit from integrated microfluidics, enzymatic sensing layers, and wireless telemetry for real-time data transmission [124].

Kim et al. proposed an innovative electromagnetic sensor designed for subcutaneous implantation that detects minute changes in dielectric permittivity related to blood glucose level (BGL) variations [121]. The sensor can detect subtle variations in the dielectric permittivity caused by changes in interstitial glucose levels (see Figure 7a). An illustration of the implantable sensor design is provided in Figure 7b. Its compact size which is measuring just 4 mm in diameter is shown in Figure 7c alongside a coin for scale, making it well-suited for subcutaneous implantation.

Figure 7d displays how the sensor’s frequency shifts correspond to fluctuations in blood glucose levels. To validate the concept, intravenous glucose tolerance tests (IVGTT) were conducted on swine and beagle subjects under controlled laboratory conditions. Furthermore, comprehensive sensor interface modules, mobile applications, and glucose mapping algorithms were developed to facilitate continuous glucose tracking during an oral glucose tolerance test (OGTT) in freely moving beagles. These results include data from both short-term (1 h, IVGTT) and long-term (52 h, OGTT) experiments, demonstrating a clear correlation between sensor frequency response and blood glucose levels in both animal models. This work highlights the potential of electromagnetic-based implantable sensors as a promising alternative for continuous glucose monitoring [121].

4.2.2. Neurological and Neural Interface Systems

Implantable LoC biosensors form the foundation of advanced neural interface devices, including brain–computer interfaces (BCIs) and deep brain stimulation systems [132,133,134]. These sensors monitor neural activity or neurotransmitter fluctuations, enabling treatment of neurological diseases and enhancement of neuroprosthetic control [135]. Microelectrode arrays combined with chemical sensors on a chip enable multimodal sensing capabilities [136,137].

Sensory nerve damage, such as optic nerve injury leading to vision impairment, disrupts the transmission of input to the thalamus. In such cases, reestablishing functional sensory input requires bypassing the damaged neural pathways. One potential strategy involves direct stimulation of the sensory thalamic nuclei. However, conventional deep brain stimulation (DBS) electrodes lack the fine resolution necessary for accurate sensory signal restoration. To overcome this limitation, a novel implantable biohybrid neural interface was designed to enable precise innervation and synaptic stimulation of deep brain targets [138]. The device consists of two primary components: a soft, stretchable electrode array for electrical stimulation, and an aligned microfluidic axon guidance platform seeded with neural spheroids. These spheroids support the development of a nerve-like structure approximately 3 mm in length. A bioresorbable hydrogel conduit was integrated to serve as a transitional bridge between host neural tissue and the implant. Functional validation was conducted in vitro, where stimulation of neural spheroids and recordings using high-density CMOS microelectrode arrays demonstrated consistent and reliable signal conduction across the interface. Although this study did not achieve full in vivo synaptic integration or functional innervation, implantation of the biohybrid nerve onto the mouse cortex confirmed axonal growth from the neural spheroids and sustained neural activity for more than 22 days post-implantation [138].

4.2.3. Cardiac Monitoring

Implantable loop recorders and pacemaker-integrated biosensors use LoC technology to provide continuous cardiac monitoring [139,140,141]. These devices detect arrhythmias, ischemia, and other cardiac events in real time, with integrated sensing and data processing enabling early intervention [142]. LoC integration allows for miniaturization and improved biocompatibility within these critical cardiac implants [143].

A secure design methodology was proposed for hardware intellectual properties (IPs) used in implantable cardiac pacemakers, focusing on the filter bank and QRS complex detection modules [142]. This approach was developed to ensure patient safety and device reliability by embedding robust protection against intellectual property piracy and counterfeiting. The design process was initiated by deriving data flow graphs from the transfer functions of the target hardware modules. Subsequently, a security signature was generated and encrypted using the Advanced Encryption Standard (AES) by the original IP vendor. This encrypted signature was then encoded as a covert digital proof and embedded discreetly during the register allocation stage of the high-level synthesis (HLS) procedure. Register-transfer level (RTL) designs were produced carrying the embedded digital evidence, allowing for post-production detection of unauthorized replication or tampering. The security feature was integrated with negligible overhead on design resources, preserving efficiency. Experimental evaluation demonstrated that the probability of random matching was extremely low, ranging from 8.40 × 10⁻¹⁷ to 4.78 × 10⁻³, which validated the uniqueness of the embedded digital proof. Additionally, tamper resistance was significantly enhanced, with tolerance levels spanning from 1.34 × 10⁺¹⁵⁴ to 2.41 × 10⁺⁴⁶². The results further showed improvements in entropy, tamper resilience, and proof robustness compared to existing methods applied to pacemaker hardware IPs [142].

The development of implantable biosensor for the coronary sinus marks a notable step forward in the management of heart failure by facilitating continuous, real-time tracking of essential cardiac biomarkers [144]. Its capacity to detect early increases in troponin I and BNP introduces a proactive strategy for identifying impending decompensation and potentially minimizing hospital readmissions. Pilot evaluations (Figure 8) were conducted using wired, flexible biosensor prototypes to generate preclinical insights and to assess device performance in both in vivo and ex vivo settings. In the in vivo study, the device was implanted into the coronary sinus of canine models (n = 2), and continuous monitoring was carried out over a two-hour period. Myocardial ischemia was induced, leading to immediate elevations in troponin I and BNP, which were detected by the biosensor prior to their systemic appearance by several hours. For the ex vivo investigation, perfused human heart tissues obtained from transplant discards (n = 2) were utilized, and the device’s sensitivity to gradual biochemical variations in the myocardial environment was demonstrated. Across both models, high stability, specificity, and biocompatibility were observed, with only minimal inflammatory response noted at the implantation site. This technology demonstrates strong potential to enhance patient care and contribute meaningfully to the field of precision bioelectronic cardiology [144].

4.2.4. Drug Delivery Systems

Implantable LoC biosensors are increasingly integrated with drug delivery modules, enabling closed-loop therapeutic systems [145,146]. These “smart implants” can sense biochemical markers and trigger precise dosing of medications such as insulin or anti-inflammatory drugs [147,148]. This synergy between sensing and actuation facilitates personalized medicine and reduces side effects [149]. Accurate delivery of therapeutics to specific target sites is critical for both treatment effectiveness and patient safety. Traditional drug administration routes face numerous transport barriers, making it difficult to achieve and sustain the desired local drug concentration, often leading to unintended systemic side effects. Additionally, patient adherence to prescribed treatment schedules poses a significant challenge. Implantable drug delivery systems (IDDSs) offer a promising solution by being surgically implanted directly into tissues, bypassing first-pass metabolism and minimizing systemic toxicity through localized drug release near the target area. These devices exemplify the successful translation of research and engineering advances into clinical practice, and their use is expected to expand rapidly in the coming years [148]. Clinically available and market approved IDDSs are generally categorized into inserts, pumps, and stents (see Figure 9) [148].

Implanted materials and devices designed for various organs and tissues, as illustrated in Figure 9, must satisfy a set of stringent properties specific to their anatomical and functional environments. Universally, these devices require high biocompatibility to prevent immune reactions, fibrotic encapsulation, and long-term tissue damage. Mechanical compliance is essential to ensure conformability with soft or dynamic biological structures, particularly in the brain, eyes, and muscles. Long-term operational stability is also critical, with materials needing to resist corrosion, biofouling, and degradation over extended periods. In cardiovascular applications such as stents, the materials must provide sufficient mechanical strength, anti-thrombogenic properties, and, in many cases, drug-eluting capabilities to mitigate restenosis.

Pacemakers and cardiac monitors require precise electrophysiological compatibility, low-latency telemetry, and robust signal fidelity. Neural implants necessitate ultra-flexible substrates and neuro-compatible coatings to minimize tissue damage and ensure reliable interfacing with delicate neural circuits. Implants targeting cancerous tissues must facilitate localized drug delivery or in situ biochemical monitoring, often relying on biodegradable or retrievable materials with embedded feedback control. Devices embedded in muscular tissue must exhibit stretchability and fatigue resistance, supporting mechanical loads during contraction and movement without functional loss. Across all applications, implantable systems must integrate efficient power sources, secure wireless communication, and miniaturized architectures to enable long-term, autonomous operation within complex biological environments.

These devices can be introduced into the body through various methods: injections or small incisions requiring minimal anesthesia (e.g., inserts and osmotic pumps for subcutaneous use), intravascular procedures (such as stents), or more invasive surgeries (mechanical pumps). It is important to note that terminology related to IDDSs is sometimes unclear. The terms “implant” and “insert” are frequently used interchangeably, often influenced by marketing preferences. For the purpose of this review, “inserts” refer to solid implants placed inside the body via at least minor surgical intervention involving tissue puncture or incision. According to the FDA, an “implant” is defined as a device positioned within a surgically or naturally created cavity in the body intended to remain in place for a prolonged period, typically 30 days or more, although shorter durations are also recognized for safety assessments [148].

While many wearable and implantable LoC biosensors have demonstrated significant promise in lab-scale experiments and pilot studies, relatively few have progressed to clinical validation or commercial availability. For example, continuous glucose monitors such as the Dexcom G6/G7 and Abbott FreeStyle Libre have received FDA and CE approvals and have been validated through large-scale clinical trials for diabetes management [150,151]. Similarly, the Medtronic LINQ II is a commercially available, FDA-approved implantable cardiac monitor with long-term clinical validation [152]. On the other hand, many advanced LoC biosensors described in research, such as sweat cortisol sensors, neural interface systems, or GI-implantable biosensors, remain at the proof-of-concept or preclinical stage. These devices are typically validated in vitro, in animal models, or short-term human feasibility studies [109]. Their transition to clinical use is often hindered by regulatory challenges, biocompatibility concerns, and the need for long-term safety data. Therefore, it is important to distinguish between devices already deployed in healthcare settings and emerging technologies still undergoing development. Continued progress will depend not only on technological innovation but also on rigorous clinical trials and adherence to regulatory frameworks.

4.3. Design Considerations

Implantable biosensors must maintain functionality over extended periods within a complex biological environment. Biofouling—accumulation of proteins, cells, and biofilms on sensor surfaces can degrade sensor sensitivity and accuracy [153]. Advanced surface coatings, antifouling materials, and sensor regeneration techniques are critical design elements to ensure long-term operational stability [154]. Powering implantable LoC biosensors poses significant challenges [44]. Conventional batteries add bulk and have limited lifespans. Emerging solutions include energy harvesting from body movement or heat and wireless power transfer technologies such as inductive coupling. Wireless recharging capabilities minimize the need for surgical battery replacements and support continuous operation [155]. Safety considerations encompass biocompatibility, minimizing tissue damage during implantation, and avoiding inflammatory or immune responses [156,157]. Implantation procedures must balance invasiveness with clinical benefits, often requiring specialized surgical techniques. Regulatory approval for implantable devices is stringent, demanding rigorous biocompatibility, reliability, and safety testing to ensure patient welfare and device efficacy [158].

Table 4. Characteristics of implantable LoC biosensors.

Category	Sub-Category	Description
Types of Implantable Biosensors	Subcutaneous sensors [121,130]	Minimally invasive devices placed beneath the skin to access interstitial fluid. Commonly used for glucose, lactate, and ion monitoring. Known for relatively simple implantation and moderate longevity.
	Intravascular sensors [126]	Sensors implanted in blood vessels to directly access and analyze blood components. Offer high temporal resolution for analytes like oxygen, glucose, and electrolytes. Require biocompatibility and anticoagulant surfaces to reduce thrombosis risk.
	Intracranial/neurological implants [127]	Highly specialized biosensors inserted into brain tissue or cerebrospinal spaces. Used for monitoring intracranial pressure, EEG, or neurochemical levels. Must maintain precise function under immune-reactive conditions.
	Gastrointestinal and organ-targeted implants [131]	Devices tailored for specific organs (e.g., gut, liver, bladder). Enable localized sensing or modulation (e.g., pH, motility, enzymes). Must withstand complex physiological environments and mechanical stress.
Applications	Continuous glucose monitoring (CGM) [124]	Long-term monitoring of glucose levels in blood or ISF using enzymatic, optical, or electromagnetic sensors. Integration with telemetry enables real-time glycemic control in diabetes care.
	Neural interfaces and neuroprosthetics [132]	Capture neural signals or modulate brain activity for treatment of epilepsy, Parkinson’s, or for use in BCIs. Require ultra-miniaturized electronics and neural-friendly biocompatible interfaces.
	Cardiac monitoring and pacemakers [26]	Integrated within pacemakers or standalone to detect arrhythmias, ischemia, and heart rate variability. LoC sensors allow closed-loop control and precise event-triggered therapy.
	Smart drug delivery systems [147]	LoC platforms integrated with micro-reservoirs or micropumps to enable real-time, analyte-triggered drug release (e.g., insulin, anti-inflammatories). Support precision medicine with localized, on-demand therapy.
Design Considerations	Biocompatibility and encapsulation [159]	Implantable sensors require materials that resist immune rejection, inflammation, and fibrotic encapsulation. Common materials include medical-grade silicones, Parylene-C, titanium, and hydrogel coatings.
	Power supply and energy harvesting [44]	Power sources include miniaturized batteries, inductive wireless charging, biofuel cells, or energy harvesting from body motion/heat. Energy efficiency and longevity are critical.
	Data transmission and telemetry [106]	Communication is achieved via radio frequency (RF), Bluetooth Low Energy (BLE), or near-field communication (NFC). Requires high signal integrity, low latency, and data encryption.
	Long-term stability and signal fidelity [153]	Must maintain sensitivity over weeks to years. Challenges include biofouling, corrosion, material degradation, and sensor drift. Self-calibrating or regenerable sensors are preferred for extended deployment.
	Miniaturization and integration [160]	Requires integration of sensors, microfluidics, and processing circuits within mm-scale footprints. Must be mechanically and electrically stable without compromising sensing performance.
	Safety and regulatory compliance [158]	Devices must meet stringent safety, toxicity, and sterility standards (e.g., ISO 10993, FDA Class III). Preclinical validation, human trials, and post-market surveillance are essential for clinical deployment.

Table 4. Characteristics of implantable LoC biosensors.

Category	Sub-Category	Description
Types of Implantable Biosensors	Subcutaneous sensors [121,130]	Minimally invasive devices placed beneath the skin to access interstitial fluid. Commonly used for glucose, lactate, and ion monitoring. Known for relatively simple implantation and moderate longevity.
	Intravascular sensors [126]	Sensors implanted in blood vessels to directly access and analyze blood components. Offer high temporal resolution for analytes like oxygen, glucose, and electrolytes. Require biocompatibility and anticoagulant surfaces to reduce thrombosis risk.
	Intracranial/neurological implants [127]	Highly specialized biosensors inserted into brain tissue or cerebrospinal spaces. Used for monitoring intracranial pressure, EEG, or neurochemical levels. Must maintain precise function under immune-reactive conditions.
	Gastrointestinal and organ-targeted implants [131]	Devices tailored for specific organs (e.g., gut, liver, bladder). Enable localized sensing or modulation (e.g., pH, motility, enzymes). Must withstand complex physiological environments and mechanical stress.
Applications	Continuous glucose monitoring (CGM) [124]	Long-term monitoring of glucose levels in blood or ISF using enzymatic, optical, or electromagnetic sensors. Integration with telemetry enables real-time glycemic control in diabetes care.
	Neural interfaces and neuroprosthetics [132]	Capture neural signals or modulate brain activity for treatment of epilepsy, Parkinson’s, or for use in BCIs. Require ultra-miniaturized electronics and neural-friendly biocompatible interfaces.
	Cardiac monitoring and pacemakers [26]	Integrated within pacemakers or standalone to detect arrhythmias, ischemia, and heart rate variability. LoC sensors allow closed-loop control and precise event-triggered therapy.
	Smart drug delivery systems [147]	LoC platforms integrated with micro-reservoirs or micropumps to enable real-time, analyte-triggered drug release (e.g., insulin, anti-inflammatories). Support precision medicine with localized, on-demand therapy.
Design Considerations	Biocompatibility and encapsulation [159]	Implantable sensors require materials that resist immune rejection, inflammation, and fibrotic encapsulation. Common materials include medical-grade silicones, Parylene-C, titanium, and hydrogel coatings.
	Power supply and energy harvesting [44]	Power sources include miniaturized batteries, inductive wireless charging, biofuel cells, or energy harvesting from body motion/heat. Energy efficiency and longevity are critical.
	Data transmission and telemetry [106]	Communication is achieved via radio frequency (RF), Bluetooth Low Energy (BLE), or near-field communication (NFC). Requires high signal integrity, low latency, and data encryption.
	Long-term stability and signal fidelity [153]	Must maintain sensitivity over weeks to years. Challenges include biofouling, corrosion, material degradation, and sensor drift. Self-calibrating or regenerable sensors are preferred for extended deployment.
	Miniaturization and integration [160]	Requires integration of sensors, microfluidics, and processing circuits within mm-scale footprints. Must be mechanically and electrically stable without compromising sensing performance.
	Safety and regulatory compliance [158]	Devices must meet stringent safety, toxicity, and sterility standards (e.g., ISO 10993, FDA Class III). Preclinical validation, human trials, and post-market surveillance are essential for clinical deployment.

5. Materials and Fabrication Technologies

The successful development of wearable and implantable LoC biosensors hinges critically on the careful selection of materials and the deployment of advanced micro/nanofabrication techniques [161]. These biosensors require materials that are not only biocompatible and flexible but also conducive to precise microfluidic and sensing architectures [35,66,162,163]. In parallel, the choice of fabrication strategies influences the device’s scalability, resolution, and integration with functional components (See Table 5). This section elaborates on the key materials and fabrication methods used in the construction of wearable and implantable LoC biosensors.

5.1. Biocompatible and Flexible Materials

Wearable and implantable biosensors must maintain prolonged contact with biological tissues or fluids, necessitating the use of biocompatible materials that do not provoke immune responses or cytotoxicity [164]. Furthermore, the flexibility of materials plays a significant role in conformability and mechanical compatibility, especially for devices attached to skin or embedded in soft tissues [165]. PDMS is a widely used elastomer in LoC systems due to its excellent biocompatibility, optical transparency, gas permeability, and mechanical flexibility [166,167]. Its ease of molding and bonding makes it a standard substrate for microfluidic structures. However, PDMS can absorb small hydrophobic molecules, which may interfere with sensor accuracy in some applications [168].

Hydrogels, such as polyethylene glycol (PEG), alginate, and polyacrylamide, are hydrophilic polymer networks that closely mimic the natural extracellular matrix [169]. Their high water content and tunable mechanical properties make them suitable for tissue-interfacing sensors and drug-delivery integrated biosensors [170]. Conductive hydrogels are gaining attention for their ability to interface bioelectrically with tissues [171]. Materials like poly(methyl methacrylate) (PMMA) [172,173], cyclic olefin copolymer (COC) [174,175], and polycarbonate (PC) [176] are commonly used for rigid implantable LoC systems. These materials offer superior mechanical strength, chemical resistance, and optical clarity, and can be processed using injection molding or hot embossing. For wearable applications, materials like polyimide, thermoplastic polyurethane (TPU), and conductive fabrics enable integration into garments or direct skin application [18,66,67]. These materials maintain function under strain and deformation, essential for dynamic environments like joint movement or respiration monitoring.

5.2. Nanomaterials for Sensitivity and Selectivity

Nanomaterials are increasingly incorporated into LoC biosensors to enhance sensitivity, specificity, and signal transduction [177]. Their high surface area-to-volume ratio and tunable surface chemistry make them ideal for immobilizing biomolecules and facilitating rapid analyte interaction. Gold (Au) and silver (Ag) nanoparticles are commonly used in optical (e.g., plasmonic) and electrochemical sensors [178,179]. They offer excellent electrical conductivity and functionalizability, enhancing detection limits in applications like DNA hybridization and protein detection [180]. In addition to their excellent electrical conductivity, Au and Ag nanoparticles exhibit localized surface plasmon resonance (LSPR), a phenomenon where conduction electrons resonate with incident light at specific wavelengths. This optical resonance significantly amplifies the local electromagnetic field near the nanoparticle surface, enhancing the sensitivity of biosensors by improving the detection of minute changes in the local refractive index [181]. LSPR-based enhancement is particularly valuable in label-free optical biosensing, where even subtle biomolecular interactions can produce detectable spectral shifts, thereby enabling ultra-sensitive and selective analyte detection [182,183,184].

Carbon nanotubes (CNTs), graphene, and graphene oxide are frequently integrated into biosensors due to their outstanding electrical, thermal, and mechanical properties [185]. These materials serve as transducers or conductive channels in field-effect transistors (FETs), enabling real-time monitoring of biomolecular interactions with high sensitivity [186]. Quantum dots (QDs) are semiconductor nanocrystals used for fluorescent labeling and optical sensing [187]. Their size-tunable emission wavelengths and photostability make them suitable for multiplexed biomarker detection within LoC systems [188]. Metal–Organic Frameworks (MOFs) provide high porosity and specific surface areas, facilitating selective analyte capture [189,190]. Similarly, conducting polymers like polyaniline (PANI) and polypyrrole (PPy), especially in nanoform, are used for electrochemical biosensors due to their redox properties and ease of functionalization [191,192].

5.3. Fabrication Techniques

Fabrication strategies for wearable and implantable LoC biosensors aim to combine miniaturization, precision, and adaptability. A wide range of microfabrication techniques is used depending on the material system and functional requirements. Photolithography remains a gold standard for patterning micro- and nanoscale features on silicon or glass substrates [193]. It enables high-resolution structures necessary for microfluidics and sensor arrays. However, its reliance on cleanroom facilities and rigid substrates limits its applicability for flexible devices [194]. Developed as an alternative to conventional photolithography, soft lithography uses elastomeric stamps (usually PDMS) to replicate microstructures [195,196]. It is well-suited for fabricating flexible microfluidic channels and integrating biocompatible materials. Techniques under this category include replica molding, microcontact printing, and microtransfer molding [197]. Additive manufacturing has emerged as a promising method for rapid prototyping and producing complex, multi-material biosensors [198]. Inkjet, stereolithography (SLA), and fused deposition modeling (FDM) enable direct fabrication of intricate microfluidic geometries and sensor housings [199]. Bioprinting with cell-laden inks extends applications toward organ-on-chip and in vivo tissue integration [200].

Ravariu et al. presented the technological process for fabricating an enzyme field-effect transistor (ENFET) [201]. Key steps in the FET fabrication included gate oxide formation and channel conductivity tuning via ion implantation. Microphysical and chemical analyses were conducted on the nanostructured TiO₂ film and the glucose oxidase (GO_x) membrane, using two types of crosslinkers. Optimal annealing was achieved at 450 °C for 45 min in an N₂ atmosphere, ensuring strong adhesion of the TiO₂ film to the silicon substrate. FTIR and SEM analyses confirmed that the most effective immobilization of the GO_x membrane was achieved using the composition: GO_x + glutaraldehyde + TiO₂/SiO₂/Si. The clear spectral signals indicated strong anchoring of the enzyme layer to the substrate. Calibration tests showed that operating the ENFET in saturation mode provided a wide linear range (0.001–100 mM) but low sensitivity (0.43 μA/mM). In contrast, operation in the linear regime at low V_DS significantly improved sensitivity (1.5 μA/0.0001 mM), albeit with a much narrower linear range [201].

Laser-based methods offer maskless, high-precision fabrication of channels and sensor components on a variety of substrates, including glass, polymers, and metals [202]. These techniques are particularly useful for rapid iteration and customization of LoC devices [203]. Screen and inkjet printing are low-cost, scalable techniques that are increasingly used for depositing conductive inks (e.g., silver, carbon) and biomolecules on flexible substrates [199,204]. Inkjet printing enables patterning of nanomaterial inks for sensor arrays, while screen printing is well-suited for mass production of wearable biosensor patches. For implantable biosensors, MEMS fabrication techniques are employed to integrate sensing elements, microfluidics, and electronics on a single chip [205]. Bulk and surface micromachining processes allow for compact, multifunctional devices capable of operating in vivo over extended periods.

Table 5. Characteristics of materials and fabrication technologies in wearable and implantable LoC biosensors.

Category	Material/Technique	Key Characteristics	Applications/Benefits
Biocompatible and Flexible Materials	PDMS [166,206]	Biocompatible, flexible, optically transparent, gas permeable; easy to mold and bond	Standard for microfluidics; skin-conforming devices
	Hydrogels (PEG, alginate, polyacrylamide) [169]	High water content, ECM-like, tunable mechanics	Tissue-interfacing and drug-delivery biosensors
	Conductive Hydrogels [169]	Electrical conductivity + hydrogel benefits	Bioelectrical interfacing
	PMMA, COC, PC [173]	Rigid, strong, chemically resistant, optically clear	Rigid implantable LoC systems; compatible with molding
	Polyimide, TPU, conductive fabrics [207]	Flexible, durable under strain	Wearables integrated in clothing or skin-contact devices
Nanomaterials for Sensitivity/Selectivity	Gold (Au), Silver (Ag) NPs [208]	High conductivity, plasmonic, easy to functionalize	Optical/electrochemical sensing, enhanced detection limits
	Carbon Nanotubes, Graphene, Graphene Oxide [185]	Excellent electrical/mechanical properties	High-sensitivity transducers in FETs
	Quantum Dots (QDs) [209]	Size-tunable fluorescence, stable	Multiplexed biomarker detection
	Metal–Organic Frameworks (MOFs) [189]	High porosity, large surface area	Selective analyte capture
	Polyaniline (PANI), Polypyrrole (PPy) [210]	Conductive polymers, redox-active, functionalizable	Electrochemical biosensing
Fabrication Techniques	Photolithography [194]	High-resolution, silicon/glass-based, cleanroom required	Precision microstructures for sensor arrays
	Soft Lithography [197]	Uses PDMS stamps; flexible, cost-effective	Microfluidic channel fabrication on soft substrates
	Additive Manufacturing (3D Printing) [198]	Inkjet, SLA, FDM; fast prototyping	Multi-material biosensors, bioprinting
	Laser-based Fabrication [202]	Maskless, precise, customizable	Rapid prototyping across diverse substrates
	Screen and Inkjet Printing [199]	Low-cost, scalable, nanomaterial-compatible	Conductive inks, wearable sensor patches
	MEMS Fabrication [205]	Microelectronics integration; bulk/surface micromachining	Compact, implantable, multifunctional LoC systems

Table 5. Characteristics of materials and fabrication technologies in wearable and implantable LoC biosensors.

Category	Material/Technique	Key Characteristics	Applications/Benefits
Biocompatible and Flexible Materials	PDMS [166,206]	Biocompatible, flexible, optically transparent, gas permeable; easy to mold and bond	Standard for microfluidics; skin-conforming devices
	Hydrogels (PEG, alginate, polyacrylamide) [169]	High water content, ECM-like, tunable mechanics	Tissue-interfacing and drug-delivery biosensors
	Conductive Hydrogels [169]	Electrical conductivity + hydrogel benefits	Bioelectrical interfacing
	PMMA, COC, PC [173]	Rigid, strong, chemically resistant, optically clear	Rigid implantable LoC systems; compatible with molding
	Polyimide, TPU, conductive fabrics [207]	Flexible, durable under strain	Wearables integrated in clothing or skin-contact devices
Nanomaterials for Sensitivity/Selectivity	Gold (Au), Silver (Ag) NPs [208]	High conductivity, plasmonic, easy to functionalize	Optical/electrochemical sensing, enhanced detection limits
	Carbon Nanotubes, Graphene, Graphene Oxide [185]	Excellent electrical/mechanical properties	High-sensitivity transducers in FETs
	Quantum Dots (QDs) [209]	Size-tunable fluorescence, stable	Multiplexed biomarker detection
	Metal–Organic Frameworks (MOFs) [189]	High porosity, large surface area	Selective analyte capture
	Polyaniline (PANI), Polypyrrole (PPy) [210]	Conductive polymers, redox-active, functionalizable	Electrochemical biosensing
Fabrication Techniques	Photolithography [194]	High-resolution, silicon/glass-based, cleanroom required	Precision microstructures for sensor arrays
	Soft Lithography [197]	Uses PDMS stamps; flexible, cost-effective	Microfluidic channel fabrication on soft substrates
	Additive Manufacturing (3D Printing) [198]	Inkjet, SLA, FDM; fast prototyping	Multi-material biosensors, bioprinting
	Laser-based Fabrication [202]	Maskless, precise, customizable	Rapid prototyping across diverse substrates
	Screen and Inkjet Printing [199]	Low-cost, scalable, nanomaterial-compatible	Conductive inks, wearable sensor patches
	MEMS Fabrication [205]	Microelectronics integration; bulk/surface micromachining	Compact, implantable, multifunctional LoC systems

6. Challenges and Limitations

Despite the rapid advancements in wearable and implantable LoC biosensor technologies, several critical challenges and limitations must be addressed to ensure their successful translation from laboratory prototypes to clinically and commercially viable systems. These challenges span regulatory, technical, economic, and ethical domains, each presenting significant implications for long-term reliability, safety, scalability, and public acceptance.

6.1. Regulatory and Ethical Concerns

One of the primary challenges in advancing wearable and implantable biosensors is complying with the rigorous safety and approval standards imposed by regulatory bodies such as the FDA and EMA [211]. For implantable devices in particular, regulatory approval from bodies such as the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA) involves extensive biocompatibility, safety, and efficacy evaluations. The integration of electronic components into the human body raises concerns about long-term tissue response, infection risks, and device stability, which require robust preclinical and clinical validation protocols [212]. From an ethical perspective, continuous monitoring especially in implantable systems raises significant privacy and data ownership issues [213]. Users may not always be aware of what data is being collected, how it is processed, or who can access it. Ethical concerns are amplified when dealing with sensitive health parameters, such as mental health markers, hormonal fluctuations, or disease progression, where data misuse could lead to discrimination or stigmatization [214].

6.2. Data Accuracy and Reliability over Time

Maintaining data integrity and sensor performance over extended periods is a major technical and practical challenge [215]. Implantable sensors are exposed to dynamic biological environments, where biofouling, immune responses, and protein adsorption can alter sensor sensitivity and baseline signals [216]. Similarly, wearable biosensors may be affected by sweat, motion artifacts, skin impedance, and environmental conditions such as humidity and temperature. Over time, sensor drift, calibration issues, and material degradation can compromise measurement accuracy, leading to false readings or signal loss [217]. Additionally, variations in individual physiology and inter-user differences complicate the establishment of universal calibration standards. Long-term studies and real-world trials are still limited, highlighting a gap between early-stage performance claims and actual deployment reliability [43,172].

To address signal drift and calibration challenges in long-term use, researchers are exploring a range of in situ calibration and sensor regeneration strategies. Hardware-based methods include incorporating reference electrodes or redundant sensor arrays that provide internal baselines for real-time drift correction [218]. Some implantable systems employ electrochemical regeneration cycles or biofouling-resistant coatings that restore sensor performance periodically [219,220]. On the software side, advanced signal processing techniques such as Kalman filters, adaptive filtering, and drift-compensating algorithms are being implemented to correct for time-dependent signal degradation [221]. Machine learning models, including recurrent neural networks and drift-aware algorithms, are also showing promise for recalibration by recognizing long-term trends and contextual changes in biosensor data [222]. Additionally, multi-modal biosensors that combine complementary sensing modes (e.g., optical and electrochemical) enable cross-validation for higher accuracy and reliability [223]. These hardware-software co-design approaches are key to extending sensor lifetime and ensuring consistent signal quality in real-world biomedical applications.

The feasibility of utilizing a pressure switch mechanism for the in situ recalibration of drifted implanted pressure sensors was demonstrated [224]. A system was designed and characterized to quantify the sensor offset after implantation. The benchtop device was constructed using a titanium diaphragm with a thickness of 25 µm and a working diameter of 10 mm. A characteristic change in the pressure response, caused by the activation of the pressure switch, was detected by an optimization algorithm. Repeatability of the detection was achieved across three sensors, with variations maintained within ±0.23 mmHg over eight pressurization cycles [224].

6.3. Cost, Mass Production, and User Adoption

For both wearable and implantable LoC systems to reach mass-market applications, issues related to cost, manufacturability, and user acceptance must be overcome [225]. Fabrication processes involving microfluidics, biosensing elements, and flexible electronics are often costly, requiring cleanroom conditions and highly specialized techniques, which restrict scalability [162]. Economic barriers are particularly significant for implantable systems, where surgical procedures, post-operative care, and device maintenance introduce high costs. Meanwhile, wearable devices must be affordable, durable, and esthetically acceptable to users to gain widespread adoption. For instance, Zhang et al. presented a flexible, low-cost wearable patch for sweat collection and biomarker detection [226]. Wax-printed channels on filter paper guide sweat to specific zones that measure volume, pH, glucose, and lactate. Glucose detection in sweat is challenging due to low concentrations, but the design enhances sweat absorption and evaporation, concentrating the indicator to boost sensitivity. The sensor detected glucose reliably within physiological levels (50–300 μM). Integrated with smartphone imaging, the device provides immediate quantitative results. Additionally, air-dried sweat samples can be collected for further analysis, expanding its use in personalized health and nutrition [226].

Moreover, public skepticism, especially concerning implantable devices, can hinder acceptance due to invasiveness, lack of awareness, or fear of bodily harm. Moreover, achieving interoperability with consumer electronics, ensuring rechargeability or energy autonomy, and providing simple user interfaces are essential for mainstream integration but remain difficult to achieve in a cost-effective manner [227,228].

6.4. Technical Hurdles: Miniaturization, Integration, and Power Management

At the core of LoC biosensor development are technical barriers related to system miniaturization, functional integration, and power management [229]. The need to combine biological sensing, signal processing, data transmission, and power supply into a compact form factor presents significant design complexity [25]. Miniaturization can compromise sensitivity or reduce the signal-to-noise ratio [230]. Integrating multiple sensor modalities (e.g., electrochemical, optical, thermal) on a single chip while ensuring fluid handling, sample integrity, and signal isolation remains an engineering challenge [231]. For implantable devices, wireless data communication, biocompatible encapsulation, and long-term battery-free operation are critical requirements that are still being refined [53]. Additionally, thermal management, real-time processing, and secure wireless communication must be optimized without increasing device size or compromising patient safety [232]. The integration of artificial intelligence (AI) and edge computing on-device for real-time analysis adds another layer of complexity in terms of power consumption, chip design, and software reliability [233].

Moreover, a critical dimension of power management involves the trade-offs between energy source types and their implications for system design. Batteries, while common, can increase device size and limit flexibility, particularly in wearables, where comfort and form factor are essential. Wireless power transfer reduces the need for batteries but often suffers from efficiency losses and requires precise alignment, which may not be practical in dynamic, real-world conditions. In implantable systems, options such as micro-batteries, inductive charging, and biofuel cells each carry trade-offs among power density, longevity, and biocompatibility. These constraints influence not only power architecture but also affect choices in sensor types, data processing strategies, and communication protocols. As a result, design decisions must carefully balance power requirements with reliability, safety, and autonomy, especially for long-term deployment in medical contexts.

7. Future Trends and Research Directions

As wearable and implantable LoC biosensors continue to mature, emerging innovations are set to further transform their role in healthcare. These next-generation systems are moving toward greater intelligence, integration, and personalization [71,234]. This section outlines the key future trends and research directions expected to shape the evolution of LoC-based continuous health monitoring systems.

7.1. Smart and Autonomous Systems

Future biosensing platforms are expected to transition from passive data collection devices to intelligent and autonomous systems capable of decision-making, self-regulation, and adaptive responses [56,235]. These devices will increasingly incorporate embedded artificial intelligence (AI) and machine learning (ML) algorithms to enable real-time signal interpretation, anomaly detection, and predictive analytics [236]. For instance, an autonomous LoC biosensor could detect abnormal glucose fluctuations and trigger alerts, recommend interventions, or even coordinate with drug delivery systems for immediate response [102]. Closed-loop systems, where sensing, analysis, and actuation occur automatically, represent a key goal for managing chronic diseases such as diabetes, epilepsy, and heart failure [237].

Min et al. presented a wearable biosensor powered by a flexible quasi-two-dimensional perovskite solar cell [235]. This solar module delivered sufficient power both indoors and outdoors, achieving over 31% efficiency under indoor lighting conditions. This self-sustained device enables long-term metabolic monitoring without external power sources. This wearable system continuously measured multiple sweat-related parameters such as glucose, pH, sodium ion concentration, sweat rate, and skin temperature during a variety of physical activities indoors and outdoors for more than 12 h. This approach highlights the potential for practical, real-time health and fitness tracking using autonomous sweat sensing technology [235].

7.2. Multiparameter Sensing

Current LoC devices often focus on single-analyte detection [238,239]. However, the future lies in multiparameter biosensors capable of simultaneously measuring a range of physiological and biochemical markers. These systems will provide a more comprehensive view of an individual’s health status by correlating data such as pH, temperature, glucose, lactate, cortisol, electrolytes, and more. Multiplexed sensing not only enhances diagnostic accuracy but also enables better differentiation between overlapping clinical conditions [240]. Advances in microfabrication, nanomaterials, and signal processing will be essential in developing compact and low-power sensors that maintain sensitivity and selectivity across multiple analytes.

Engineered living materials (ELMs), which incorporate genetically modified cells to produce functional substances with biological-like traits, hold significant promise across various sectors. Despite this potential, the practical use of ELM-based biosensors outside laboratory environments remains limited by several challenges. To address this, Xu et al. developed a field-deployable biosensing platform referred to as ELMlab-on-Chip that integrated ELMs within a microfluidic device to enable the simultaneous detection of multiple analytes in real-world settings [240]. This platform employed a bottom-up approach beginning with the molecular engineering of living biosensors, where hybrid receptors were designed and receptor concentrations were carefully controlled to fine-tune sensitivity and specificity. The ELMs themselves were constructed using a combination of ionic and covalent cross-linking methods, which provided both mechanical strength and optimal permeability for substance transport. Additionally, a specially designed microfluidic chip supported the orthogonal stimulus-responsive behavior of the ELMs, organizing them spatially into a sensor array. Detection was facilitated by a miniaturized smartphone-based device that captures the output signals, allowing for rapid, on-site analysis. The ELMlab-on-Chip system has demonstrated effectiveness in simultaneously identifying various chemicals from single environmental samples under field conditions, offering a viable strategy to accelerate the translation of engineered living materials into practical applications [240].

7.3. Personalized and Precision Medicine

The integration of LoC biosensors into personalized and precision medicine strategies is one of the most promising avenues for future research [241,242]. By continuously monitoring individual biomarkers and physiological patterns, these devices can support tailored interventions based on a person’s unique biological profile and lifestyle [243]. Real-time feedback from wearable and implantable LoC devices can guide personalized treatment regimens, optimize drug dosing, and predict adverse reactions before symptoms manifest. In oncology, for example, biosensors may help track treatment efficacy by detecting circulating tumor markers or drug metabolism rates [244,245]. The synergy between biosensor data, genomic information, and digital health records will support truly individualized healthcare delivery [246,247].

7.4. Advances in Wireless Power and Communication

Power supply and data transmission remain significant challenges in long-term deployment of wearable and especially implantable LoC biosensors [248]. Future systems will benefit from next-generation wireless power technologies, including radio frequency (RF) harvesting, inductive coupling, ultrasound energy transfer, and even bioenergy harvesting from body heat or motion. In parallel, innovations in wireless communication protocols such as Bluetooth Low Energy (BLE) [40], near-field communication (NFC) [39], and emerging 6G networks [249] will enable faster, more secure, and energy-efficient data transfer. Seamless integration with smartphones, wearable hubs, and cloud-based platforms will improve data accessibility for both patients and healthcare providers, facilitating continuous remote care and real-time medical decision-making.

A lab-on-chip biosensor was engineered to enable rapid assessment of waterborne toxicants using live cell cultures within a sealed microfluidic chamber [250]. The design uniquely integrated two complementary detection modalities, such as electrical cell–substrate impedance sensing (ECIS) and quartz crystal microbalance (QCM) resonation, within a single platform. This was achieved by configuring the working electrode for ECIS as the top electrode of the QCM resonator, allowing for simultaneous monitoring of cell-induced impedance and mass-related frequency shifts [250]. Upon exposure to toxic substances, compromised cell health was reflected through a measurable decrease in electrical impedance and a concurrent increase in resonant frequency. This dual-parameter measurement strategy was found to enhance the accuracy of toxicity detection while minimizing false-positive outcomes.

Bovine aortic endothelial cells (BAECs) were employed as the biological sensing elements to evaluate the biosensor’s response to three representative toxicants: ammonia, nicotine, and aldicarb. Cell responses to these chemicals were captured by both ECIS and QCM within the initial 5 to 20 min of exposure, with response time and magnitude varying by compound and concentration. The biosensor demonstrated high sensitivity to low toxicant concentrations. Notably, in tests involving aldicarb, the QCM exhibited clearer frequency shifts compared to impedance variations at lower concentrations, indicating a higher sensitivity of the mass-sensing component under these conditions. Furthermore, the integration of both sensing methods on a single chip allowed for internal cross-validation of results, reinforcing the hypothesis that multi-modal sensing improves detection reliability. A strong linear correlation between toxicant concentration and sensor signal response was consistently observed across all tested chemicals [250].

In addition to materials and sensing innovations, future developments in wearable and implantable LoC biosensors will rely heavily on advances in electronics. A key challenge is achieving sustained operation with minimal power consumption, particularly for implantable devices where battery replacement is impractical [37,251]. Emerging solutions include ultra-low-power circuit design, such as sub-threshold analog processing, energy-efficient microcontrollers, and power-aware data acquisition systems. Furthermore, neuromorphic computing, inspired by the architecture of biological neural networks, offers a promising paradigm for on-device, low-power analysis of complex biosignals [252]. These innovations will enable intelligent, autonomous biosensors capable of local data processing, adaptive operation, and extended deployment without frequent recharging or external computation.

7.5. Wearable–Implantable Hybrid Systems

Another emerging trend is the development of hybrid biosensing platforms that combine the benefits of both wearable and implantable systems [253]. These hybrid configurations may feature coordinated sensing across surface-mounted and internal devices, allowing for multi-layered monitoring of physiological states [254]. For instance, an external patch could monitor sweat biomarkers while communicating with an implanted device that tracks blood metabolites, offering a richer and more reliable health assessment. Such systems can be especially valuable in critical care, sports performance, and high-risk patient monitoring [255]. Integration of data from multiple biosensor nodes, coupled with advanced analytics, will enable context-aware diagnostics and treatment recommendations [147,256].

8. Concluding Remarks

The evolution of LoC biosensors into wearable and implantable formats marks a pivotal advancement in the pursuit of continuous, real-time health monitoring. By consolidating complex biochemical analyses into compact, integrated systems, these devices bridge the gap between conventional clinical diagnostics and personalized, on-the-go healthcare. As this review illustrates, the integration of microfluidics, biosensing technologies, wireless communication, and intelligent data processing has unlocked vast potential for LoC platforms in applications spanning chronic disease management, physiological monitoring, and therapeutic feedback.

A critical enabler of this transformation has been the development of advanced materials tailored to meet the stringent demands of long-term biosensing. Biocompatible and mechanically compliant substrates such as PDMS, hydrogels, and thermoplastics have facilitated seamless interfacing with the human body. Simultaneously, nanomaterials including metallic nanoparticles, carbon-based structures, and quantum dots have greatly enhanced the sensitivity, specificity, and functionality of LoC biosensors. These material innovations, coupled with scalable fabrication techniques like soft lithography, 3D printing, screen printing, and MEMS micromachining, have propelled the field toward higher integration, lower cost, and faster development cycles.

Wearable LoC biosensors ranging from skin-mounted patches and smart textiles to wristband-integrated systems are already demonstrating utility in non-invasive glucose monitoring, sweat analysis, ECG tracking, and respiratory assessments. On the other hand, implantable LoC biosensors enable highly sensitive in vivo monitoring of blood metabolites, neurological signals, intracranial pressure, and drug pharmacokinetics. When integrated with closed-loop drug delivery systems, implantables have the potential to provide real-time therapeutic intervention, moving toward fully autonomous disease management.

Despite these advancements, widespread clinical adoption of LoC biosensors faces several unresolved challenges. For wearable systems, ensuring stable signal quality amidst motion artifacts, environmental fluctuations, and skin variability remains a concern. Implantable devices face more complex issues, including immune rejection, biofouling, signal drift, and power limitations. Ensuring long-term operational reliability in dynamic physiological environments is critical. Moreover, both categories must contend with issues of data privacy, cybersecurity, and regulatory approval, particularly as biosensors increasingly handle sensitive health data and interface with wireless networks.

Looking forward, the convergence of LoC biosensors with artificial intelligence (AI), edge computing, and next-generation communication protocols (e.g., 6G, IoT ecosystems) promises to drive the emergence of autonomous, intelligent health monitoring systems. Future directions include the development of multi-analyte sensors capable of context-aware diagnostics, energy-harvesting systems to support battery-free operation, and hybrid wearable–implantable platforms offering layered sensing capabilities. These innovations will not only enhance the precision and efficiency of healthcare delivery but also empower individuals to engage proactively in managing their health.