Smarter Chips, Safer Lives: Lab-on-a-chip Biosensors for Pharmacological Applications and Healthcare Transformation

Ankit Kumar Singh¹ and Ida Tiwari²

OPEN ACCESS

PUBLISHED: 31 March 2025

CITATION: SINGH, Ankit Kumar; TIWARI, Ida. Smarter Chips, Safer Lives: Lab-on-a-chip Biosensors for Pharmacological Applications and Healthcare Transformation. Medical Research Archives, [S.l.], v. 13, n. 3, mar. 2025. Available at: <https://esmed.org/MRA/mra/article/view/6337>. 

COPYRIGHT: © 2025 European Society of Medicine. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

DOI: https://doi.org/10.18103/mra.v13i3.6337.

ISSN 2375-1924

ABSTRACT

Keywords

lab-on-a-chip, biosensors, pharmacological applications, healthcare transformation, drug testing

1. Introduction

The pharmaceutical sector is facing significant obstacles due to rising expenses and inefficient medication research. The low predictive capacity of current preclinical models is the reason behind drug failures in trials, hence drug development researchers have confirmed the urgent need for novel testing methods that can reliably anticipate drug safety and efficacy in people¹. According to data from the 2019 United Nations Office on Drugs and Crime (UNODC) World Drugs Report, 271 million persons worldwide abused drugs in 2017, resulting in approximately 585,000 drug-related deaths². This demonstrates not only the substantial number of drug users but also the considerable number of drug-related deaths that occur worldwide.

Thus, devices and methods for identifying and monitoring harmful substances are essential for ensuring human health. In this age of rapid material evolution, it is critical to describe and evaluate the toxicity associated with pharmaceutical residues. Toxic pharmaceuticals must be closely monitored to prevent any risks to human health, even if national authorities have strict control over these systems. One important element that boosts the impact of treatment is early detection³. Despite ongoing advancements in drug screening techniques, only a small percentage of drug candidates are approved for clinical use by the U.S. Food and Drug Administration (FDA)⁴.

Drugs in various samples can be analysed using a variety of contemporary laboratory-based methods, including mass spectrometry⁵, chromatography⁶, immunoassays⁷, spectrophotometry⁸, and colorimetry⁹. These advanced methods, however, are typically linked to difficulties with sample handling, miniaturisation, or skilled lab personnel. When millions of distinct chemical combinations must be tested during drug discovery, the need for numerous read-outs puts a significant strain on the testing procedures. Small chemical volumes and parallel operation are required for a high-throughput system to handle these many samples while maintaining an inexpensive development cost¹⁰.

There is a growing trend of miniaturisation using chemical and biological analytical techniques. An approach that shows promise for analyte detection and for enabling wireless communication of analysis results to remote areas is chip-based sensing technology. These instruments are affordable, portable, ensure speedy findings, and can be included into biological systems that are responsive and sophisticated¹¹,¹². The advancement in the miniaturisation of these analysis techniques is directly reflected in lab-on-a-chip (LOC) technology. Devices that are capable of controlling and modifying fluid flows at the micro level are known as LOC devices. They offer a wide range of fascinating applications in a number of domains, such as drug release investigations, environmental analysis, clinical diagnostics, and food control¹³. Numerous laboratory procedures, biological processes, DNA sequencing, and chemical production all make use of these microdevices. By combining microfluidic devices with biosensors, they can be used in industries like environmental monitoring, food processing and safety, pharmaceuticals, medical diagnostics, and agriculture. A few examples of applications where LOC platforms can be useful include the analysis of ions from various compositions used in forensics, explosives identification, water quality assessment, bodily fluid research, agriculture, and pollution level detection¹⁴,¹⁵. The history in the development and applications of LOC techniques is represented in Fig. 1.

Lab-on-a-chip tools provide automation and high-throughput analysis by combining various laboratory processes onto a single chip. The LOC technologies have the following key characteristics¹⁶,¹⁷: (i) Transporting liquid samples containing bioparticles, such as cells, proteins, and DNA, into a field with electrode molecules that have been previously stored; (ii) Electrode and extracting non-specific and lossy binding, as well as mixing and binding reactions of extracted bioparticles; and (iii) Detecting the

corresponding change in chemical, physical, electrical, mechanical, or magnetic signals¹⁸. These methods provide portable equipment by performing several laboratory operations on a smaller scale, such as chemical synthesis and analysis on a single chip. Developments in micro and nanotechnology have made it possible to fabricate LOC tools in smaller sizes. This is comparable to the revolution in semiconductors, which has been significantly influenced by lithographic methods.

The integration of many laboratory processes on a micro or nanoscale facilitates automation and high-throughput screening. A number of factors, such as capillary forces, electrokinetics (EKs), and pressure gradients, affect LOC manufacturing. By controlling low-volume samples, microfluidic systems can achieve high analysis rates while saving money and time. It can be applied to chemical and biological studies, as well as chemical synthesis¹⁹.

complexity of the field. Indeed, it is frequently and incorrectly believed that a biosensor is a device that detects the existence and usually the amount of a biomolecule such a protein or a DNA strand or possibly a cell. The biosensors field is large and complicated. The number of findings reported in the literature and now being studied virtually reaches astronomical proportions when we include the potential to integrate a biosensing element with microfluidic sample handling capabilities.

The last few years have seen a significant development of LOC platforms for biosensor development, with a particular emphasis on three-dimensional (3D) designs. As device sizes decrease, small quantities offer several advantages, such as lower reagent costs and higher analytical accuracy. Single cell analysis and other cellular biological investigations are made possible by these glass or polymer-based biochips. The quasi-realistic reproduction of the physiological systems in these 3D in vitro models may make them viable substitutes for in vivo investigations and animal sacrifices²⁶. Point-of-care (POC) tests have the potential to significantly improve the standard of healthcare. Clinical diagnostic technologies have advanced significantly and been implemented successfully in a number of fields during the last ten years²⁷. The latest developments in MIP-based LOC detection technologies using a variety of biomolecule samples are observed. With the new MIP technology, which enables direct detection of target biomolecules and sensitive and selective detection of biomolecules in a sampling of biofluids, we firmly believe that the current difficulties of LOC can be resolved¹¹,²⁶.

The urgent need for a novel method to more accurately replicate human drug responses in preclinical research has driven the development of Organoids-on-chips (OOC) technologies or microphysiological systems (MPS)⁴. The OOC is a new and creative concept that combines sophisticated organ-on-chip technology with stem cell-derived organoids to create biomimetic micro-physiological systems in vitro. The synergistic union surpasses the constraints of conventional methods for safety evaluation and drug screening, including animal models and 2D cell cultures.

Although few reviews are available on chip-based devices for drug detection²⁷,²⁸,²⁹, but these include only limited descriptions and do not summarize the advantages and limitations of their clinical approaches. Here, we focus on a set of recently developed LOC and OOC techniques that facilitate high-throughput analysis and review their applications in drug detection for healthcare transformations. We highlighted the important features and virtues of LOC devices, clarifying their power to genuinely imitate human physiology, so addressing contemporary hurdles. We comprehensively overviewed the recent endeavors where LOC and OOC have been harnessed for drug screening and safety assessment and delved into potential opportunities and challenges for resolving sophisticated, near-physiological chips. Based on recent successes, we go on to explore how multidisciplinary convergent innovation can improve the viability of chips and hasten the transition from preclinical to clinical stages in industry and healthcare³⁰. We also provide an outlook into their key features and various fabrication approaches. Additionally, it discusses the limitations of current methods that must be addressed in the future for healthcare transformation.

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2. Lab-on-a-chip sensors

Microfluidic approach can be included into a LOC device to enable the miniaturisation of certain laboratory-based analytical methods³¹,³². The manipulation of fluids in micrometer-scale channels is known as microfluidics. In addition to providing notable benefits over more conventional approaches, this also makes new advancements viable that would not be feasible on a wider scale. The general benefits include reduced sample requirements, low reagent consumption, and less waste effluent, quicker reaction times because of a higher surface area to volume ratio, greater portability, and cost-effectiveness in terms of equipment required and no need

specialised staff³¹,³²,³³. Microfluidics has developed into a very interdisciplinary topic of study in recent years. The development of fully integrated ‘sample in–answer out’ LOC devices has focused on areas such as clinical diagnostics³³, but one fully integrated LOC for forensic purposes is the RapidHIT ID System, which analyses buccal swab samples for human identification purposes and can generate a DNA profile in just 90 minutes³⁴.

The first commercially accessible LOC system was released around two years after Hopwood et al.³⁵ published the first research journal article in 2010 describing a fully integrated LOC device that might generate a DNA profile. Since the Rapid DNA Act of 2017, law enforcement has been using this type of LOC technology to analyse reference samples³⁵. This indicates that the employment of LOC systems in forensic investigations may prove to be beneficial.

Analytical instruments are made smaller by using LOC technology, which packs numerous lab tools onto a tiny single chip¹². Two essential concepts of engineering research that are miniaturization and integration are important aspects of LOC technology. The main reason for this significant growth is the quick development of integrated circuit (IC) technology. Miniaturisation makes it possible to replace traditional heavy, costly equipment with more affordable, portable alternatives¹². These days, embedded artificial intelligence technology and smartphone integration are popular.

Depending on the intended use, the literature contains a wide variety of design types. Lab-on-a-chip systems have certain basic components, but the types of components differ depending on the application. The working parts include an injector, a transporter, a preparator, a mixer, a reactor, a separator, a detector, a controller, and a power source. Since the components are represented by appropriate symbols, designers can display their LOC products consistently¹⁴. To elucidate these counters, the elements of a LOC device are shown in Fig. 2.

3. Key Features of Lab-on-a-chip Sensors

The LOC systems differ from conventional laboratory equipment in a number of significant ways, including microfluidics, integration and miniaturization¹²,¹⁵,²⁰,³⁶.

• Microfluidics: The technology used in LOC devices is microfluidic, which manipulates fluids in channels that range in size from tens to hundreds of micrometres. Microfluidics makes it possible to precisely control fluid flow, mixing, and reactions, which makes sample processing and analysis more effective¹²,³¹.

• Integration: The LOC devices combine several laboratory processes onto a single chip, including sample preparation, separation, reaction, and detection. This integration speeds up and increases the accuracy of the analysis while lowering the need for manual intervention and consuming fewer samples and reagents¹².

• Miniaturization: The LOC instruments drastically cut down on the quantity of necessary samples and reagents by minimising laboratory procedures, which lowers expenses and waste production. Additionally, miniaturisation makes it possible to create POC and portable diagnostic tools¹²,³⁷.

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4. Fabrication of lab-on-a-chip sensors

A wide range of inorganic, organic, and composite materials are being employed to build the fundamental structure of LOC devices. Among the most widely used materials in fabrication include crystalline minerals like silicon and glass, polymers including photoresists, acrylate, and thermoplastics, and elastomers like polydimethylsiloxane³⁸. Silicon used to rule the microfabrication industry because of its semiconducting characteristics. Due to its well-documented surface engineering capabilities based on the silanol group (SiOH), silicon is seen as a viable material for LOCs devices³⁸.

There are several techniques such as photolithography, soft lithography, laser micromachining, screen printing, 3D printing, and nano imprinting for fabrication of LOC devices³⁹,⁴⁰. The term chip refers to the initial manufacturing process, which used an enhanced type of photolithographic etching to create computer microchips and allowed for uniform control over the sizes and shapes of surface features³⁹. The various steps involved in photolithography method of LOC manufacturing is illustrated in Fig. 3.

Usually, microfabrication methods taken from the semiconductor industry are used to create LOC devices³⁷ and the general fabrication process are represented in Fig. 4. The following are the primary steps in LOC fabrication:

• Design: Computer-aided design (CAD) software is used to create the functionality and layout of the LOC devices. Reaction chambers, integrated sensors or detectors, and microfluidic channels are all part of the design.

• Master Fabrication: The planned LOC device is made into a master mould by employing either soft lithography or photolithography methods. For the microfluidic structures to be replicated, the master acts as a template.

• Replication: Polydimethylsiloxane (PDMS), a flexible and optically transparent polymer, is one of the materials used to recreate the microfluidic structures from the master mould. The entire LOC device is then created by bonding the duplicated structures to a substrate, like glass or plastic.

• Integration: As required, further parts are added to the LOC device, such as electrodes, sensors, or microvalves. These parts make it possible to identify and analyse samples as well as regulate and track fluid flow.

Figure 3: Steps involved in photolithography method for fabrication of lab-on-a-chip.

 

 

 

7. Lab-on-a-chip Sensors in Pharmacological Applications

In order to eventually replace animals in preclinical testing, microfluidic LOCs may be utilised as drug testing platforms, disease modelling, biomarker identification, and distinct cellular and molecular mechanisms¹¹,⁵⁴,⁵⁵. As a result, LOCs can provide suitable conditions for assessing medication efficacy and toxicity, cellular activity, and drug metabolism⁵⁶. The use of such testing microdevices in pharmacokinetic applications has been examined in a number of studies aimed at developing innovative strategies for customised cancer treatments⁵⁷,⁵⁸,⁵⁹.

For example, it was proposed to use a LOC platform to evaluate up to five drugs against osteosarcoma cells in real time⁵⁷. Other LOC microdevices were developed to perform single-cell cytotoxic and genotoxic experiments and simulate a hypoxic cancer microenvironment⁶⁰. Anti-inflammatory medicines were also assessed using a ‘small airway-on-a-chip’ model of human lung inflammation with dynamic flow conditions⁶¹. It should be mentioned that LOC technology has been authorised by the U.S. Food and Drug Administration for use in pharmaceutical medicine security testing and screening⁶²,⁶³.

Jiang et al. investigated the possible drug metabolisms and assessed drug cytotoxicity using a microwell-based microfluidic chip⁶⁴. It had the advantage of strong integration in a more physiologically appropriate setting and was easy to use. Drug cytotoxicity was assessed using a microfluidic sidewall-attached droplet array, according to Fang et al.⁶⁵. They cultivated cells in a 3D droplet array, which has the benefit of preventing cell adhesion on the chip surface and enabling the execution of several operations on cells within droplets. Additionally, they tested the effectiveness of the anticancer drug doxorubicin, and the results showed that doxorubicin clearly reduces cell viability in a dose-dependent manner. A number of microfluidic chips have been published to assess the cytotoxicity of anticancer medications in various settings⁴⁶,⁶⁷,⁶⁸.

First, a multiple-channel array chip was created, allowing for the management of oxygen tension and the completion of cell-based high throughput toxicity studies for cisplatin and tirapazamine. The outcomes of the experiment demonstrated that cisplatin and tirapazamine exhibit opposing mechanisms of oxygen-dependent cytotoxicity.

By mimicking the composition and operations of human organs, OOC biomimetic systems are proposed as non-traditional models for assessing the efficacy or safety of medications. In vitro co-culture models can mimic the complex interactions between cells in an environment similar to that found in vivo.

By simulating microfluidic dynamics, these devices can also be used in medically appropriate ways. Additional advantages of cell co-cultures on the chip include regulated medication administration, sensor integration on the same platform, microscopic super-resolution analysis, and high-throughput analysis with reduced costs and time⁶⁹. One disadvantage of these platforms is that they are designed for specific uses, which prevents them from being used in a general way⁵⁸.

According to the standard guidelines, it may be crucial to concentrate on simulating several organs in order to identify genuine advantages and link the OOC models with particular local tissue structures and cellular phenotypes in order to eventually replicate human physiology in vivo [126]. As a result, standard open technology platforms can be obtained by assembling adaptable models for fit-for-purpose OOC with technical and biological modules⁷⁰. Chips composed of soft tissue materials are the best options for the toxicity or effectiveness of medications using the OOC method. Glass or PDMS biochips are the best options for creating the right circumstances for a variety of tests that show how sensitive the organs are to medications. These materials provide transparency for optical interrogation and may confer qualities similar to the physiological environment, making it possible to create replicas of body components. They are also very easy to process into complicated shapes⁷¹. The use of these platforms in drug tests and pharmacological screening studies has the benefit of lowering the number of experiments for many organ types, including the heart, kidneys, liver, lungs, and central nervous system⁷⁰ or cancer research⁷¹. Another benefit of LOC microfluidic devices is their ability to evaluate medications with low permeability⁷². Innovative medication delivery methods are still desperately needed, and microfluidics offers a state-of-the-art method for this.

Numerous studies have proven the benefits of LOCs over traditional techniques for the synthesis of sophisticated delivery systems. Fontana et al.⁷³ provided an overview of droplet microfluidic techniques as a potent tool for the creation of monodisperse drug delivery systems, including liposomes, polymersomes, microcapsules, and microspheres. In contrast to conventional (2D, static) pharmaceutical assays, Cavero et al. discussed the advantages of OOCs microdevices for human-predictive biological insights on drug candidates in an Expert Opinion on Drug Safety review paper. In addition to discussing the importance of these OOC platforms for drug research and development, the authors present a wide range of them, including those related to cancer, lung, blood-brain barrier, heart, intestine, kidney, liver, pharmacokinetics, placenta, and vessel-on-chip⁷⁴.

The following provides some clear and particular instances of testing methodologies that are concentrated on one drug–one or multiple organs⁷⁵, multiple drug–one organ systems⁷⁶, and combinations of these. Kim et al.⁷⁷ investigated the pharmacokinetic profile that reduces the nephrotoxicity of gentamicin under dynamic conditions in a kidney-on-a-chip model. Using a specialised OOC, the study aimed to bridge the renal clearance gap between people and animals. Gentamicin was discovered to change cell-cell junctions, increase membrane permeability, and reduce cell viability, particularly when exposed at low levels for an extended period of time. For the assessment of cardiovascular toxicity, artificial endothelialised myocardium and heart-on-a-chip models were created using three-dimensional (3D) bioprinting⁷⁸. After that, the dose-dependent reactions of endothelial cells and cardiomyocytes to doxorubicin exposure were assessed. Using multi-material 3D printing, Lind et al.⁷⁹ created cardiac micro-physiological models with strain sensors integrated into microarchitectures. Over a four-week period, the OOC platform was validated by analysing the mechanical responses of human stem cell-derived laminar cardiac tissues and the effects of isoproterenol and verapamil medications. To replicate the intricacy of in vivo physiology, Phan et al.⁴ suggested a vascularised OOC platform for extensive drug screening. In order to successfully

identify both anti-angiogenic and antitumor medicines, a number of arrays of vascularised micro-tumors were developed and evaluated against up to twelve FDA-approved anti-cancer medications. In a multi-organ human-OOC model system, the impact of hepatic metabolism on off-target cardiotoxicity was examined⁸⁰. To evaluate terfenadine and fexofenadine medications, which may have cardiac side effects reliant on hepatic metabolism, human primary hepatocytes were co-cultured with iPSC-derived cardiomyocytes. In order to study the toxicity of drug metabolites, Theobald et al. reported creating a liver-kidney-on-chip model⁸¹.

The technology used for in vitro drug screening makes it possible to simulate the flow-dependent interaction between several organ-specific cell types. The effectiveness of this OOC method was confirmed by the toxicity assessment of benzo[a]pyrene and aflatoxin B1 medications. To screen for organophagonsic hepatotoxicity, a 3D tetraculture brain-on-chip platform was suggested⁸². By assessing the impact of drugs on barrier integrity, the study demonstrated the great usefulness of such platforms. However, Isoherranen et al.⁸³ examined the growing use of OOCs in quantitative clinical pharmacology evaluation. Advances in the microphysiological system, such OOC technology, are said to have the potential to better personalise treatments, forecast drug effects, and plan preclinical and clinical trials. A evaluation of OOC technology’s use in drug development was conducted relatively recently⁸⁴.

The biomimetic OOC system, which mimics the biology and physiology of human organs, has demonstrated more benefits than conventional methods for medication efficacy and testing. It is explained how a ‘human-on-chip’ system can more accurately assess the toxicity and efficacy of drugs by simulating intricate and dynamic processes such as drug absorption, distribution, metabolism, and excretion. A detailed assessment of the integration of microfluidic LOCs with pharmacological/toxicological experiments and pharmaceutical analysis was recently conducted by Ai et al.⁸⁵. The scientific community’s efforts to create ‘Pharm-LOC’ systems that can handle the entire spectrum of pharmacological advancements, from post-marketing product management to recent drug discovery, were compiled by the authors. Applications including drug separation and analysis on a chip, the creation of novel tools for pharmacological/toxicological models on a chip, and the use of chip-based models for drug safety and efficacy screening were the main topics of their literature review⁸⁵. Several perspectives for the future challenges and breakthroughs related to Pharm-LOC advances, such as automating drug discovery, precision nanomedicine, and personalized therapy, are then highlighted.

However, its poor resemblance to real in vivo tissues and the lack of development of human disease models may be a bottleneck in the therapeutic usage of the OOCs model⁸⁶. One of the new applications of LOC technology that has garnered increased attention is the importance of microfluidics to pharmaceutical science. In response to the need for LOC technologies for pharmaceutical science, Pharm-LOC was created. It represents chip-based platforms for the full chain of pharmacy applications, from drug discovery to post-marketing product management. All aspects of chip-based ideas, procedures, and tools for pharmaceutical production, pharmacological/toxicological testing, and analysis are included in Pharm-LOC. This review focused on the latest advancements in the use of LOC for pharmaceutical testing and analysis. The primary topics include the creation of innovative pharmacological and toxicological models on a chip, the isolation and analysis of drug molecules on a chip, and the use of chip-based models to assess the safety and effectiveness of drugs. We also attempt to provide an overview and outlook on the difficulties and potential innovations of Pharm-LOC development.

8. Advantages, Disadvantages and Limitations of the Nanoscale Sensor Chips

 

Small fluid volumes in LOC devices, lower reaction times, costs, and reagent amounts, which is advantageous when handling clinical samples, particularly in underdeveloped nations where low sample concentrations result in less chemical waste being produced. Thus, these small systems can also aid in large-scale manufacturing. But as a developing area, LOC has drawbacks at the microscale level, where capillary forces, surface roughness, and material-to-material chemical interactions become more noticeable. This could result in experimental issues that are not possible with conventional lab apparatus. A low signal-to-noise ratio may result from the detecting principles with microscale dynamics¹⁹,³²,⁸⁷. But by saving thousands of dollars on diagnostic equipment, LOC has gradually expanded its global presence.

Comparing LOC technology to conventional laboratory techniques reveals a number of benefits:

• Reduced Sample and Reagent Volumes: The sample and reagent volumes used by LOC devices are usually very small, ranging from microlitres to nanolitres. When handling hazardous materials, this volume decrease results in lower costs, less waste production, and increased safety.

• Faster Analysis: The time needed for sample preparation, reaction, and analysis is substantially reduced by LOC devices, which integrate and automate several laboratory procedures on a single chip. High-throughput screening and quick diagnostic tests are made possible by this acceleration.

• Enhanced Sensitivity and Specificity: Improved sensitivity and specificity in sample analysis are the results of precise fluid flow control and miniaturisation of LOC devices. The efficiency of biological reactions and the limit of detection are improved by the high surface-to-volume ratio in microfluidic channels.

• Portability and Point-of-Care Use: LOC devices require little instrumentation to operate and are small and portable. The portability makes it possible to use LOC devices in POC settings like clinics, emergency rooms, or distant sites by putting laboratory-grade analysis closer to the patient or sample source.

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9. Biological, technical and clinical challenges and future outlook

LOC technology has many benefits, but before it can be widely used, a few issues must be resolved. Integrating several functions on a single chip while preserving the resilience and dependability of device is one of the primary problems. The mass production and commercialisation of LOC devices depend on the creation of standardised manufacturing procedures and quality control techniques³⁰.

In order to enhance the functionality and performance of LOC devices, future LOC technology research will concentrate on creating new materials and fabrication processes. The sensitivity and multiplexing capabilities of LOC devices will be improved by integrating cutting-edge sensing and detecting techniques, such as optical detection or sensors based on nanomaterials. Furthermore, automated analysis and interpretation of the complex data produced by LOC devices will be made possible by the integration of machine learning and artificial intelligence technologies⁵².

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10. Conclusions

The high surface area to volume ratio of LOC devices makes them particularly advantageous for POC biosensing. Significant academic and industrial research is being conducted owing to the urgent need for POC devices to develop LOC based biosensors using proteins, cells, nucleic acids, and metabolites as analytes. The working of LOC devices

advancements in various components, and a preview of specific applications were all covered in this review. It is determined that the use of LOC devices will move quickly from POC research to proven clinical applications. It is strongly advised that a comprehensive validation method be used in the early phases of development in order to expedite the introduction of the product in clinical settings. In this review, the evolution of LOC technology for toxic drug detection and healthcare transformation are covered. It also discussed the possibility for commercialisation and miniaturisation of LOC systems.

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Acknowledgements:

The author IT is grateful to IOE incentive grant for faculty (Scheme Number-6031), BHU.

Author contributions:

AKS: Methodology, Conceptualization, Visualization, Writing – original draft; Writing – Review & Editing, Data curation, Investigation; Formal analysis;
IT: Supervision, Validation.

Conflicts of interest:

The authors declare that they have no known competing financial interests, personal relationships that could have appeared to influence the work reported in this paper.

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