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. 2024 Oct 28;24:101928. doi: 10.1016/j.fochx.2024.101928

A comprehensive review on the pretreatment and detection methods of nitrofurans and their metabolites in animal-derived food and environmental samples

Xiaoling Zheng a,1, Yong Xie b,1, Zhuoer Chen a, Mingdong Cao a, Xianlu Lei a, Tao Le a,⁎
PMCID: PMC11558636  PMID: 39539437

Abstract

In recent years, the residues of nitrofurans (NFs) and their metabolites in animal-derived food and environmental samples have gained widespread attention. The parent drugs and their metabolites have displayed significant toxicity to human health including carcinogenic, mutagenic and teratogenic effects, leading to banned in animal husbandry in many countries. Hence, monitoring the residues of NFs is necessary to guarantee public health and ecological security. This review aims to summarize and assess the structural properties, residue status, sample pretreatment methods (liquid-liquid extraction, solid-phase extraction, Quick, Easy, Cheap, Effective, Rugged, and Safe (QuEChERS), and field-assisted extraction), and detection methods (chromatographic analysis, immunoassay, and some innovative detection methods) for NFs and their metabolites in animal-derived food and environmental samples. This paper provides a detailed reference and discussion for the analysis of NFs and their metabolites, which can effectively promote the establishment of innovative detection methods for NFs and their metabolites residues.

Keywords: Nitrofurans, Metabolites, Sample pretreatment, Detection technology

Highlights

  • •

    A comprehensive overview of pretreatment and detection methods for NFs and their metabolites.

  • •

    Describes the structural properties and residue status of NFs and their metabolites.

  • •

    Detail discussion and predict the future trends of NFs and their metabolites in samples.

  • •

    Provide theoretical support for development and application of detection NFs.

1. Introduction

Nitrofurans (NFs) containing furazolidone (FZD), furaltadone (FTD), nitrofurantoin (NFT), and nitrofurazone (NFZ) are a group of synthetic broad spectrum antimicrobial drugs that were commonly used to prevent and treat gastrointestinal infections caused by Escherichia coli and Salmonella in livestock, fish, shrimp, and bees due to their strong pharmaceutical and antibacterial properties (Aldeek, Hsieh, Ugochukwu, Gerard, & Hammack, 2017; Xie, Wang, Yan, Gan, & Le, 2021). The use of NFs has been prohibited in animal husbandry in the European Union and the most other countries due to concerns pertaining to public health and safety, particularly regarding the potential carcinogenic, mutagenic and teratogenic effects of the parent drugs or their metabolites (Aidoo et al., 2023; Li et al., 2023). Nevertheless, NFs are still used in some countries for treating livestock because of their effectiveness, availability and relatively low cost. Therefore, it is crucial to persistent and efficient monitor the residues of NFs.

However, monitoring NFs residues in animal tissues based on the identification of parent drugs has proven inefficient for regulatory enforcement. Studies have shown that after administration, FZD, FTD, NFT, and NFZ are rapidly metabolized in vivo into 3-amino-2-oxazolidone (AOZ), 3-amino-5-morpholinomethyl-2-oxazolidone (AMOZ), 1-aminohydantoin (AHD), and semicarbazide (SEM), respectively (Mei et al., 2024). These protein-bound metabolites, which are stable in the animal body, can be detected even several weeks after administration with a derivatization reagent under mildly acidic conditions (Le & Yu, 2014). The structures of NFs and their metabolites are shown in Fig. 1. Therefore, metabolites of NFs could be used as markers of the illegal usage of NFs.

Fig. 1.

Fig. 1

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The structure of nitrofurans and their metabolites.

Various methods that have been developed for analyzing NFs and their metabolites, including chromatographic techniques, immunoassays, optical detection methods, and more innovative detection techniques (Tang, Xu, Wang, Xiang, & Yang, 2010). Moreover, efficient sample pretreatment methods are required to remove matrix interferences and enhance enrichment factors, such as liquid-liquid extraction (LLE), solid-phase extraction (SPE), Quick, Easy, Cheap, Effective, Rugged, and Safe (QuEChERS), field-assisted extraction, and several novel sample preparation methods (Melekhin et al., 2021). These analytical methods have been applied to extract and detect NFs or their metabolites in many sample matrices, including animal-derived food, feed, and environmental samples (Fig. 2).

Fig. 2.

Fig. 2

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An overview of pretreatment and detection methods for nitrofurans and their metabolites.

This review focused on studies related to the analysis of NFs and their metabolites in animal-derived food, feed, and environmental samples. The main point of this paper was to summarize and discuss the structural properties, residue status, various sample pretreatment and detection methods for NFs or their metabolites analysis. This review maybe a valuable database to provide a reference for NFs or their metabolites residues analysis.

2. NFs and their metabolites

The parent drugs of NFs have a short half-life in organisms and are rapidly metabolized due to their structural properties. Among the four NFs, NFZ is generally considered the most toxic, as it not only exhibits similar mutagenic and carcinogenic effects as the others but also shows greater toxicity in livestock and poultry. FZD is relatively less toxic but still possesses potential carcinogenic and teratogenic effects. These antibiotics consist of a furan ring and a nitro group, both chemically reactive, forming the basic structure of NFs (Sun et al., 2018). The furan ring, a five-membered ring with one oxygen atom and four carbon atoms, is stabilized by the high electron density of the carbon atom attached to the nitro group, facilitating interactions with DNA. The nitro group, which is a strong electron-attracting group containing nitrogen and oxygen, reduces the electron cloud density on the furan ring, enhancing the molecule's reactivity. In the presence of reductase enzymes in organisms, the nitro group is reduced to an amino group, leading to the rapid metabolism of the drug (Anupriya et al., 2022; Pipoyan, Beglaryan, Chirkova, & Mantovani, 2023). In addition, as an electrophilic group, the nitro group is susceptible to attack by nucleophilic reagents. In living organisms, electron-rich nucleophilic reagents (e.g., glutathione, amino acids, sulfhydryl groups on proteins) may attack the nitro group of NFs, causing rapid metabolism, with the resulting metabolites binding tightly to animal proteins to form stable derivatives. If people consume foods containing NFs over a long period, the metabolites can be released in the stomach, accumulate in the body, and cause serious damage to various organs (Li et al., 2023). Therefore, metabolites of NFs are of interest to researchers, as well as a key focus in the analysis of NFs antibiotics.

NFs is prohibited to be used in edible animals in various countries due to their toxicity and carcinogenicity, and the maximum residue level of NFs metabolites in animal-derived food set at 1 μg/kg (Guichard, Laurentie, Hurtaud-Pessel, & Verdon, 2021). The limit of detection (LOD) for NFs has been lowered from 1 μg/kg to 0.5 μg/kg in China in 2022, which raises higher requirements for market control and testing technology. The lowering of the detection limit for NFs puts higher requirements on market control and testing technology. Despite the ban on NFs, issues with regulatory compliance persist. For example, a batch of white shrimp from Ecuador was found to exceed the allowable level of FZD metabolites, and another batch from India contained SEM above the limit. In Shaanxi, China, one out of 242 freshwater fish samples tested positive for FZD metabolite residues. Therefore, the residues of NF antibiotics in food and environmental samples should be of greater concern and subject to stricter monitoring.

3. Sample pretreatment

The sample pretreatment is an important step before the detection in order to maximize the extraction of target substances, eliminate impurities and reduce matrix interference (Mari et al., 2024). It involves the hydrolysis of the sample, derivatization of metabolites, and sample clean-up, with the clean-up process being crucial for achieving detection sensitivity (Zhou et al., 2023). The commonly used purification methods for biological matrices include LLE, SPE, and QuEChERS. This study focused on the key factors in these commonly used sample pretreatment methods, as well as emerging techniques in sample pretreatment.

3.1. Hydrolyzation and derivatization

NFs metabolites generally bind to proteins to form stable complexes, so the metabolites need to be separated before detection. Typically, hydrochloric acid at a concentration of 0.1 M is used to hydrolyze the metabolites from proteins (Stastny, Frgalova, Hera, Vass, & Franek, 2009). Since the metabolites have small relative molecular masses, their chromatographic and mass spectrometric properties are not ideal for detection. Derivatization is therefore used to increase their relative molecular mass and enhance the mass spectral response (Wang et al., 2020). The mechanism of the derivatization reaction involves the keto-aldehyde group (CHO) of the derivatizing agent undergoing an aldol-ammonia nucleophilic addition reaction with the nitrogen-containing nucleophilic amino group (NH2) of the metabolites under acidic conditions. After derivatization, the mass-to-charge ratios of the molecular ions of the metabolite derivatives fall within a range more suitable for detection (Bian et al., 2017). The most commonly used derivatizing agent is 2-nitrobenzaldehyde (2-NBA), although some researchers have explored other aromatic aldehydes, such as pyridine-3‑carbonylcarboxaldehyde, 2,4-dinitrobenzaldehyde, and 2-hydroxy-5-nitrobenzaldehyde. However, none of these alternatives have significantly improved sensitivity or reduced reaction time.

3.2. Extraction and purification

When selecting extraction solvents, it is important to consider the solubility of the analyte, the effect of the sample matrix, and the compatibility with subsequent analytical methods. Common extraction solvents for NFs and their metabolites include ethyl acetate and acetonitrile, which are often used in combination with LLE for both extraction and purification. A comparison of the advantages and disadvantages of different purification methods is provided in Table S1.

3.2.1. LLE

LLE is a technique that separates a solute from one solution to another based on differences in solubility in two solvents (Fig. 3A). It has a long history and was first used for crude oil desulphurization in the petroleum industry. Currently, it has been extensively used in various fields, such as environmental monitoring, food science, and pharmaceutical analysis (Khatibi, Hamidi, & Siahi-Shadbad, 2022). The purpose of this process is to separate the target substance from the sample matrix, thereby yielding a purified target while removing interfering substances.

Fig. 3.

Fig. 3

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The principles of sample pretreatment (A) liquid-liquid extraction (B) solid-phase extraction (C) Quick, Easy, Cheap, Effective, Rugged, and Safe.

Park et al. used LLE to extract residues of NFs from bee pollen. Additionally, alkanes were extracted using organic solvents following pH adjustment to neutral; however, this extraction process was complicated and required a large amount of organic solvent (Alkan, Kotan, & Ozdemir, 2016; Park, Kim, & Kang, 2017). Salt-assisted LLE is a fast and stable method that significantly reduces the use of organic solvents. Bukhari extracted FZD using double salt-assisted LLE at pH 3 with low salt concentration, and the results demonstrated an extraction efficiency of up to 100 %. LLE is broadly applicable and inexpensive. However, its throughput capacity and separation efficiency may be influenced by several factors. To achieve efficient and accurate extraction and separation of target substances, it is necessary to select appropriate solvents and operating conditions based on specific sample types and requirements.

Liquid-liquid dispersive microextraction (LPME) is a microanalytical technique based on the principle of LLE, primarily applicable to the extraction of moderately or highly lipophilic target components in aqueous phases (Tay & See, 2024). Fayissa et al. developed a method combining dispersant LPME with high-performance liquid chromatography (HPLC) and diode array detection (DAD). In this method, a portion of the dispersant solvent, from which the analyte has been extracted, is partitioned into an extraction solvent, resulting in the formation of an emulsion. This approach reduces the duration of the hydrolysis and derivatization steps (Fayissa, Dube, & Nindi, 2022). Padró used LPME of plasma for NFs (Padró et al., 2013).

LPME is a simple, fast, and efficient method that requires fewer extractants. However, it has some drawbacks. For instance, highly volatile compounds may be lost during distillation, and there is a risk of degradation for thermally unstable compounds. To address these issues, Faraji incorporated a vortex-assisted microextraction step and a salting-out effect to eliminate the need for centrifugation in the absence of dispersing solvents (Faraji, Helalizadeh, & Kordi, 2017). The method adopted a bell-shaped device and solidifiable solvents to simplify the retrieval of extraction solvents following phase separation. This approach reduces sample volume, minimizes organic waste, replaces toxic reagents with safer alternatives, and improves operator safety.

3.2.2. SPE

SPE is a technique that selectively adsorbs target analytes using solid adsorbents, which has been used for the extraction of NFs as well (Goessens et al., 2020; Ryu, Park, Giri, Chang Park, & Wilkins, 2021) (Fig. 3B). In recent years, various novel materials have been developed for use in SPE. For example, Dong et al. successfully extracted four metabolites of NFs from meat samples using a triazine-based porous organic polymer as the SPE adsorbent, conducting a detailed study on its adsorption isotherm model and extraction selectivity (Dong, Wang, Chen, Hong, & Wang, 2023). Veach adopted microwave-assisted derivatization and automated SPE for processing NFs metabolites in fish and shrimp, achieving satisfactory recovery rates (Veach et al., 2020). While SPE offers advantages such as ease of operation, speed, efficiency, and high sensitivity, there is a risk of cross-contamination. Consequently, the effectiveness of SPE is highly dependent on the appropriate choice of solid adsorbent and preparation method.

Magnetic solid-phase extraction (MSPE) is an innovative variant of SPE that leverages the aggregation ability of magnetic sorbents under an applied magnetic field (Melekhin et al., 2021). The large specific surface area and short diffusion distance of magnetic nanoparticles (NPs) facilitate extraction and separation with minimal adsorbent use and a short equilibrium time, resulting in high extraction capacity and efficiency (Lima et al., 2024). This method eliminates the common drawbacks of conventional SPE, such as sorbent packing, high back pressure, fouling, the need for a filtration step, excessive solvent use, and significant waste (Jiang, Li, Cui, Wang, & Zhao, 2019). Melekhin used magnetic hyper-crosslinked polystyrene for sample preparation (Melekhin et al., 2022). The samples were treated in a thermostatic sonication bath to release matrix-bound NFs before performing the ultrasound-assisted derivatization technique-MSPE, thereby increasing the recycling rate (Melekhin et al., 2024). The rapid advancement in the development of adsorbent materials has increased the use of MSPE techniques in food safety testing, with current research focusing on novel adsorption materials like graphene oxide.

Dispersive solid-phase extraction (dSPE) is based on the principle of homogeneously dispersing a solid adsorbent in the sample solution using a dispersant, which facilitates interaction between the target analyte and the solid adsorbent. For example, Bongers et al. detected NFs in milk using dSPE (Bongers et al., 2021). Zhang et al. selected adsorbents and extraction solutions for dSPE to achieve acceptably high recoveries and reduce co-extractables in the final extract (Zhang et al., 2017). Gong et al. combined dSPE and pass-through SPE with ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) for the detection of NFs (Gong et al., 2020). The dSPE typically provides higher separation efficiency and better selectivity than conventional SPE. However, it also presents certain challenges, such as the need for fillers with high separation capacity, like ion-exchange resins and molecular sieves, which can increase operational complexity and associated costs. Additionally, selecting suitable packing materials and optimizing operating conditions may require significant effort and experimentation, demanding a high level of operator skill, technical expertise, and experimental experience.

3.2.3. QuEChERS

QuEChERS method is a sample preparation technique that employs adsorbent fillers to interact with and adsorb impurities from the sample matrix, facilitating decontamination and purification (Hwang et al., 2024; Zhou et al., 2023) (Fig. 3C). Since its introduction in 2003, this approach has spurred significant technological innovations, particularly in pesticide residue analysis (Yang, Li, Lin, & Bao, 2024). Classical QuEChERS typically uses adsorbents such as C18, primary secondary amine, and graphitized carbon black. Chang obtained NFs residues using the QuEChERS extraction procedure (Chang, Chen, & Lin, 2016). However, due to the physical and chemical limitations of these materials, as well as the expanding range of analytical targets and sample matrices, QuEChERS methods are continuously refined, often through enhancements to adsorbents and optimization of extraction conditions. For example, Shendy et al. (Shendy, Al-Ghobashy, Gad Alla, & Lotfy, 2016) used an optimized extractant for NFs in honey samples, substantially reducing the matrix effect and improving detection accuracy. Zhang optimized the parameters of QuEChERS (Zhang et al., 2015), while Chen employed a modified QuEChERS method optimized for the extraction and purification of target analytes (Chen et al., 2020).

Although QuEChERS is simple and convenient, it can be inefficient and challenging to extract trace substances. To enhance the traditional QuEChERS approach, new materials such as polymers, multi-walled carbon nanotubes, and metal organic frameworks (MOF) can be introduced as adsorbents, thereby significantly broaden the applicability of the technique (Zhou et al., 2023). Additionally, artificial intelligence is increasingly used to screen for suitable combinations of materials, followed by experimental validation to ensure the method's reliability. This integration enhances the convenience and automation of the sample pre-treatment process, reduces the potential for human error, accelerates the development of new products, and decreases the cost of innovation.

3.2.4. Field-assisted extraction

Field-assisted sample pretreatment technology utilizes various fields, such as electric, magnetic, and thermal fields, to enhance solute transfer and accelerate sample separation, thereby improving the efficiency and selectivity of analyte extraction during pretreatment processes (Wang et al., 2018). Ultrasonic-assisted extraction is a modern technological tool that leverage the strong cavitation effect, perturbation effect, high acceleration, shattering, and stirring effects, generated by the radiation pressure of ultrasound (Shen et al., 2023). Wang's use of thermostatic ultrasound-assisted derivatization to obtain nitrofuran metabolites from fish meat (Wang et al., 2020) (Fig. 4A). This technology increases the frequency and speed of molecule movement within substances and enhances solvent penetration, thus accelerating the entry of target components into the solvent and facilitating the extraction process. Ultrasound-assisted extraction is often combined with other extraction methods. For instance, Melekhin et al. employed ultrasound-assisted derivatization in conjunction with MSPE for the rapid determination of NFs metabolite residues in honey (Melekhin et al., 2024) (Fig. 4B). In microwave-assisted extraction, organic components in solid or semi-solid substances are effectively separated from the matrix through the electromagnetic field while preserving the original compound state of the analyzed object. Regan significantly reduced traditional lengthy sample preparation times by replacing the overnight water bath derivatization with a rapid 2-h microwave-assisted reaction followed by a modified QuEChERS extraction (Regan et al., 2021). Veach et al. proposed a rapid and robust method for quantifying and confirming metabolites of NFs in various aquaculture matrices, involving microwave-assisted derivatization, automated SPE, and liquid chromatography-tandem mass spectrometry (LC-MS) (Veach et al., 2020).

Fig. 4.

Fig. 4

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(A) Sample pretreatment using thermostatic ultrasound-assisted extraction (Copyright © 2020, American Chemical Society) (Wang, K. et al., 2020). (B) Ultrasound-assisted derivatization in conjunction with magnetic solid phase extraction (Copyright © 2023, published by Elsevier Melekhin) (Melekhin, A. O. et al., 2024). (C) Sample pretreatment of magnetic field-assisted (Copyright © 2020, American Chemical Society, all rights reserved.) (Zhang, H., Lai, Wu, Li, & Hu, 2020).

Furthermore, new adsorbent materials and sample pretreatment techniques have been applied to the extraction and separation of NFs and their metabolites, Zheng filled magnetic CoFe2O4 beads inside halloysite nanotubes (HNTs) for the integrated detection of NFs by MSPE with surface-enhanced Raman spectroscopy (SERS), enabling rapid magnetic separation of substrates, simplifying pretreatment, and reducing complex matrix interference (Zhang et al., 2020) (Fig. 4C). Novel materials such as graphene, carbon nanotubes, covalent organic frameworks, MOFs, and molecularly imprinted polymers have been utilized for sample pretreatment. Additionally, inorganic and organic aerogels can also be employed for the sample pretreatment of NF antibiotics. These innovative methods simplify operational steps, reduce the consumption of organic solvents, and shorten sample preparation times, presenting great potential for development. However, the application of these new methods to analyze multi-target analytes in complex matrices still requires further research and validation.

4. Detection methods

Various analytical methods have been applied to determine NFs and their metabolites in animal-derived food and environmental samples. Chromatographic analysis (HPLC, LC-MS), immunoassay detection methods (enzyme-linked immunosorbent assay (ELISA), lateral flow immunochromatography (LFIA), fluorescence immunoassay (FIA), chemiluminescence immunoassay (CLIA)), optical detection methods (SERS, fluorescence sensors), electrochemical and other detection methods have been established to the analysis of NFs and their metabolites (Liu, Cheng, et al., 2022). Among these methods, chromatographic analysis is the most widely used for simultaneously detecting multiple NFs and their metabolites, while immunoassay methods offer rapid and specific detection of one or several NFs or their metabolites (Table S2).

4.1. Methods based on chromatographic analysis

Chromatography has been extensively applied in drug metabolism research, food safety testing, and environmental monitoring (Chan et al., 2022). In drug metabolism research, it plays a crucial role in identifying metabolic pathways and metabolites of drugs within the body. In food safety testing, chromatography is employed to detect pesticide residues, veterinary drug residues, and other hazardous substances in food products. Additionally, environmental monitoring adopts chromatography to identify contaminants in water, soil, and air (Jung, Kim, Nam, Seo, & Yoo, 2022; Øye, Couillard, & Valdersnes, 2019). The most prevalent chromatographic methods include HPLC and LC-MS. HPLC, an advanced separation and analytical technique derived from classical liquid chromatography, is widely used in drug analysis due to its excellent separation efficiency, rapid analytical speed, and user-friendly operation (Zhang et al., 2019). In contrast, LC-MS combines the capabilities of LC with MS to analyze compounds with high selectivity and sensitivity (Table 1).

Table 1.

Comparison of the performance of different detection methods.

Method Analytical Sample LOD Range Reference
HPLC/DAD NFM chicken meat 3.09–6.2 μg/kg 10–600 μg/kg (Fayissa et al., 2022)
NFT, FZD, NFZ feed, water samples 0.07–0.11 μg/L 0.5–200 μg/L (Fernando et al., 2017)
HPLC-FLD NFM pork muscle 1 μg/kg 0.5–40 μg/kg (Sheng et al., 2013)
UPLC-DAD NFT plasma, urine 27 μg/L,
0.046 mg/L		 50–1250 μg/L
4–200 mg/L		 (Wijma et al., 2019)
UPLC-QTOF-MS/MS NFM meat 0.05–0.56 μg/kg 1–50 μg/kg (Dong et al., 2023)
LC-MS AOZ, AMOZ, AHD bee pollen 0.18, 0.25, 0.30 μg/kg 1–10 μg/kg (Park et al., 2017)
NFM honey 0.1 μg/kg 0.1–0.3 μg/kg (Melekhin et al., 2021)
AHD seafood 0.1 μg/kg – (Øye et al., 2019)
LC-MS/MS NFM meat, aquaculture products 0.1–2 μg/kg 0.03–0.23 μg/kg (Guichard et al., 2021)
NFM meat 0.5 μg/kg 0.013–0.2 μg/kg (Regan et al., 2021)
NFM powder health food 0.18 μg/kg 0.5–10 μg/kg (Ryu et al., 2021)
NFM honey 0.3 μg/kg 0.3–1 μg/kg (Meng, Liu, Yang, Mao, and Li, 2024)
NFM shrimp 0.5 μg/kg – (El-Demerdash et al., 2015)
ELISA AMOZ, AOZ fish muscle 0.05, 0.2 μg/kg 0.5–2 μg/kg (Jester et al., 2014)
NFM fish, honey samples 0.05–0.52 μg/kg 0.93–5.8 μg/kg (Pipoyan et al., 2023)
LFIA FZD chicken, pork, honey 0.08 μg/L 0.2–1 μg/L (Su et al., 2020)
NFM aquatic products 1.8 μg/L 0.5–50 μg/L (Liu, Fan, et al., 2022)
FIA AMOZ animal tissues 0.09 μg/L 0.01–1 μg/L (Xie et al., 2021)
AHD, AMOZ aquatic products 3, 5 μg/L 0.01–1 μg/L (Liu et al., 2023)
AMOZ animal feeds 0.3 μg/L 0.1–100 μg/L (Xu et al., 2013)
CLIA FTD, FZD, NFT animal feed 0.4, 0.73, 0.6 μM 10–100 μM (Taokaenchan et al., 2015)
SERS NFZ meat 0.37 nM 3.3–667 nM (Bi et al., 2022)
NFT fish feed, aquatic 0.01 mg/L 0.05–1.0 mg/L (Zhang, Lai, Wu, Li, and Hu, 2020)
NFT honey 0.13 mg/kg 0–20 mg/kg (Yan et al., 2022)
NFT, AHD aquatic products 5 μg/kg 1–1000 ng/g (Fan et al., 2021)
NFZ feed, food 0.57 ng/L 1–1000 ng/L (Liu, Cheng, et al., 2022)
NFZ, SEM seafood 5.1 nM, 7.3 nM 0.1–5 nM (Bian et al., 2017)
Electrochemical
detection		 FZD biological, water samples 1.6 nM 0.04–408.9 μM (Sriram et al., 2020)
NFZ pork liver, tap water samples 1.19 μM 0.02–32 μM (Velmurugan, Yang, Ching Juan, & Chen, 2021)
NFT milk, tap water samples 0.018 μM 0.05–500 μM (Li et al., 2023)
NFT biological samples 0.0013 μM 0.005–935 μM (Vinoth et al., 2022)
AHD pork 1.35 μg/L 0.001–1000 μg/L (Wang, Fu, et al., 2022)
SEM pork 0.49 pg/mL, 0.02 μg/L 0.001–0.01 μg/L (Wang, Pei, et al., 2022)
FZD human serum 5 nM 0.015–110 μM (Chen, Peng, Song, and Du, 2022)
Microarray screen assay NFM honey 0.1, 0.04, 0.04, 0.1 μg/L 0.01–100 μg/L (Li, Li, and Xu, 2017)
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-: not mentioned.

4.1.1. HPLC

HPLC is one of the most common methods for the detection of NFs metabolites (Hameedat, Hawamdeh, Alnabulsi, & Zayed, 2022). This technique involves dissolving a sample in a suitable solvent and injecting it under high pressure into a column containing a stationary phase. Separation and detection of compounds occurs by exploiting differences in their interactions with the stationary and mobile phases. A simple and sensitive HPLC with fluorescence detector (HPLC-FLD) method for the simultaneous determination of metabolites of four NFs in pork muscle was reported by Sheng et al. (Sheng et al., 2013).The recoveries of all four metabolites were greater than 92.3 %, with RSD of less than 8.5 %. These results were in excellent agreement with those obtained using LC-MS/MS. Fernando et al. (Fernando, Munasinghe, Gunasena, & Abeynayake, 2017) employed an HPLC diode array detection method for determining metabolites of NFs in shrimp muscle, which was below the minimum requirement limit. Fayissa et al. have successfully applied HPLC to monitor the corresponding metabolites of NFs in chicken meat (Fayissa et al., 2022). HPLC is known for its high efficiency, sensitivity, wide linear range, and rapid analysis. However, it does have some drawbacks, including higher equipment costs, complex sample pretreatment, limited detector selection, sensitivity to ambient temperature and humidity, and more cumbersome data processing and analysis. When selecting and applying HPLC, it is crucial to consider both its advantages and disadvantages to maximize its benefits while overcoming its limitations. UPLC is an advanced chromatographic technique designed for the separation and analysis of complex samples. It applies ultra-small particle packing and low-viscosity solvents to control mobile phase composition and flow rate to improve separation efficiency and analysis speed. The precise control of these parameters enables effective separation of different components in a sample (Nahar, Onder, & Sarker, 2020; Wijma, Hoogtanders, Croes, Mouton, & Brüggemann, 2019). In UPLC, the mobile phase is rapidly separated by creating a rapid vortex on the surface of the packing. Dong et al. analyzed samples using UPLC-QTOF-MS/MS, achieving a good linearity (1–50 μg/kg) and LOD of 0.05–0.56 μg/kg with recovery rates ranging from 72.7 % to 111.6 % (Dong et al., 2023). Similarly, Wang simultaneously detected four NFs metabolites in fish products by UPLC-DAD. The metabolites were hydrolyzed and derivatized with 2-NBA as a derivatization reagent, assisted by thermostatic sonication. The LOD of the six replicate determinations reached 0.25–0.33 μg/kg and 0.8–1.1 μg/kg, respectively, and the recoveries ranged from 89.8 % to 101.9 % (Wang et al., 2020). UPLC offers higher separation efficiency, faster analysis, and lower solvent consumption compared to conventional HPLC. Despite its relatively recent emergence, there is limited information available on the application of UPLC. However, as technology continues to advance and applications expand, it is anticipated that more studies and applications related to UPLC will emerge in the future.

4.1.2. LC-MS

Currently the LC-MS method for the detection of NFs metabolites is developing rapidly, it is a more sensitive, selective and specific method, and many countries have used the LC-MS as a confirmed method for the detection of NFs metabolites. Usually, LC-MS combines the advantages of chromatography and MS, allowing for continuous sample separation, characterization, and quantification. It is highly selective and sensitive, making it a high-performance method (Panda, Dash, Manickam, & Boczkaj, 2022). The principle of LC-MS involves using LC to separate complex samples, followed by tandem MS to identify and quantify the target compounds (El-Demerdash, Song, Reel, Hillegas, & Smith, 2015). This technique offers several advantages over traditional detection methods, including reduced sample usage, faster analysis, and a broader detection range.

Park et al. utilized this method for the determination of AHD with a limit of quantification (LOQ) of 1.0 μg/kg, which is useful for quality control and food safety of bee pollen (Park et al., 2017). Melekhin used LC-MS/MS to identify derivatives of NF metabolites in honey, achieving recoveries greater than 85 % for all analytes, with LODs ranging from 0.1 to 0.3 μg/kg and LOQs from 0.3 to 1.0 μg/kg. This proposed LC-MS method was successfully applied to real honey samples (Melekhin et al., 2021). Guichard et al. developed a LC-MS/MS method for the confirmation of NFs metabolites in meat and aquaculture products with LOD in the range of 0.032–0.233 μg/kg (Guichard et al., 2021). Regan et al. developed and validated a rapid analytical method for analyzing eight bound NF metabolites in animal tissues, with LODs between 0.013 and 0.2 μg/kg, demonstrating significant sensitivity given the current recommended performance assessment (RPA) for NFs of 0.5 μg/kg. This innovative method plays a crucial role in monitoring the illicit use of NFs (Regan et al., 2021). Ryu presented a reliable and rapid method to reduce the time required for detection by traditional methods and has been successfully applied to detect detection in commerce (Ryu et al., 2021). Despite its high performance, selectivity, and sensitivity, LC-MS also presents some drawbacks. Its complex structure can lead to high maintenance costs, and it requires specialized training for effective operation. Additionally, LC-MS has strict requirements for ambient temperature and humidity, which may limit its application in certain environments. The testing speed of LC-MS can be relatively slow, and its intricate functionality may impact the efficiency of analyses. Therefore, while LC-MS is a powerful analytical tool, it is essential to consider these potential drawbacks when selecting it. Continued development and improvement of LC-MS technology, along with its integration with other technological advancements, are expected to enhance its pivotal role in various fields.

4.2. Immunoassay methods

Immunoassay is a methodology for identifying various chemical entities based on the specific binding interaction between antigens and antibodies, this approach has the potential to facilitate the rapid monitoring of NFs and their metabolites (Lai et al., 2024). The characterization of the proteins involved—both antigens and antibodies—significantly influences the effectiveness of immunoassays. Cross-reactivity of antibodies is a common issue, especially when endogenous components are present. Therefore, the reagents used in immunoassays must not alter the properties of these proteins. Specific antigen-antibody conjugates have been developed for the detection and analysis of non-fluorescent compounds and their metabolites (Terzapulo, Kassenova, & Bukasov, 2024). The most commonly used assays include ELISA, FIA, and CLIA, which share the common feature of facilitating rapid analysis of a large number of samples in a short period of time. Although Jia et al. reviewed immunosensors for NFs and their metabolites in foods of animal origin (Jia, Zhang, Qu, Wang, & Xu, 2022), in this review, not only the immunosensors for NFs and their metabolites are described, but also the sample pretreatment is described and compared, and the multiple detection methods in food and environmental matrices are summarized.

4.2.1. ELISA

NFs detection methods have been studied for decades, while immunoassays have been around for a shorter period of time. Immunoassays, mainly ELISA for NFs metabolites, are preferred due to the rapid metabolism of NFs, including direct ELISA, indirect ELISA, double-antibody sandwich ELISA, double-antigen sandwich ELISA and competitive ELISA (Fig. 5) (Xu et al., 2023). Given that NFs are small molecules (semi-antigens), their coupling to carrier proteins is essential for preparing specific monoclonal or polyclonal antibodies. For example, Cooper et al. adopted o-nitrobenzylamine (o-NBA) derivatization and protease digestion, followed by cation-exchange SPE, achieving a detection limit of 0.25 μg/kg (Cooper, Samsonova, Plumpton, Elliott, & Kennedy, 2007). Similarly, Vass et al. developed a direct competitive ELISA with aminourea-specific polyclonal antibody (Vass, Diblikova, Cernoch, & Franek, 2008). In addition, Liu et al. used an indirect competitive ELISA for the determination of NFT residues in drinking water of animals, with an inhibitory concentration 50 (IC50) of 3.2 ppb and a LOD of 0.2 ppb (Liu et al., 2007). Furthermore, Jester evaluated ELISA kits for NFs residues in fish muscle, achieving LODs of 0.05 and 0.2 ng/g for AOZ and AMOZ, respectively (Jester, Abraham, Wang, El Said, & Plakas, 2014). Similarly, Pipoyan also used ELISA to determine the concentration of metabolites in fish and honey (Pipoyan et al., 2023). While ELISA offers advantages such as high sensitivity, specificity, simplicity, and rapidity, it has a higher probability of false positives compared to LC-MS and its associated techniques, limiting its use as a confirmatory method.

Fig. 5.

Fig. 5

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The principles of detection based on ELISA, including direct ELISA, indirect ELISA, double-antibody sandwich ELISA, double-antigen sandwich ELISA and competitive ELISA.

4.2.2. LFIA

LFIA emerged as an immediate diagnostic method, initially pioneered in 1981. It was firstly used for the detection of human chorionic gonadotropin, serving as a diagnostic tool for early pregnancy (Xu et al., 2024). This technique enables quick on-site testing through a straightforward procedure. In recent years, advancements in technology have led to widespread improvements and applications of LFIA, particularly in food safety testing, environmental monitoring, and early disease diagnosis (Althomali et al., 2023). Colloidal gold immunochromatographic assay is a typical LFIA method for commercial products, Xie developed LFIA for the rapid AOZ detection (Xie, Zhang, & Le, 2017). The teams of Tang and Li both developed a gold-based LFA for the detection of NFs residues (Tang et al., 2011). The detection sensitivity of conventional AuNP-based LFIA is usually limited by incomplete competition between free target analytes and immobilized antigens bound to AuNP labeled antibodies. To enhance detection capabilities, novel nanolabeled metal-composite organic material probes have been developed for NF residue detection. For example, Su designed and synthesized Janus NPs using asymmetric Au-SiO2, achieving a visual limit of detection as low as 0.16 ng/g, significantly improving the competition efficiency (Su et al., 2020). Additionally, Liu et al. created a multicolored immunochromatographic assay platform utilizing quantum dot (QD) nanobeads for the simultaneous detection of NF metabolites in various aquatic products. This platform employs QDs emitting red, yellow, green, and orange colors, functionalized with corresponding antibodies for each analyte, resulting in a visual LOD of up to 50 ng/mL (Liu, Fan, et al., 2022).

4.2.3. FIA

FIA uses fluorescent markers to detect and quantify biomolecules. The prototype of FIA was developed in 1961 by Swedish scientist R. K. Porter, who combined fluorescent with an antibody to determine insulin levels in human serum (Zhao et al., 2019). Currently, FIA has undergone further development, particularly with the advancements in biotechnology and fluorescence technology in the 1980s. FIA is widely used in biomedical research and clinical diagnostics (Xie et al., 2021). Xu established a simple and rapid homogeneous FIA assay for the detection of NFs and their metabolites without the need for a separation or washing step, and the total time required for the antibody-tracer interaction to reach equilibrium was only 10 min (Xu et al., 2013). Our team utilized a QD-based FIA for the rapid and sensitive detection of AOZ, with composite QDs having higher fluorescence properties, which was followed by the development of a fast, simple and sensitive FIA based on CdSe/ZnS QDs for the detection of AHD in animal tissues (Fig. 6A and B) (Le, Xie, Zhu, & Zhang, 2016; Le, Zhang, Wu, Shi, & Cao, 2017). Recognizing that simultaneous detection of multiple NF metabolites is often more informative than single-detection methods, Liu developed a FIA using two-color aggregation-induced emission NPs as signaling markers for the simultaneous detection of AMOZ and AHD (Liu et al., 2023), and Cheng also introduced two different colors of QDs as signal tags for the rapid and accurate detection of AOZ and SEM in seafood (Fig. 6C) (Cheng et al., 2023). Recently, Mei has proposed a FIA based on europium NPs for the simultaneous detection of three NF metabolites, achieving a LOD of lower than 0.03 ng/mL and completing the assay within 10 min (Fig. 6D) (Mei et al., 2024). Additionally, Liu et al. utilized QDs as multicolor labels for the simultaneous detection of four NF metabolites in aquatic products (Fig. 6E) (Liu, Cheng, et al., 2022). Although QDs, NPs doped with organic dyes and upconverted NPs can effectively improve the sensitivity, the fluorescence intensity of these fluorescent NPs will be significantly reduced in high concentration or aggregated state due to the bursting effect induced by their aggregation, leading to the low performance, which further restricts their practical applications.

Fig. 6.

Fig. 6

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(A) QDs as a signal for the detection of AOZ (Copyright © 2016, American Chemical Society) (Le et al., 2016) (B) Composite QDs as signal for the detection of AHD (© 2017 published by Springer) (Le et al., 2017). (C) Dual QDs as signal for the detection of AOZ and SEM (© 2023 published by Elsevier Cheng) (Cheng et al., 2023). (D) Based on europium nanoparticles for the detection of three NFs metabolites (© 2023 published by Elsevier Mei) (Mei et al., 2024). (E) The QDs as multicolor labels for the simultaneous detection of four NFs metabolites (© 2022 Liu et al. published by MDPI) (Liu, Cheng, et al., 2022).

4.2.4. CLIA

CLIA is a powerful immunoassay technique that utilizes chemiluminescence to detect various biomolecules, including proteins, hormones, antibodies, environmental pollutants, drug residues, and biomarkers. This method quantifies the target substance in a sample by measuring the light signal generated through a chemical reaction (Zhang et al., 2018). In CLIA, the target substance first combines with a specific antibody to form an antigen-antibody complex. An enhancer reagent is then introduced to catalyze a chemical reaction, producing a measurable light signal. By assessing the intensity of this light signal, the amount of the target substance can be accurately quantified. Liu developed an indirect competitive CLIA for detecting AMOZ, utilizing 4-carboxybenzaldehyde-derived AMOZ as the antigen. The study optimized the effects of substrates such as luminal, p-iodophenol, and urea peroxide on assay performance, establishing an indirect competitive CLIA for AMOZ detection. The sensitivity of the developed assay was estimated with an IC50 of 0.14 μg/L, a linear working range of 0.03 μg/L to 64 μg/L, and a LOD of 0.01 μg/L (Liu et al., 2013). A novel method for the enhancement of electrogenerated chemiluminescence of tris(2,2′-bipyridine) ruthenium (II) system using resonance energy transfer of CdTe QDs capped with L-cysteine by Taokaenchan for the detection of NFs residues (Taokaenchan et al., 2015). Despite its advantages, CLIA has certain limitations, including operational complexity and high costs, as well as the need for specialized equipment and reagents. Moreover, CLIA is prone to producing false-negative results, particularly when target substances are present at low concentrations.

4.3. Optical detection

4.3.1. SERS

Spectroscopy, particularly SERS, is a powerful technique based on the principle of Raman scattering. It enhances the Raman signals of molecules through localized electric field effects on metal surfaces, allowing for highly sensitive detection of specific molecules (Zheng, Jiang, et al., 2024) In the field of antibiotic detection, the SERS technique has significant applications. It can rapidly, accurately, and sensitively detect the presence and concentration of antibiotics (Liu, Cheng, et al., 2022). Raman scattering occurs when light interacts with matter, resulting in a transfer of vibrational energy (Guo et al., 2021). When a photon collides inelastically with a molecule, the molecule absorbs the photon's energy, transitioning from a lower energy level to a higher one. This process generates one or more Raman-scattered photons, with frequencies correlating to the molecule's vibrational frequencies. Analyzing the Raman spectrum provides structural information about the molecule.

Several studies have demonstrated the effectiveness of SERS in detecting NF residues. For example, Fan et al. proposed a SERS method using potassium bromide-modified silver NPs for the detection of NFT and AHD, achieving LOD of 1 and 5 ng/g (Fan, Gao, Jiao, Wang, & Fan, 2021) (Fig. 7A), respectively. Yan et al. used SERS in combination with a spectral pre-processing technique for the detection of NFT in honey (Yan, Li, Peng, Ma, & Han, 2022). A new SERS method for the determination of NFs was established by Bi using AuNPs/γ-Al (Bi, Shao, Yuan, Zhao, & Li, 2022). The need for high sensitivity and reliability is a key factor for SERS in analytical applications. Bian et al. developed an ultra-thin layer of Au for the protection of porous silver fibers, which is a robust and sensitive substrate that provides a high enhancement factor of 13, enabling ultra-sensitive detection of NFs (Bian et al., 2017). Zhang et al. introduced a CoFe2O4@HNTs/AuNPs substrate that prevented particle aggregation, provided rapid magnetic separation, and simplified the pretreatment procedure, demonstrating great potential for the rapid detection of real samples (Zhang et al., 2020). Liu et al. demonstrated that incorporating Cu2O-Ag/AF-C3N4 not only enhanced the substrate's effectiveness but also endowed it with self-cleaning properties due to its excellent photocatalytic activity. This substrate demonstrated high homogeneity, with RSDs of 6.74 % and 4.85 %, respectively (Liu, Fan, et al., 2022). SERS is a highly promising technique for antibiotic detection, characterized by its high sensitivity, label-free operation, and real-time monitoring capabilities. However, research into SERS technology for antibiotic detection is still in its infancy. To meet the clinical demands for diagnosis and treatment, further optimization of experimental conditions and improvements in detection performance are necessary.

Fig. 7.

Fig. 7

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(A) SERS method based on potassium bromide-modified silver (Copyright © 2021 published by Wiley) (Fan et al., 2021). (B) Detection of NFs based on fluorescent (Copyright © 2023, American Chemical Society) (Sun et al., 2023). (C) Detection of NFZ based on the probe of aptamer (© 2023 published by Elsevier Wen) (Wen et al., 2023). (D) Detection of NFs by electrochemical immunosensors (© 2021 published by Elsevier Anupriya) (Anupriya et al., 2022). (E) Detection of NFs using microarray screen assay (© 2022 published by Elsevier Li) (Li et al., 2017). (F) Detection of NFs by Freeze bio-barcode (© 2022 published by Elsevier Zhang) (Zhang et al., 2022).

4.3.2. Fluorescent sensors

Fluorescent sensors function through the interaction between a fluorescent probe and a target molecule. The fluorescent probe, a molecule with fluorescent properties, is capable of detecting the presence and quantifying the concentration of the target molecule by modulating the fluorescent signal (Meng, Liu, Yang, Mao, & Li, 2024). Fluorescent probes, such as carbon dots, QDs, and MOF materials, can be used to measure and analyze changes in fluorescent signals when they specifically bind to target molecules. QDs, in particular, possess unique chemical and optical properties that make them ideal for applications in the fields of biosensing and bio-imaging (Le et al., 2016). Sun synthesized highly fluorescence N-doped graphene QDs for the detection of NFs using sugarcane molasses as the carbon source and ethylenediamine as the nitrogen source (Sun et al., 2023) (Fig. 7B). The LOD of the sensor was 0.29 μM, the LOQ was 0.97 μM, and the detection range was 5–130 μM (Sun et al., 2023). Wang developed a novel silver-based fluorescent probe QBs/g-C3N4 for sensitive detection of NFZ (Wang, Pei, et al., 2022). Additionally, Cong created two MOF-based sensors for NFs detection, laying a solid foundation for turn-on sensors for trace antibiotics (Cong et al., 2021). Furthermore, Yue synthesized luminescent shuttle-shaped aluminum (III)-containing MOF for selective NFs detection with good linearity. Novel nanomaterials have also been applied to the detection of antibiotics (Yue et al., 2022). Huang established a stable, anti-interfering, reusable fluorescent probe for NFZ, offering a range of 0.13–16.5 mg/L and the recoveries of 87 %–110.6 % (Huang, Zhou, Hu, Li, & Xia, 2022). Wen used a carboxyfluorescein-labeled aptamer probe to detect NFZ in aquaculture water samples, introducing a new method for identifying NFZ residues (Wen et al., 2023) (Fig. 7C), aptamers are single-stranded oligonucleotide sequences that are screened in vitro using exponentially enriched ligand phylogenetic techniques. Compared to antibodies, aptamers exhibit superior chemical stability, facilitate easy chemical modification, do not elicit an immune response, and demonstrate exceptionally high affinity and specificity for target molecules. However, aptamers have certain limitations, including reduced stability and half-life in vivo, as well as susceptibility to degradation by nucleases. Generally, fluorescence analysis offers high sensitivity, simplicity, and speed. However, it can be challenging to find suitable energy donors and fluorescent markers, and the development of new fluorescent energy donors and markers remains a focus of research.

4.4. Electrochemical detection

Electrochemical detection is a device based on electrochemical technology to detect biomolecules, which consists of three main components: electrodes, antibodies and electrolytes (Farka, Juřík, Kovář, Trnková, & Skládal, 2017). The electrode is the core component of the sensor to provide current or voltage signals, the antibody is the molecule that recognize the target substance usually immobilized on the electrode surface, and the electrolyte maintains the electrochemical reaction on the electrode surface. During operation, the immobilized antibody on the electrode surface specifically binds to the target substance (e. g., protein, DNA, drug, etc.). This binding causes a change in the charge distribution on the surface of the electrode, which can alter the potential or current output. By measuring and analyzing this change, the presence and concentration of the target substance can be determined (Chen et al., 2022). Electrochemical detection have become widely used due to their rapidity, sensitivity, and affordability, finding applications across various fields, including healthcare, food, industry, agriculture, and the environment.

Sriram decorated cobalt molybdate nanorods on boron-doped graphite carbon nitride sheets for electrochemical sensing of FZD with a LOD of 1.6 nM and concentration range of 0.04–408.9 μM (Sriram et al., 2020). Jeyaraman Anupriya synthesized sulfur-doped graphitic carbon nitride and copper tungstate hollow spheres using a simple ultrasonication method. Subsequently, they conducted electrochemical investigations using cyclic voltammetry and differential pulse voltammetry electroanalytical techniques (Fig. 7D). The sensors they developed were successfully applied for the determination of NFs in human urine and serum samples, yielding satisfactory recovery rates (Anupriya et al., 2022). Sethupathi Velmurugan investigated visible light-active tungsten trioxide/copper manganese oxide (WO3/CuMnO2) prepared as p-n heterojunction nanocomposites. The nanocomposites exhibited enhanced photoelectrochemical properties, attributed to increased absorption of visible light and the synergistic effect associated with the formation of an n-type heterojunction. The designed WO3/CuMnO2 nanocomposite sensor provided satisfactory photocurrent signals for NF detection in the range of 0.015 to 32 μM with a LOD of 1.19 nM (Velmurugan et al., 2021). Li synthesized a composite material of cobalt NPs encapsulated in nitrogen-doped carbon nanotubes using an in-situ growth and sublimation-gas phase transition strategy and established an ultrasensitive electrochemical sensor for NFT determination with a LOD of 18.41 nM (Li et al., 2023). Subramaniyan Vinoth developed a FZD sensor based on transition metal tungstate nanorods doped with sulfur doped carbon nitride matrix. The sensor was prepared using differential pulse voltammetry and demonstrated gave a linear response across a concentration range of 0.005–935 μM, with a LOD of 0.0013 μM (Vinoth, Govindasamy, & Wang, 2022).

While electrochemical detection offers advantages such as high efficiency and accuracy in detecting biomolecules, it also has some drawbacks. The stability of electrochemical detection is a significant concern that cannot be overlooked. In traditional electrochemical detection, the enzyme can be affected by temperature, pH, and other factors, leading to a loss of activity in certain chemical environments, which compromises the stability of the immunosensors. Despite years of development, few electrochemical biosensors have been successfully industrialized. The most successful product to date is the blood glucose meter. This success is attributed to the steps and interferences involved in converting biological signals to electrical signals. In practical applications, optimizing the sensor's sensitivity and selectivity is crucial. It can be achieved through improvements in electrode materials, optimization of the antibody immobilization method, and enhancement of the electrolyte. Moreover, the high fabrication cost of electrochemical detection is a major limitation for large-scale applications. Therefore, future research should prioritize reducing manufacturing costs and increasing the popularity of electrochemical detection.

4.5. Others

The biochip array technique typically detects NFs through specific binding reactions, characterized by high sensitivity, specificity, and throughput. John O'Mahony used a multiplexed biochip screening assay for the simultaneous detection of four NFs metabolites in honey at an action level of 1 μg/kg (O'Mahony et al., 2011). Li developed a visual microarray sensing technique by spot-sampling individual antigens on a 96-well plate using a non-directional competitive assay format with a visual signal response. This technique has been applied to screen honey samples for the detection of banned NF antibiotic residues, achieving recovery rates ranging from 78 % to 93 % (Li et al., 2017) (Fig. 7E). Zhang used four fluorophore-labeled single-stranded DNAs conjugated with corresponding monoclonal antibodies to detect four metabolites of NFs on the surface of AuNPs. This formed a four-biological barcode fluorescent immunoprobe capable of simultaneously detecting four metabolites of NFs in aquatic products, sensitively and accurately detecting NFs in the range of 0.05 to 28 μg/L, providing a promising strategy for the simultaneous detection of multiple targets (Fig. 7F) (Zhang et al., 2022).

5. Future challenges and perspectives

With the continuous development of science and technology, newly developed NF detection software and portable intelligent detectors are progressing in automation and intelligence. To meet the needs of detecting NFs in various environments, NFs detection must not only be highly efficient, rapid, and high-throughput but also characterized by portability and on-site availability (Wang, Fu, et al., 2022). In the future, in-depth analysis of the structural features of NFs should be conducted to develop sensing materials that can specifically interact with the characteristic functional groups. Furthermore, optimizing the structure of these sensing materials according to their structural features can enhance detection performance and provide new ideas and methods for further method development (Abhishek et al., 2022). Simultaneously, the development of new detection materials, cost reduction, optimization of instrument configurations and improvement of the versatility of detection methods will make them more suitable for on-site monitoring, simultaneous detection and large-scale screening (Zheng, Ye, et al., 2024). Simplifying the operation process by integrating sample processing with detection technology can reduce operational complexity and improve detection efficiency. In addition, the combination of immunoassays, smartphones, and machine learning holds great promise for elucidating binding mechanisms and facilitating rapid detection, which is an emerging trend in the field of sensing technology. The use of innovative technologies such as microfluidic chip technology, nanotechnology, and artificial intelligence for monitoring NFs and their metabolites will play a significant role in achieving rapid, intelligent, automated, and high-throughput detection of NFs.

In short, the research and development of methods for detecting NFs are crucial for addressing the issue of drug resistance. Future detection methods should prioritize efficiency, speed, throughput, sensitivity, specificity, the ability to detect multiple indicators and targets, portability, on-site capabilities, intelligence, and automation. These advancements are expected to provide robust support for the research, development, and application of strategies aimed at combating antibiotic resistance.

6. Conclusion

The review provided an overview of the current situation and hazards associated with antibiotic residues of NFs, highlighting their prevalence due to overuse in poultry farming and the potential for accumulation in the human body through the food chain. This accumulation could lead to adverse effects such as allergic reactions and drug resistance. Moreover, the review described the latest advances in sample pretreatment techniques and detection methods.

In terms of sample preparation, several novel methods have been devised, and a wide range of extractive sorbents have been applied for extraction and enrichment from complex matrices. These methods use fewer adsorbents and organic solvents, are easy to operate, and are more cost-effective compared to traditional sample pretreatment techniques. Although these novel extraction methods have been successfully used to isolate analytes, their applicability and stability across a wide range of real samples still require further investigation. Additionally, selecting a broad spectrum of NFs and their metabolites under these novel extraction procedures remains a challenge.

To address the need for analyzing a large number of samples, high-throughput sample pretreatment techniques will be further developed to enhance the speed and efficiency of sample processing. Furthermore, combining pretreatment techniques with detection methods can further improve detection performance. Currently, LC-MS has been an irreplaceable method for the simultaneous determination of NFs and their metabolites; however, it requires complex pretreatment processes and long analysis times, making it unsuitable for rapid detection in daily life. Other methods, such as immunoassays, optical, and electrochemical detection, have been developed for sensitive, rapid, real-time, and in situ detection. Immunoassays offer advantages such as simple processes, fast detection, and clear color change responses, making them well-suited for various applications. However, the immunoassays currently used for antibiotic detection face challenges, including limited assay types and the need for improved linear range reproducibility and robustness. Additionally, the application of these techniques for the simultaneous detection of a wide range of NFs and their metabolites remains a significant challenge.

CRediT authorship contribution statement

Xiaoling Zheng: Writing – original draft, Investigation, Formal analysis. Yong Xie: Writing – review & editing, Supervision, Software, Funding acquisition. Zhuoer Chen: Validation, Methodology, Data curation. Mingdong Cao: Validation, Software. Xianlu Lei: Validation, Supervision, Investigation. Tao Le: Writing – review & editing, Writing – original draft, Supervision, Resources, Methodology, Funding acquisition, Data curation.

Declaration of competing interest

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

Acknowledgements

This work was supported by the Science and Technology Research Program of Chongqing Municipal Education Commission (KJZDK202203101 and KJZD-M202400501) and the Chongqing Natural Science Foundation project (cstc2021jcyj-msmX0314).

Footnotes

Appendix A

Supplementary data to this article can be found online at https://doi.org/10.1016/j.fochx.2024.101928.

Appendix A. Supplementary data

Supplementary material

mmc1.docx (22.8KB, docx)

Data availability

Data will be made available on request.

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Further-reading

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary material

mmc1.docx (22.8KB, docx)

Data Availability Statement

Data will be made available on request.

Articles from Food Chemistry: X are provided here courtesy of Elsevier

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