1. Introduction
In recent decades, emerging analytical devices (
biosensors) have gained the attention of the research community and have improved the early diagnosis of clinical biomarkers [
1], contaminants [
2], allergens [
3] and microorganisms [
4] in diverse fields of applications. Additionally, biosensors are a good example of interdisciplinarity collaboration where many fields of science and engineering converge (e.g., analytical chemistry, surface and material sciences, molecular biology, biochemistry, electrochemistry, electrical and electronic engineering). A biosensor is an electronic device used to transform a biological interaction into an electrical signal [
5]. This device is based on the direct spatial coupling of the immobilized biologically active element, the so-called “bioreceptor”, with a transducer that acts as a detector and electronic amplifier. Different types of bioreceptors (e.g. enzymes, antibodies, aptamers, oligonucleotides, affinity proteins) combined with electrochemical, optical, or mechanical transductions have been used for the fabrication of biosensors with excellent results [
6]. Among these approaches, electrochemical transduction offers the advantages of high sensitivity, which can be enhanced by attaching (bio)catalytic labels to the bioreceptor-target to amplify the detection signal [
7]. Other benefits include their potential for miniaturization, the low cost of production and that they do not require expensive instrumentation for read-out [
8]. There are two basic properties of these devices that make them interesting in analytical chemistry: (1) high specificity generated by the biological component that selectively interacts with the target analyte and (2) high sensitivity determined by the transducer properties. Finally, multiplexed detection of several biomarkers integrated into low-cost biosensing platforms opens a wide range of opportunities for their use as point-of-care (PoC) test in early diagnosis applications [
9,
10]. As a result of these advantages, today such technology is gradually supplanting other more sophisticated techniques and they are set to become a vital tool in healthcare and other areas of applications. Undoubtedly, the most important biosensor, with a high impact in the health and the control of diabetes, is the glucometer [
11]. Such device enables the detection of discrete glucose concentration by pricking the finger to obtain a blood sample (
finger stick monitors). Such methodology may result tedious in some patients, such as children, as it requires adult supervision for obtaining blood samples multiple times a day and may result painful and time-consuming. However, recent advancements in commercial devices have enabled the measurement of glucose from interstitial fluids just underneath the skin in continuous mode, offering automatic monitoring without patient interaction.
Another example where biosensor will have an important impact is in the diagnosis of infectious diseases (Dengue, Malaria, Chikungunya Fever) [
12]. According to the WHO guidelines, the recommended diagnostic tests of such infections include microbiological isolation, serological tests and molecular techniques such as polymerase chain reaction (PCR) [
13,
14]. However, although PCR is the most convenient method due to its high sensitivity and relatively short analysis time, it has an elevated cost of equipment and supplies. On the other hand, it requires specialized skills from laboratory personnel for the execution and interpretation of results, which makes its use in routine analysis difficult. Moreover, they are prone to generating false positives due to non-specific amplifications, and its integration into PoC systems is complicated.
To overcome these problems, user-friendly, low-cost, and fast methods are still needed. In this context, the development of more efficient bioassays, including biosensors, has the potential to significantly contribute to the development of enhanced and more effective analytical tools for biomedical diagnosis [
15,
16].
The main drawback of conventional non-structured biosensors is associated with the proper immobilization of the biocatalytic or biorecognition element on the surface of the transducer. Non-oriented immobilization of the biomolecules may produce reusability and reproducibility problems, and low sensitivity and selectivity due to loss of catalytic activity or biorecognition reaction, which in turn hinders the electron transfer reaction and reduces the electrochemical signal. To address these issues, different approaches have been introduced such as nano-structuration of the transducer and the utilization of magnetic nanoparticles (MNPs) and magnetic beads (MBs) as solid phases for the recognition reaction.
Nanomaterials, with dimensions ranging from 1 to 100 nm, have played a crucial role for science, technology, and medicine over the past two decades [
17,
18]. Their unique characteristics (small size, high surface-to-volume ratio, excellent biocompatibility, biodistribution, outstanding catalytic properties, etc.) offer great possibilities for its integration into new and better devices, analytical methods, diagnosis tools, among others. [
18]. One of the main properties of such materials is that their chemical and physical properties are drastically different from those of their bulk materials and can be tailor-made for a specific task [
19,
20]. In this sense, MNPs have been receiving remarkable attention in multiple areas such as data storage, biosensing, catalyst, bioremediation, neural stimulation, pharmacological liberation, and clinical diagnosis [
21]. The use of magnetic sorbents significantly simplifies the sample manipulation by isolating the target (after the extraction process) applying an external magnetic field. Similar strategies may be used in other analytical applications (protein purification, remediation, chromatography applications) improving the selectivity, sensitivity, and time for results [
22]. Even the correct design and modification of the MNPs offer a plethora of possibilities to design biocompatible and biomimetic surfaces for biosensing applications in the detection of different analytes [
23,
24,
25,
26].
MNPs may be synthesized using different methods, grouped in top-down and bottom-up approaches [
27,
28]. The correct selection of the synthetic route and their later biofunctionalization are one of the most important steps to adjust the magnetic properties, phase composition, biodistribution and biocompatibility, stability, aggregation effects, degradation, toxicity, and size distribution of the MNPs. On the other hand, the combination of MNPs and electrochemical read-out methods has allowed the development of new analytical techniques such as Enzyme Linked Immuno Magnetic Electrochemical (ELIME) methods [
29]. Here, MNPs act as nanosized supports for the immobilization of biomolecules (antibodies, aptamers, oligonucleotides) and are used for the isolation of the target from complex matrices and its concentration before detection. The utilization of MNPs enhances the effectiveness of analyte isolation and concentration, minimizes matrix effects due to simplified washing and separation procedures, allows faster assay kinetics, and improves the sensitivity, limits of detection (LOD) and reduces the time for analysis [
30]. Usually, ELIME bioassays are developed as sandwich-type format, where two specific antibodies are used (capture-Ab and labeled-Ab). The read-out is done using differential pulse voltammetry (DPV), constant potential amperometry (CPA), linear sweep voltammetry (LSV), or similar electrochemical techniques with screen-printed electrodes (SPEs) as transducers [
31]. Moreover, the use of magnetic beads in combination with biosensing strategies can avoid individual electrode surface modifications with biological elements, which simplify storage and ensures proper washing and preconcentration of the sample on the working electrode area, and finally, improves the reproducibility, sensitivity, and the limit of detection (LOD) of the strategies.
This review highlights the latest advancements in (1) the synthesis of magnetic nanosupports (MNPs and MBs) and (2) the most common surface modifications and materials with improved characteristics for its incorporation in different areas of applications such as biomedicine, veterinary, bioanalytical and contaminant applications, allergens detection, and quality control in agro-food and pharmacy industries, among others.
3. Conclusions
In recent years several strategies have been developed for the synthesis of magnetic nanoparticles finding that the most popular approaches are co-precipitation, solvothermal, microemulsion and green synthesis methods. Here, we presented most widely employed synthesis methods, including the adequate modification or development of new magnetic nanomaterials to overcome the main difficulties and add novel properties to the MNPs. In this regard, functionalizing nanomaterials enables the improvement of sensitivity, chemical stability, catalytic efficiency, and biocompatibility of the biosensing platforms. Briefly, the most widespread functionalizing agents, introduced in this review, are chitosan, polyethylene glycol and silica, among others. In addition, various organic (polyaniline, polydopamine and polypyrrole) and inorganic coatings (gold, silica or platinum) are also broadly employed. Despite the challenges, advances in MNPs research have demonstrated their great potential for use in biomedical, environmental, and food safety applications, among others. Finally, in each section of this review, a wide variety of works were introduced illustrating the synthesis and functionalization methods and their application in different areas of science, mainly focused on analytical and biomedical aspects.